Blood compatible modification method and modified hollow fiber membrane

Abstract

The invention relates to the field of medical equipment, in particular to a blood compatible modification method and a modified hollow fiber membrane. The method comprises the following steps: immersing a matrix into a solution containing a polyphenol raw material, heating and oscillating to enable polyphenol to be self-polymerized on the surface of the matrix to introduce phenolic hydroxyl groups, immersing into a solution containing an anticoagulant polymer, taking out, and carrying out heat treatment to obtain a modified body. The anticoagulant polymer comprises a phosphorylcholine group, a hydrophobic block with hydrophobicity and an epoxy group, and the epoxy group is connected with a phenolic hydroxyl group through a chemical reaction, so that the phosphorylcholine group and the hydrophobic block are stably connected to the surface of a matrix. The phosphorylcholine group provides an anticoagulant effect, and the hydrophobic block provides pollution resistance, so that the modifier is not easy to pollute in a blood environment. After the hollow fiber membrane is modified, performance reduction caused by deposition of components such as thrombus and protein can be inhibited, so that the service life of a matrix is prolonged.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medical devices, in particular to a blood compatible modification method and a modified hollow fiber membrane. BACKGROUND

[0002] Extracorporeal membrane oxygenation (ECMO) system is mainly used to provide continuous extracorporeal respiration and circulation for patients with severe heart and lung failure, so as to maintain the life of the patient. At present, the oxygenator composed of poly-4-methyl-1-pentene (PMP) hollow fiber membrane is one of the core components of ECMO system. Its fibrous structure has a large effective area, which can provide more gas exchange surface area, thereby improving the exchange efficiency of oxygen and carbon dioxide. Generally, the surface of the PMP hollow fiber membrane needs to be modified to improve the blood compatibility, prevent thrombosis caused by protein adsorption and platelet adhesion, and thus affect the performance and service life of the oxygenator.

[0003] Forming an anticoagulant coating on the surface of the PMP hollow fiber membrane is one of the commonly used surface modification methods, and the anticoagulant coating is easily carried into the patient's body by blood during use, or directly affects the blood properties of the patient. For example, the anticoagulant coating formed by heparin can easily cause anti-platelet reduction during use, and the patient's resistance to heparin can cause osteoporosis and other problems, increasing the morbidity and mortality of the patient. At the same time, heparin has a short half-life and is easily dissolved in water, and the long-term activity and stability of the coating are questioned, which is not conducive to the long-term use of the PMP hollow fiber membrane. SUMMARY

[0004] The purpose of the present application is to provide a blood compatible modification method and a modified hollow fiber membrane which can prolong the service life of the oxygenator.

[0005] In order to achieve the above purpose, the present application provides the following technical scheme:

[0006] A blood compatible modification method, comprising:

[0007] obtaining a substrate;

[0008] preparing a complex solution with a pH value of a first value from a polyphenol raw material, immersing the substrate in the complex solution, and oscillating at a first frequency at a first temperature for a first time to obtain an intermediate;

[0009] polymerizing a plurality of copolymer raw materials by a copolymerization reaction to obtain an anticoagulant polymer, the anticoagulant polymer comprising a phosphorylcholine group, a hydrophobic block having hydrophobicity, and an epoxy group, dissolving the anticoagulant polymer and triethylamine in an organic solvent to form an anticoagulant solution;

[0010] The intermediate is taken out after being soaked in the anti-coagulation solution for a second time, and is heat-treated at a second temperature for a third time to obtain a modified body.

[0011] Optionally, the polyphenol raw material is one or more of gallic acid, pyrogallic acid, tannic acid, epigallocatechin gallate, epicatechin gallate.

[0012] Optionally, the concentration of the polyphenol raw material in the complex solution is any value in the range of 1mg / mL to 10mg / mL, the first value is any value in the range of 6 to 9, the first temperature is any value in the range of 25℃ to 45℃, the first frequency is any value in the range of 100rpm to 200rpm, and the first time is any value in the range of 1h to 24h.

[0013] Optionally, the hydrophobic block is a long-chain perfluorinated segment.

[0014] Optionally, the copolymerization raw material comprises 2-methacryloyloxyethyl phosphorylcholine, dodecafluoroheptyl methacrylate, and glycidyl methacrylate.

[0015] Optionally, the mass ratio of 2-methacryloyloxyethyl phosphorylcholine:dodecafluoroheptyl methacrylate:glycidyl methacrylate in the copolymerization raw material is any value in the range of 1.5:(0.8 to 1.2):(0.16 to 0.24), the temperature of the copolymerization reaction is any value in the range of 50℃ to 75℃, and the time is any value in the range of 2h to 24h.

[0016] Optionally, the concentration of the anti-coagulation polymer in the anti-coagulation solution is any value in the range of 5mg / mL to 30mg / mL, and the concentration of triethylamine in the anti-coagulation solution is any value in the range of 1.0mg / mL to 5.0mg / mL, the second time is any value in the range of 1min to 30min, the second temperature is any value in the range of 50℃ to 130℃, and the third time is any value in the range of 2h to 8h.

[0017] Optionally, the carbon dioxide flux of the modified body is any value in the range of 75% to 100% of the carbon dioxide flux of the base body, the oxygen flux of the modified body is any value in the range of 65% to 100% of the oxygen flux of the base body, and the adsorption amount of bovine serum albumin of the modified body is less than or equal to 50% of the adsorption amount of bovine serum albumin of the base body. The application also provides a modified hollow fiber membrane, wherein the outer surface of a poly-4-methyl-1-pentene hollow fiber membrane is modified by the above blood-compatible modification method.

[0018] Optionally, the base body is part or the entirety of an oxygenator.

[0019] The polyphenol raw material is easy to adhere to the surface of the base body and further deposit to generate a polymer through oxidative self-polymerization, so that abundant phenolic hydroxyl groups are introduced on the surface of the material. The anti-coagulation polymer provides active hydrogenation sites through the epoxy groups, and can chemically react with the phenolic hydroxyl groups under the catalysis of triethylamine in a gradient temperature environment, so that a larger strength connection is realized, and the loss of the anti-coagulation polymer is prevented. The phosphorylcholine groups have good anti-protein adsorption, anti-platelet adhesion and activation effects, and have excellent biocompatibility. The hydrophobic block provides hydrophobicity for the anti-coagulation polymer, and can reduce the adhesion and accumulation of proteins, red blood cells, white blood cells and platelets. The anti-coagulation performance is provided through the phosphorylcholine groups, the connection is strengthened through the polyphenol to inhibit peeling, and the hydrophobic block inhibits the combination of the phosphorylcholine groups and water molecules to cause the swelling of the polymer, so that the stability of the anti-coagulation polymer is improved, and the adhesion and accumulation of proteins, red blood cells, white blood cells and platelets on the surface of the anti-coagulation polymer are also avoided. The binding sites are introduced through the polyphenol raw material, and the anti-coagulation polymer with stable structure and anti-coagulation effect is connected through the binding sites, so that a continuous, uniform and stable modification layer is formed on the surface of the base body, which helps to improve the blood compatibility of the base body and prolong the service life of the base body.

[0020] The above description is only a summary of the technical scheme of the present application. In order to more clearly understand the technical means of the present application, and to implement the content of the description, the following will be described in detail with the preferred embodiments of the present application and with the help of the accompanying drawings. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 The flow chart of the blood compatible modification method shown in embodiment one of the present application;

[0022] Figure 2 The chemical reaction formula of the anti-coagulation polymer generated by the reaction of the copolymerization raw material shown in embodiment one of the present application;

[0023] Figure 3 The Fourier transform infrared spectrogram of the surface of the modified body shown in embodiment one of the present application;

[0024] Figure 4 The electron microscope graph of the base body, intermediate and modified body shown in embodiment one of the present application;

[0025] Figure 5 The Fourier transform infrared spectrogram of the surface of the modified body after being washed with physiological saline for different times shown in embodiment one of the present application;

[0026] Figure 6 The gas flux detection graph of the base body and the modified body shown in embodiment one of the present application;

[0027] Figure 7Protein adsorption amount detection chart of the base and the modifier shown in Example 1 of the present application;

[0028] Figure 8 Electron microscope chart of the base and the modifier shown in Example 1 of the present application after blood immersion;

[0029] Figure 9 Fourier transform infrared spectrum chart of the surface of the modifier shown in Comparative Example 1 of the present application;

[0030] Figure 10 Electron microscope chart of the modifier shown in Comparative Example 1 of the present application after blood immersion;

[0031] Figure 11 Fourier transform infrared spectrum chart of the surface of the modifier shown in Comparative Example 2 of the present application;

[0032] Figure 12 Electron microscope chart of the modifier shown in Comparative Example 2 of the present application after blood immersion. DETAILED DESCRIPTION

[0033] The technical solutions of the present application will be described clearly and completely below with reference to the drawings. Obviously, the described embodiments are some of the embodiments of the present application, but not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative work fall within the scope of protection of the present application.

[0034] In the description of the present application, it should be noted that the orientations or positional relationships indicated by the terms "center", "upper", "lower", "left", "right", "vertical", "horizontal", "inner", "outer", etc. are based on the orientations or positional relationships shown in the drawings, and are only for the convenience of describing the present application and simplifying the description, and therefore cannot be understood as indicating or implying that the devices or elements referred to must have a particular orientation, be constructed and operated in a particular orientation, and therefore cannot be understood as a limitation on the present application. In addition, the terms "first", "second", "third" are only for the purpose of description, and cannot be understood as indicating or implying relative importance.

[0035] In the description of the present application, it should be noted that unless otherwise explicitly specified and limited, the terms "mounting", "connection", "connection" should be understood broadly, for example, it can be fixed connection, or detachable connection, or integral connection; it can be mechanical connection, or electrical connection; it can be directly connected, or indirectly connected through an intermediate medium, or the internal communication of two elements. For those skilled in the art, the specific meaning of the above terms in the present application can be understood according to the specific circumstances.

[0036] In addition, the technical features involved in the different embodiments of the application described below can be combined with each other as long as they do not conflict with each other.

[0037] The blood compatible modification method protected by the present application comprises:

[0038] S1, obtaining a substrate.

[0039] S2, preparing a complex solution with a pH value of a first value from a polyphenol raw material, immersing the substrate in the complex solution, and oscillating at a first frequency at a first temperature for a first time to obtain an intermediate.

[0040] S3, obtaining an anti-coagulation polymer by polymerizing a plurality of co-polymerization raw materials through a co-polymerization reaction, the anti-coagulation polymer comprising a phosphorylcholine group, a hydrophobic block with hydrophobicity, and an epoxy group, dissolving the anti-coagulation polymer and triethylamine in an organic solvent to form an anti-coagulation solution.

[0041] S4, immersing the intermediate in the anti-coagulation solution for a second time, taking it out, and heat-treating at a second temperature for a third time to obtain a modified body.

[0042] The polyphenol raw material is easy to adhere to the surface of the substrate and further deposit to generate a polymer through oxidative self-polymerization by π-π stacking of aromatic rings, so as to introduce abundant phenolic hydroxyl groups on the surface of the material. The anti-coagulation polymer can chemically react with the phenolic hydroxyl groups under the catalysis of triethylamine in a gradient temperature environment through the active hydroxyl sites provided by the epoxy group, so as to realize a larger strength connection and prevent the loss of the anti-coagulation polymer. The phosphorylcholine group has good anti-protein adsorption, anti-platelet adhesion, and anti-activation effects, and has excellent biocompatibility. The hydrophobic block provides hydrophobicity for the anti-coagulation polymer, and can reduce the adhesion and accumulation of proteins, red blood cells, white blood cells, and platelets. The anti-coagulation performance is provided by the phosphorylcholine group, the connection is strengthened by the polyphenol to inhibit peeling, and the hydrophobic block inhibits the combination of the phosphorylcholine group and water molecules to cause the swelling of the polymer, so as to improve the stability of the anti-coagulation polymer, and also avoid the adhesion and accumulation of proteins, red blood cells, white blood cells, and platelets on the surface of the anti-coagulation polymer. The binding sites are introduced by the polyphenol raw material, and the anti-coagulation polymer with stable structure and anti-coagulation efficacy is connected through the binding sites, so as to form a continuous, uniform, and stable modification layer on the surface of the substrate, which helps to improve the blood compatibility of the substrate and prolong the service life of the substrate.

[0043] In some embodiments, the polyphenol raw material is one or more of gallic acid, pyrogallic acid, tannic acid, epigallocatechin gallate, and epicatechin gallate.

[0044] In some embodiments, the concentration of the polyphenol raw material in the composite solution is any value between 1 mg / mL and 10 mg / mL, the first value is any value between 6 and 9, the first temperature is any value between 25℃ and 45℃, for example, it can be any value between 25℃, 30℃, 35℃, 40℃ and 45℃, the first frequency is any value between 100 rpm and 200 rpm, for example, it can be any value between 100 rpm, 120 rpm, 140 rpm, 160 rpm, 180 rpm and 200 rpm, the first time is any value between 1 h and 24 h, for example, it can be any value between 1 h, 6 h, 12 h, 18 h and 24 h. By providing an oxygen-rich environment through shaking and restricting the temperature, the deposition and self-polymerization of the polyphenol raw material are facilitated.

[0045] In some embodiments, the hydrophobic block is a long-chain perfluorinated segment, which can not only increase the hydrophobicity of the anti-coagulation polymer, but also reduce the surface energy of the material, thereby inhibiting the damage and peeling of the anti-coagulation polymer coating.

[0046] In some embodiments, the copolymerization raw material includes 2-methacryloyloxyethyl phosphorylcholine, dodecafluoroheptyl methacrylate and 3-glycidyl methacrylate. The three compounds all include methacrylate double bonds, which can be copolymerized through free radical chain reaction under the action of an initiator. After the double bond is broken, the monomers form a polymer main chain through chain growth.

[0047] In some embodiments, the mass ratio of 2-methacryloyloxyethyl phosphorylcholine:dodecafluoroheptyl methacrylate:3-glycidyl methacrylate in the copolymerization raw material is any value between 1.5:(0.8-1.2):(0.16-0.24), for example, it can be any value between (1.5:0.8:0.16), (1.5:1.0:0.16), (1.5:1.2:0.16), (1.5:1.0:0.2) and (1.5:1.0:0.22). The copolymerization reaction needs to be initiated by an initiator and needs to occur under the protection of an inert gas after being dissolved in a matched organic solvent. The temperature of the copolymerization reaction is any value between 50℃ and 75℃, for example, it can be any value between 50℃, 55℃, 60℃, 65℃, 70℃ and 75℃. The time is any value between 2 h and 24 h, for example, it can be any value between 2 h, 6 h, 12 h, 16 h, 20 h and 24 h. By restricting the ratio of the copolymerization raw material, the reaction temperature and the reaction time, the yield of the anti-coagulation polymer is improved.

[0048] In some embodiments, the concentration of the anti-aggregation polymer in the anti-coagulation solution is any value between 5 mg / mL and 30 mg / mL, for example, can be any value between 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 15 mg / mL and 30 mg / mL, the concentration of triethylamine in the anti-coagulation solution is any value between 1.0 mg / mL and 5.0 mg / mL, for example, can be any value between 1.0 mg / mL, 2.0 mg / mL, 3.0 mg / mL, 4.0 mg / mL and 5.0 mg / mL, the second time is any value between 1 min and 30 min, the second temperature is any value between 50℃ and 130℃, for example, can be any value between 50℃, 70℃, 90℃, 110℃ and 130℃, the third time is any value between 2 h and 8 h, for example, can be any value between 2 h, 4 h, 6 h and 8 h.

[0049] In some embodiments, the carbon dioxide flux of the modified body is any value between 75% and 100% of the carbon dioxide flux of the base body, for example, can be any value between 75%, 80%, 85%, 90%, 95% and 100%, the oxygen flux of the modified body is any value between 65% and 100% of the oxygen flux of the base body, for example, can be any value between 65%, 70%, 80%, 90% and 100%, the adsorption amount of bovine serum albumin of the modified body is less than or equal to 50% of the adsorption amount of bovine serum albumin of the base body, for example, can be any value between 50%, 45%, 40%, 35% and 30%.

[0050] In some embodiments, the base body is part or the whole of an oxygenator, for example, can be a PMP hollow fiber membrane or a packaged oxygenator as a whole.

[0051] The present application protects a modified hollow fiber membrane, which is obtained by modifying the outer surface of a poly-4-methyl-1-pentene hollow fiber membrane by the above-mentioned blood compatible modification method, and has a relatively strong service life.

[0052] For details, please refer to the following examples.

[0053] Example One:

[0054] For details, please refer to the following examples. Figure 1 The blood compatible modification method shown in a preferred embodiment of the present application includes:

[0055] S1, obtaining a base body.

[0056] S2, preparing a polyphenol raw material into a composite solution with a pH value of a first value, immersing the base body into the composite solution, and oscillating at a first frequency at a first temperature for a first time to obtain an intermediate body.

[0057] S3, polymerizing the plurality of copolymerization raw materials through a copolymerization reaction to obtain an anti-fouling polymer, the anti-fouling polymer comprising a phosphorylcholine group, a hydrophobic block having hydrophobicity, and an epoxy group, dissolving the anti-fouling polymer and triethylamine in an organic solvent to form an anti-fouling solution.

[0058] S4, soaking the intermediate in the anti-fouling solution for a second time, and then taking out the intermediate and heat treating the intermediate at a second temperature for a third time to obtain a modified body.

[0059] In step S1, the base body is a PMP hollow fiber membrane, which is obtained by purchase.

[0060] In step S2, the polyphenol raw material is gallic acid, which is dissolved in a Tris-HCl buffer at a concentration of 10 mg / mL, and the pH value is adjusted to 8.5 to obtain a complex solution. After the two ends of the PMP hollow fiber membrane are closed, the membrane is immersed in the complex solution. The detection room temperature is 27°C, and the complex solution is oscillated at a frequency of 150 rpm for 12 h at room temperature. After the reaction is completed, the membrane is washed with deionized water and dried at 60°C to obtain an intermediate.

[0061] In step S3, the copolymerization raw materials include 2-methacryloyloxyethyl phosphorylcholine 0.15 g, dodecafluoroheptyl methacrylate 0.12 g, and 3-glycidyl methacrylate 0.02 g. Step S3 includes:

[0062] S310, the copolymerization raw materials, 10 mL of isopropyl alcohol, and 10 mg of azobisisobutyronitrile (AIBN) are added to a sealable container, which is heated to 75°C under the protection of argon and stirred for 24 h. After the reaction is completed, the reaction solution is poured into acetone, and the precipitate is filtered and dried to obtain a solid anti-fouling polymer. The chemical reaction formula is shown in Figure 2 .

[0063] S320, the anti-fouling polymer and triethylamine are dissolved in isopropyl alcohol, so that the concentration of triethylamine is 2 mg / mL, and the concentration of the anti-fouling polymer is 10 mg / mL to obtain an anti-fouling solution.

[0064] In step S4, the intermediate obtained in step S2 is immersed in the anti-fouling solution, taken out after 10 min, and placed in an oven at 80°C for 30 min. The tubular fiber after heat treatment is washed with deionized water and dried at 60°C to obtain a modified body.

[0065] The modified body obtained in this embodiment is a PMP hollow fiber membrane with a coating formed after surface modification. The base body, the intermediate, and the modified body each have a total length of 18 cm, and performance detection and characterization are performed.

[0066] See Figure 3The Fourier transform infrared spectrometer is used to test the functional groups on the surface of the modified body. It can be seen from the Fourier transform infrared spectrum of the surface of the modified body that the characteristic peaks of the functional groups such as carbonyl, oxygen-phosphorus bond and ether bond appear, which are not possessed by the substrate but are unique to the coating. This indicates that the coating is successfully coated.

[0067] See Figure 4 The scanning electron microscope is used to observe the microstructure of the outer surface and radial cross section of the substrate, intermediate body and modified body. It can be seen that many irregular small particles are deposited on the surface of the intermediate body, and the film surface becomes rough. A layer of polymer film is covered on the surface of the modified body. At the same time, it can be observed that the cross-sectional channel structure of the modified body has no obvious change, which indicates that the coating is successfully coated on the surface of the oxygenation membrane without affecting or slightly affecting the internal channel structure of the membrane.

[0068] See Figure 5 The Fourier transform infrared spectrometer is used to test the modified body after being washed with physiological saline for different times. It can be seen that the characteristic peaks corresponding to the carbonyl and oxygen-phosphorus bond groups still exist and are very obvious in the infrared spectrum of the modified body after long-time washing. This indicates that the coating has good stability.

[0069] See Figure 6 Ten groups of substrate and modified body are respectively made into membrane assemblies, and the gas flux is measured. It can be seen that the CO2 gas flux of the modified body decreases by 10% and the O2 gas flux decreases by 33% compared with the substrate after surface modification, but both of them still remain near 0.2 mL / (cm 2 ·min·bar).

[0070] The substrate and the modified body are respectively subjected to protein adsorption experiment. After being immersed in phosphate buffer solution (PBS) for 2h, the excess PBS on the surface is absorbed by filter paper, and then the two are immersed in 2mg / mL bovine serum albumin solution at 37℃ for 2h. The ultraviolet spectrophotometer is used to measure the absorbance of the bovine serum albumin solution at 280nm before and after adsorption, and the protein adsorption amount of the surface modified oxygenation membrane is calculated. See Figure 7 It can be seen that the protein adsorption amount of the substrate is 78.6μg / cm 2 , and the protein adsorption amount of the modified body is 17.3μg / cm 2 , which decreases by 78% compared with the substrate. This indicates that the modification method in this embodiment can significantly improve the anti-protein adsorption performance of the substrate.

[0071] The base body and the modified body were respectively subjected to whole blood contact experiment. After the two were respectively soaked in phosphate solution (PBS) with pH of 7.0 for 2h, the excess PBS on the membranes was absorbed by filter paper, then the two were respectively immersed in bovine whole blood at 37℃, and taken out after oscillation at 80rpm for 2h, and then washed, dried and sprayed with gold before observation of the surface of the oxygenation membrane by scanning electron microscope, please refer to Figure 8 It can be seen that the surface of the base body has a dense thrombus layer, while the surface of the modified body is smooth and clean without trace of thrombus deposition, which indicates that the modified body has good anti-pollution performance. The blood clotting time (PTT) of the base body is 215 seconds, and the blood clotting time of the modified body is greater than 600 seconds, which indicates that the surface modified oxygenation membrane has excellent anticoagulant performance.

[0072] Example Two:

[0073] The difference between this example and Example One is that the polyphenol raw material in this example is tannic acid, and the concentration of the polyphenol raw material in the complex solution is 5mg / mL, and the first frequency is 200rpm, the second time is 2min, and the second temperature is 60℃.

[0074] When performance detection was carried out, the base body, the intermediate body and the modified body with total length of 16cm were used, 10 groups of base bodies and modified bodies were subjected to gas flux detection, and the comparison of the detection results showed that the O2 gas flux decreased by 21.5%, and the CO2 gas flux decreased by 10.2%. The protein adsorption experiment results showed that the protein adsorption amount of the modified body was 23.6μg / mL, which decreased by 68.8% compared with the base body. The blood clotting time of the modified body was greater than 600 seconds, which indicates that the phosphatidylcholine surface modified oxygenation membrane has excellent anticoagulant performance.

[0075] Example Three:

[0076] The difference between this example and Example One is that the polyphenol raw material in this example is epigallocatechin gallate, and the concentration of the polyphenol raw material in the complex solution is 5mg / mL, and the pH value is 8.0. And the first frequency is 200rpm, and the second temperature is 85℃.

[0077] When performance detection was carried out, the base body, the intermediate body and the modified body with total length of 16cm were used, 10 groups of base bodies and modified bodies were subjected to gas flux detection, and the comparison of the detection results showed that the O2 gas flux decreased by 28%, and the CO2 gas flux decreased by 15.8%. The protein adsorption experiment results showed that the protein adsorption amount of the modified body was 25.7μg / mL, which decreased by 66% compared with the base body. The blood clotting time of the modified body was greater than 600 seconds, which indicates that the phosphatidylcholine surface modified oxygenation membrane has excellent anticoagulant performance.

[0078] Example Four:

[0079] The difference between this embodiment and embodiment one is that the base body in this embodiment is an encapsulated oxygenator as a whole, and the second time is 5 min and the second temperature is 85°C.

[0080] The modified oxygenator was used in a heart transplant operation of a mouse. After the venous blood passed through the oxygenator, the color of the blood was obviously changed to bright red, indicating that the oxygen content of the blood was increased. During the two-hour operation, the vital signs of the mouse remained stable. After the operation, the part of the modified body in contact with the blood was flushed with physiological saline, and the surface of the modified body in contact with the blood remained clean.

[0081] Comparative Example One:

[0082] The difference between this comparative example and embodiment one is that step S2 is not performed in this comparative example, and step S3 is directly performed by soaking the base body in the anticoagulation solution.

[0083] The modified body in this comparative example was tested by a Fourier transform infrared spectrometer. Please refer to Figure 9 As can be seen from the spectrum, there are no obvious characteristic peaks of functional groups such as carbonyl and oxygen-phosphorus bond. This is because the PMP hollow fiber membrane has a hydrophobic surface and low surface energy, and the efficiency of directly coating the anticoagulation polymer is low.

[0084] The protein adsorption experiment results show that the protein adsorption amount of the modified body in this comparative example is 75.1 μg / mL, which has no obvious difference compared with the base body, indicating that the surface of the base body is not completely modified by the PC polymer.

[0085] Please refer to Figure 10 The electron microscope image obtained from the whole blood contact experiment shows that the surface of the modified body in this comparative example is obviously contaminated compared with the modified body in embodiment one after contacting with the blood, indicating that the antithrombotic performance of the modified body in this comparative example is weaker than that of the modified body in embodiment one.

[0086] By comparing the modification methods and performance test results in this comparative example and embodiment one, it can be seen that without pretreatment of the base body by the polyphenol raw material, directly modifying the base body by the anticoagulation polymer can cause the anticoagulation polymer to be difficult to deposit on the surface of the base body to form a film, resulting in a low coating coverage, no obvious increase in the anti-protein adsorption capacity, and limited improvement in the antithrombotic property. The in vitro coagulation experiment test shows that the coagulation time of the modified body in comparative example one is 210 seconds, which is less than that of the blank control group (250 seconds), indicating that the modified body in this comparative example has a slight activation of blood coagulation.

[0087] Comparative Example Two:

[0088] The difference between this comparative example and embodiment one is that the copolymer raw material in this comparative example does not include dodecafluoroheptyl methacrylate.

[0089] The modified body in the present comparative example was tested by Fourier transform infrared spectrometer. Please refer to Figure 11 It can be seen that the characteristic peaks of functional groups such as carbonyl and oxygen-phosphorus bond appear in the spectrum, which are not possessed by oxygenated membranes but are unique to the coating. This indicates the successful coating of the coating. The electron micrographs of the outer surface and radial section also show that the coating is successfully coated on the surface of the oxygenated membrane without affecting or slightly affecting the internal pore structure of the membrane.

[0090] The water contact angle test of the substrate and the modified body in the present comparative example showed that the water contact angle of the modified body was reduced by 23° compared with the substrate, indicating that the surface hydrophilicity of the modified body in the present comparative example was greatly improved compared with the substrate.

[0091] The protein adsorption experiment results showed that the protein adsorption amount of the modified body in the present comparative example was 65.1 μg / mL, which was slightly reduced compared with the substrate. It is indicated that the modification of PC group on the surface of the substrate cannot effectively improve the pollution resistance. Please refer to Figure 12 The electron micrographs obtained by whole blood contact experiment showed that the surface contamination of the modified body in the present comparative example was slightly improved compared with the modified body in Example 1 after contacting with blood. The in vitro blood coagulation experiment test showed that the coagulation time of the modified body in Comparative Example 2 was greater than 600 seconds, indicating that the phosphorylcholine modified body in the present comparative example had the function of resisting activated blood coagulation. However, due to the lack of low surface energy groups, the surface of the material is too hydrophilic, resulting in a large amount of protein adsorption.

[0092] Comparative Example 3:

[0093] The difference between the present comparative example and Example 1 is that the raw material for copolymerization in the present comparative example does not include 2-methacryloyloxyethyl phosphorylcholine.

[0094] The water contact angle test of the substrate and the modified body in the present comparative example showed that the water contact angle of the modified body was increased by 25° compared with the substrate, indicating that the surface hydrophobicity of the modified body in the present comparative example was greatly improved compared with the substrate. The in vitro blood coagulation experiment test showed that the coagulation time of the modified body in Comparative Example 3 was 200 seconds, which was less than the coagulation time of the substrate, i.e. 250 seconds, indicating that the modified body in the present comparative example had a mild to moderate blood coagulation phenomenon due to the lack of phosphorylcholine group.

[0095] As can be seen from the above, in the modification method in the application, the polyphenol composite layer is first deposited on the surface of the substrate, the rich phenolic hydroxyl groups contained in the structure of the polyphenol compound can provide interaction sites for the introduction of the anti-coagulation polymer, and the anti-coagulation polymer is fixed on the surface of the substrate through chemical bonds and hydrogen bonds, covalent bonds and the like, so that the surface group density is improved, and the stability of the anti-coagulation polymer coating is also improved. The modification method in the application is used to modify the surface of the substrate, especially the surface of the PMP hollow fiber membrane or the whole surface of the oxygen and device package, so that the blood compatibility and the blood pollution resistance can be significantly improved, and the anti-protein adsorption and the anti-thrombus functions can be improved. The modification method in the application has simple process, mild conditions, is suitable for various materials, is easy to modify a large area, and can be used for large-scale continuous production. Moreover, the coating modified by the method has good stability and can remain stable under the continuous flushing of physiological saline, so that a new idea is provided for the blood compatibility modification of the artificial lung component, and the method has good application prospect in the field of artificial lung.

[0096] The technical features of the above-described embodiments can be combined in any manner, and to make the description concise, all possible combinations of the technical features in the above-described embodiments are not described, however, as long as the combinations of the technical features do not exist contradictions, they should be considered as the scope of the description.

[0097] The above-described embodiments only express several implementation manners of the application, the description is relatively specific and detailed, however, it should not be understood as the limitation of the patent scope of the application. It should be pointed out that, for ordinary skilled in the art, without departing from the concept of the application, a number of modifications and improvements can be made, and these all belong to the protection scope of the application. Therefore, the patent protection scope of the application should be subject to the appended claims.

Claims

1. A blood compatibility modification method, characterized in that: include: Obtaining a matrix; The polyphenol raw material is prepared into a composite solution with a first pH value, the substrate is immersed in the composite solution, and is shaken at a first temperature and a first frequency for a first time to obtain an intermediate; Polymerizing a plurality of copolymer raw materials through a copolymerization reaction to obtain an anticoagulant polymer, wherein the anticoagulant polymer includes a phosphorylcholine group, a hydrophobic block having hydrophobicity, and an epoxy group; and dissolving the anticoagulant polymer and triethylamine in an organic solvent to form an anticoagulant solution; The intermediate is taken out after being immersed in the anticoagulant solution for a second time, and is heat-treated at a second temperature for a third time to obtain a modified form.

2. The blood compatibility modification method according to claim 1, characterized in that The polyphenol raw material is one or more of gallic acid, pyrogallic acid, tannic acid, epigallocatechin gallate, and epicatechin gallate.

3. The blood compatibility modification method according to claim 2, characterized in that: The concentration of the polyphenol raw material in the composite solution is any value between 1 mg / mL and 10 mg / mL, the first value is any value between 6 and 9, the first temperature is any value between 25°C and 45°C, the first frequency is any value between 100 rpm and 200 rpm, and the first time is any value between 1 hour and 24 hours.

4. The blood compatibility modification method according to claim 1, wherein: The hydrophobic block is a long-chain perfluorinated segment.

5. The blood compatibility modification method according to claim 1, wherein: The copolymerization raw materials include 2-methacryloyloxyethyl phosphorylcholine, dodecafluoroheptyl methacrylate and 3-glycidyl methacrylate.

6. The blood compatibility modification method according to claim 5, characterized in that: The mass ratio of 2-methacryloyloxyethyl phosphorylcholine: dodecafluoroheptyl methacrylate: 3-glycidyl methacrylate in the copolymerization raw material is any value between 1.5: (0.8-1.2): (0.16-0.24), the temperature of the copolymerization reaction is any value between 50° C. and 75° C., and the time is any value between 2 hours and 24 hours.

7. The blood compatibility modification method according to claim 1, characterized in that: The concentration of the anticoagulant polymer in the anticoagulant solution is any value between 5 mg / mL and 30 mg / mL, and the concentration of triethylamine in the anticoagulant solution is any value between 1.0 mg / mL and 5.0 mg / mL, the second time is any value between 1 min and 30 min, the second temperature is any value between 50°C and 130°C, and the third time is any value between 2 h and 8 h.

8. The blood compatibility modification method according to claim 1, wherein: The carbon dioxide flux of the modified body is any value between 75% and 100% of the carbon dioxide flux of the base body, the oxygen flux of the modified body is any value between 65% and 100% of the oxygen flux of the base body, and the adsorption amount of bovine serum albumin by the modified body is less than or equal to 50% of the adsorption amount of bovine serum albumin by the base body.

9. The blood compatibility modification method according to claim 1, wherein: The substrate is a part or the whole of the oxygenator.

10. A modified hollow fiber membrane, characterized in that: The blood-compatible modification method according to any one of claims 1 to 9 is used to modify the outer surface of the poly-4-methyl-1-pentene hollow fiber membrane.

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