Dopamine-mediated zwitterionic modified PMP membrane and application thereof in ECMO

Abstract

The invention relates to the technical field of biomedical materials, in particular to a surface modification method of a poly (4-methylpentene) (PMP) hollow fiber membrane, the blood compatibility of the material is synergistically improved through a polydopamine (PDA) coating and a zwitter-ion grafting technology, and the surface modification method is suitable for blood contact instruments such as extracorporeal membrane oxygenation (ECMO) and the like. The invention provides a dopamine-mediated zwitterionic modified PMP membrane, which comprises a PMP membrane and a modification layer on the surface of the PMP membrane, and the modification layer comprises a polydopamine intermediate layer formed on the surface of the PMP membrane through dopamine in-situ oxidation auto-polymerization and a zwitterionic polymer brush grafted on the polydopamine intermediate layer.

Description

Technical Field

[0001] This invention relates to the field of biomedical materials technology, specifically to a surface modification method for poly(4-methylpentene) (PMP) hollow fiber membranes. By synergistically improving the blood compatibility of the material through polydopamine (PDA) coating and zwitterionic grafting technology, the method is suitable for blood contact devices such as extracorporeal membrane oxygenation (ECMO). Background Technology

[0002] Extracorporeal membrane oxygenation (ECMO) is a technology that temporarily replaces or assists a patient's cardiopulmonary function through extracorporeal circulation. As a high-end life support device, the blood compatibility and stability of the core membrane lung material directly determine the clinical outcome of ECMO. Currently, the hydrophobicity of PMP hollow fiber membranes and the limitations of traditional modification methods necessitate breakthroughs through surface chemical modification and functional synergistic design.

[0003] However, existing modification technologies still have some drawbacks. For example, physical coatings (such as heparinization) are prone to peeling and have poor stability; chemical grafting methods (such as plasma treatment) may damage the PMP bulk structure and affect air permeability; and a single modification strategy is difficult to achieve both anticoagulation and antifouling properties. Existing technologies have disclosed the use of amphoteric polymers as hydrophilic coatings, such as phosphatidylcholine (PC), carboxybetaine (CB), and sulfobetaine (SB).

[0004] In the inventors' earlier work, they co-deposited the zwitterionic polymer poly(sulfobetaine methacrylate) (PSBMA) and dopamine on the surface of PMP hollow fiber membranes to construct an antithrombotic coating, thereby reducing protein adsorption and improving the blood compatibility of the original PMP membrane. However, the modified PMP hollow fiber membranes formed by the above method do not meet the requirements of scenarios with high antifouling requirements, and further improvements to the above technology are necessary.

[0005] Phosphobetaine (PBMA), a novel zwitterionic monomer, has gradually become a research hotspot for improving the blood compatibility of materials due to its unique chemical structure and performance advantages. The anticoagulant properties of phosphate betaine stem from the negative charge of its phosphate group, which inhibits platelet adhesion and activation of coagulation factors through electrostatic repulsion. Compared to traditional sulfonate betaine (SBMA) or carboxylate betaine (CBAA), the phosphate group has a more significant blocking effect on the coagulation cascade reaction, especially under high shear stress conditions (such as ECMO blood circulation). Phosphobetaine maintains its solubility in acidic, neutral, and alkaline media and does not precipitate due to changes in environmental pH, making it suitable for surface modification of medical devices under various physiological conditions. The phosphate group and quaternary ammonium group in its chemical structure form a stable zwitterionic structure, ensuring that even in long-term blood contact or PBS immersion experiments, the coating maintains a contact angle change of less than 5% and exhibits no peeling. The inventors attempted to form a hydrophilic coating on PMP hollow fiber membranes by co-deposition of phosphate betaine (PBMA) and dopamine. However, the co-deposition method struggled to ensure the uniformity of PBMA grafting and exhibited poor stability. Therefore, there is an urgent need to improve existing dopamine-mediated zwitterionic modified PMP membranes and their preparation methods to meet higher requirements. Summary of the Invention

[0006] To address the aforementioned issues, this invention provides a dopamine-mediated zwitterionic modified PMP membrane, its preparation method, and its applications. Through the synergistic effect of dopamine self-polymerization and specific zwitterionic grafting, long-term and stable improvement in blood compatibility is achieved while maintaining the membrane's gas exchange performance.

[0007] First, the present invention provides a dopamine-mediated zwitterionic modified PMP membrane, which includes a PMP membrane and a modified layer on its surface, the modified layer including a polydopamine interlayer formed on the surface of the PMP membrane by in-situ oxidation and self-polymerization of dopamine, and a zwitterionic polymer brush grafted onto the polydopamine interlayer.

[0008] Preferably, the zwitterion is a phosphate betaine (PBMA) monomer.

[0009] Preferably, the PMP membrane is a hollow fiber membrane.

[0010] Secondly, the present invention also provides a method for preparing the above-mentioned dopamine-mediated zwitterionic modified PMP membrane, which includes the following steps:

[0011] (1) Cu 2+ H2O2-catalyzed dopamine polymerization

[0012] The PMP membrane was immersed in Tris buffer containing dopamine, CuSO4·5H2O and H2O2, and reacted for 4-8 hours.

[0013] (2) PBMA grafting modification

[0014] The PMP membrane treated in step (1) was removed and washed, and then placed in PBS buffer (pH=5.6) containing 10wt% PBMA and reacted for 12h.

[0015] (3) Drying

[0016] The modified PMP membrane is obtained by cleaning and drying the PMP membrane grafted with zwitterions.

[0017] Preferably, the dopamine concentration of the Tris buffer in step (1) is 1-5 mg / mL, the concentration of CuSO4·5H2O is 0.2-1 mM, the concentration of H2O2 is 1-3 wt%, and the pH value is 8-10.

[0018] Preferably, in step (2), the pH of the PBS buffer is 5-7 and the concentration of PBMA is 5-15 wt%.

[0019] Preferably, in step (3), the PMP membrane grafted with zwitterions is washed with ultrapure water and then hung to dry.

[0020] Finally, the present invention provides an ECMO oxygenator that uses any of the above-described dopamine-mediated zwitterionic modified PMP membranes as the gas exchange site.

[0021] Preferably, the dopamine-mediated zwitterionic modified PMP membrane is used in ECMO membrane lungs to oxygenate and remove excess CO2.

[0022] Compared with the prior art, the present invention has the following advantages:

[0023] 1. The modified membrane disclosed in this invention innovatively combines a superhydrophilic layer formed by polybutyl methacrylate (PBMA) with the negatively charged surface of polydopamine (PDA). This unique design significantly reduces platelet adhesion density, and its performance far surpasses that of traditional sulfonate betaine (SBMA) coatings. Particularly noteworthy is that the modified membrane material extends the activated partial thromboplastin time (APTT) by 40% compared to the unmodified membrane, fully meeting the high standards of long-term anticoagulation performance required by extracorporeal membrane oxygenation (ECMO) systems.

[0024] 2. The hybrid matrix membrane coating developed in this invention exhibits excellent stability and material integrity. After immersion in phosphate-buffered saline (PBS) for 30 days, its contact angle change is less than 5%, ensuring the coating's long-term durability under complex physiological environments.

[0025] 3. The mixed matrix membrane (MMMs) preparation process proposed in this invention is not only simple to operate, but also significantly reduces the preparation time of the dopamine coating from the traditional 12 hours to 6 hours by introducing catalytic polymerization technology, thus significantly improving production efficiency by 50%. More importantly, this technology has broad applicability and is compatible with various zwitterionic monomers (such as thiobetaine) and various medical device substrates (such as polyurethane and silicone), thus possessing extremely high industrialization and promotion value. Attached Figure Description

[0026] Figure 1 These are electron microscope images of the original PMP membrane and the modified membrane prepared in Example 2;

[0027] Figure 2 These are gas permeability data graphs for the original PMP membrane and the modified membranes prepared in Examples 1, 2, 3, and 5.

[0028] Figure 3 The graph shows the protein adsorption data of the original PMP membrane, the modified membranes prepared in Examples 2, 5 and 6.

[0029] Figure 4 The graph shows the hemolysis rate data of the original PMP membrane, the modified membranes prepared in Examples 2, 5, and 6.

[0030] Figure 5 The graph shows the contact angle data of the original PMP membrane and the modified membranes prepared in Examples 2 and 6.

[0031] Figure 6 This is a comparison chart of contact angle data of PBMA+DA / PMP modified membrane before and after rinsing;

[0032] Figure 7 This is a comparison diagram of platelet adhesion between the original PMP membrane and the modified membrane in Example 2;

[0033] Figure 8 These are coagulation data graphs of the original PMP membrane and the modified membranes prepared in Examples 2, 5, and 6. Detailed Implementation

[0034] Example 1

[0035] (1) Preparation of DA solution: Prepare Tris buffer (pH = 8.5-9.0) containing dopamine (1 mg / mL), CuSO4·5H2O (0.5 mM) and H2O2 (2 wt%);

[0036] (2) Preparation of DA / PMP composite membrane: Cut a 20cm PMP hollow fiber membrane, place it in DA solution, and then react it in a shaker at 30℃ for 6h.

[0037] (3) Preparation of PBMA+DA / PMP composite membrane: The PMP hollow fiber membrane from step (2) was taken out and washed three times with ultrapure water. Then the membrane fibers were placed in PBMA (10wt%) PBS buffer (pH=5.6) and reacted at 60℃ in a shaker for 12h;

[0038] (4) Drying

[0039] The PMP hollow fiber membrane grafted with zwitterions was taken out, washed with ultrapure water, and then hung up to dry.

[0040] Example 2

[0041] (1) Preparation of DA solution: Prepare Tris buffer (pH = 8.5-9.0) containing dopamine (3 mg / mL), CuSO4·5H2O (0.5 mM) and H2O2 (2 wt%);

[0042] (2) Preparation of DA / PMP composite membrane: Same as in Example (1)

[0043] (3) Preparation of PBMA+DA / PMP composite membrane: Same as in Example (1)

[0044] (4) Drying: Same as in Example (1)

[0045] Example 3

[0046] (1) Preparation of DA solution: Prepare Tris buffer (pH = 8.5-9.0) containing dopamine (5 mg / mL), CuSO4·5H2O (0.5 mM) and H2O2 (2 wt%);

[0047] (2) Preparation of DA / PMP composite membrane: Same as in Example (1)

[0048] (3) Preparation of PBMA+DA / PMP composite membrane: Same as in Example (1)

[0049] (4) Drying: Same as in Example (1).

[0050] Example 4

[0051] (1) Preparation of DA solution: Prepare dopamine (3 mg / mL) Tris buffer (pH = 8.5-9.0);

[0052] (2) Preparation of DA / PMP composite membrane: Cut a 20cm PMP hollow fiber membrane, place it in DA solution, and then react it in a shaker at 30℃ for 12h.

[0053] (3) Preparation of PBMA+DA / PMP composite membrane: Same as in Example (1)

[0054] (4) Drying: Same as in Example (1).

[0055] Example 5

[0056] (1) Preparation of DA solution: Prepare Tris buffer (pH = 8.5-9.0) containing dopamine (3 mg / mL), CuSO4·5H2O (0.5 mM) and H2O2 (2 wt%);

[0057] (2) Preparation of DA / PMP composite membrane: Cut a 20cm PMP hollow fiber membrane, place it in DA solution, and then react it in a shaker at 30℃ for 6h.

[0058] (3) Drying

[0059] The PMP hollow fiber membrane is removed, rinsed with ultrapure water, and then hung up to dry.

[0060] Example 6

[0061] (1) Preparation of DA solution: Prepare Tris buffer (pH = 8.5-9.0) containing dopamine (3 mg / mL), CuSO4·5H2O (0.5 mM) and H2O2 (2 wt%);

[0062] (2) Preparation of DA / PMP composite membrane: Cut a 20cm PMP hollow fiber membrane, place it in DA solution, and then react it in a shaker at 30℃ for 6h.

[0063] (3) Preparation of SBMA+DA / PMP composite membrane: The PMP hollow fiber membrane from step (2) was taken out and washed three times with ultrapure water. Then the membrane fibers were placed in 10wt% SBMA in PBS buffer (pH=5.6) and reacted at 60℃ in a shaker for 12h;

[0064] (4) Drying

[0065] The PMP hollow fiber membrane grafted with zwitterions was taken out, washed with ultrapure water, and then hung up to dry.

[0066] Related performance tests

[0067] Gas flux test:

[0068] Cut a hollow fiber membrane (2-3 cm) and place it in a homemade mold. Introduce pure gas into the mold and adjust the pressure to approximately 1 bar. Measure the gas permeation flux using a soap bubble flow meter.

[0069] Cut a section of hollow fiber membrane (2-3 cm) and place the membrane fibers into a self-made assembly. Open the gas valve to introduce pure gas (O2, CO2, or N2) at 0.1 MPa, and use a soap bubble flow meter to measure the gas flux for different gases. The gas flux is calculated as shown in Equation 2-1:

[0070]

[0071] In the formula, Ji is the permeation rate of gas i, in mL / (cm2·min·bar), v is the permeation volume of gas (cm3), Sm is the effective area of ​​the membrane (cm2), t is the time for gas to pass through the membrane (min), and Δp is the pressure difference across the membrane (bar).

[0072] Test results:

[0073] Figure 1 The images show cross-sectional electron microscope (TEM) images of the original PMP membrane of this invention and the modified membrane prepared in Example 2. The images show that a uniform coating has formed on the surface of the modified membrane, and the internal structure of the membrane remains intact and undamaged. The gas selectivity test results of the modified composite membranes prepared in Examples 1-5 are shown below. Figure 2 As shown in the figure, the CO2 and O2 gas fluxes decrease with increasing DA concentration. When the DA concentration is 5 mg / L, the PDA layer becomes too thick, clogging the membrane pores and causing excessive reduction in permeability. Therefore, 2-3 mg / mL was determined to be the optimal concentration window, balancing blood compatibility and permeability.

[0074] Figure 3 The graph shows the protein adsorption test results of the original PMP membrane and the modified membrane. As can be seen from the graph, the protein adsorption of SBMA+PDA / PMP is reduced by 31.7% compared with the original membrane. Figure 4 The results of hemolysis rate tests for PMP original membrane, DA / PMP, and PBMA+DA / PMP are displayed sequentially. The graph shows that the hemolysis rate decreases sequentially and is less than 5% for all of them. The hemolysis rate of PBMA+DA / PMP is less than 1%. Figure 5 The test results of contact angle for the original PMP film, DA / PMP, and PBMA+DA / PMP are shown. The contact angle decreased from 109° for the original film to 18° for the modified PBMA+DA / PMP film. Figure 6 The contact angle of the PBMA+DA / PMP modified membrane after 14 days of PBS immersion was less than 5°, which proves that the modification method of the present invention has stability. Figure 7 Platelet adhesion was significantly reduced in the PBMA+DA / PMP modified membrane compared to the original membrane. Figure 8 The coagulation time of the original PMP membrane, DA / PMP, PBMA+DA / PMP, and SBMA+DA / PMP modified membranes were shown. PBMA+DA / PMP improved the coagulation time by 40% compared to the original membrane.

[0075] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. However, the above description is merely a specific embodiment of the present invention, and the technical features of the present invention are not limited thereto. Any other embodiments derived by those skilled in the art without departing from the technical solution of the present invention should be covered within the patent scope of the present invention.

Claims

1. A dopamine-mediated zwitterionic modified PMP membrane, characterized in that, It includes a PMP membrane and a modified layer on its surface, the modified layer comprising a polydopamine interlayer formed on the surface of the PMP membrane by in-situ oxidation and self-polymerization of dopamine, and a zwitterionic polymer brush grafted onto the polydopamine interlayer.

2. The dopamine-mediated zwitterionic modified PMP membrane according to claim 1, characterized in that, The zwitterion is a phosphate betaine (PBMA) monomer.

3. The dopamine-mediated zwitterionic modified PMP membrane according to claim 1, characterized in that, The PMP membrane is a hollow fiber membrane.

4. The method for preparing the modified PMP membrane according to claim 1, comprising the following steps: (1) Cu 2+ H2O2-catalyzed dopamine polymerization The PMP membrane was immersed in Tris buffer containing dopamine, CuSO4·5H2O and H2O2, and reacted for 4-8 hours. (2) PBMA grafting modification The PMP membrane treated in step (1) was removed and washed, and then placed in PBS buffer (pH=5.6) containing 10wt% PBMA and reacted for 12h. (3) Drying The modified PMP membrane is obtained by cleaning and drying the PMP membrane grafted with zwitterions.

5. The method according to claim 4, characterized in that, In step (1), the Tris buffer solution has a dopamine concentration of 1-5 mg / mL, a CuSO4·5H2O concentration of 0.2-1 mM, an H2O2 concentration of 1-3 wt%, and a pH value of 8-10.

6. The method according to claim 3, characterized in that, In step (2), the pH of the PBS buffer is 5-7, and the concentration of PBMA is 5-15 wt%.

7. The method according to claim 3, characterized in that, In step (3), the PMP membrane grafted with zwitterions is washed with ultrapure water and then hung to dry.

8. An ECMO oxygenator, characterized in that... The dopamine-mediated zwitterionic modified PMP membrane described in any one of claims 1-3 is used as the gas exchange site.

9. The modified membrane according to claim 1 for use in ECMO, characterized in that: The dopamine-mediated zwitterionic modified PMP membrane is used in ECMO membrane lungs to oxygenate and remove excess CO2.

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