Bionic antithrombotic PMP gas-blood exchange membrane based on zwitter-ion gradient grafting and preparation method thereof

Abstract

The invention belongs to the technical field of biomedical materials, and particularly relates to a poly-4-methyl-1-pentene (PMP) gas-blood exchange membrane for an extracorporeal membrane oxygenation (ECMO) system, which realizes a long-acting antithrombotic function through a bionic interface construction technology. The invention aims to provide a bionic antithrombotic PMP gas-blood exchange membrane based on zwitter-ion gradient grafting, and through material and process innovation, the following problems existing in a traditional ECMO gas-blood exchange membrane: an antithrombotic coating is easy to fall off, and the long-term effect is insufficient; the risk of blood injury caused by dependence on heparin or anticoagulants; and the surface modification process destroys the membrane pore structure and air permeability.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials technology, specifically relating to a poly-4-methyl-1-pentene (PMP) gas-blood exchange membrane for extracorporeal membrane oxygenation (ECMO) systems, which achieves long-term antithrombotic function through biomimetic interface construction technology. Background Technology

[0002] Extracorporeal membrane oxygenation (ECMO) systems, as life support devices for patients with severe cardiopulmonary failure, rely heavily on the material properties of their core component, the oxygenator, for performance. Currently, the global ECMO gas exchange membrane market has long been monopolized by 3M, which uses the third-generation material poly-4-methyl-1-pentene (PMP). While PMP offers advantages such as high permeability and low plasma leakage, it still faces technological bottlenecks. For example, plasma leakage occurs due to insufficient hydrophilicity of the membrane surface, leading to lipoprotein adsorption in the micropores after prolonged use, resulting in a membrane lifespan of less than 15 days. Thrombosis risk exists because current antithrombotic regimens rely on heparin coatings or systemic anticoagulants, which can easily lead to heparin-induced thrombocytopenia (HIT) or damage to blood components. Furthermore, existing membrane modifications often damage the membrane pore structure and permeability.

[0003] SBMA is an amphoteric compound containing a sulfonic acid group (-SO3) in its molecule. - ) and quaternary ammonium groups (-N + (CH3)3) can form a highly hydrophilic interface through charge balance. SBMA has the following advantages: strong negative charge: the sulfonic acid groups provide a stable negative charge, repelling negatively charged platelets and proteins (such as fibrinogen) in the blood, significantly reducing thrombus formation. Anti-protein adsorption: the "hydration layer effect" of zwitterions can form a dense water molecule barrier, inhibiting the non-specific adsorption of plasma proteins and reducing the probability of triggering the coagulation cascade reaction. Chemical stability: the sulfonic acid groups are resistant to hydrolysis and oxidation, and their performance decays slowly during long-term blood contact. In ECMO gas exchange membranes, SBMA grafted layers can reduce the thrombus formation rate by about 50%-70%, but when used alone, the excessive charge may lead to an imbalance in the hydrophilicity of the interface. Existing antithrombotic coating technologies include plasma pretreatment of grafted sulfonated betaine (SBMA), but the grafted layer has poor uniformity and is prone to detachment after long-term use.

[0004] PC is one of the main components of cell membrane phospholipids, and its molecule contains a phosphocholine group (-PO4). - -CH2CH2N +(CH3)3), possessing biomimetic neutral charge properties. PC exhibits biomimetic compatibility: the PC structure is highly similar to the vascular endothelial cell membrane, which can deceive blood components into mistaking it for autologous tissue, significantly reducing platelet activation and inflammatory responses; dynamic anticoagulation: the phosphocholine groups bind to water molecules through hydrogen bonds, forming a dynamic hydration layer that hinders the adsorption and activation of coagulation factors (such as thrombin); interfacial flexibility: the flexibility of the PC molecular chain can adapt to changes in blood flow shear force, reducing the risk of coating detachment due to mechanical stress. PC graft membranes have shown a 60%-80% reduction in thrombosis rate in animal experiments, but when used alone, they may lack strong charge support and have insufficient adaptability to high shear force environments. Summary of the Invention

[0005] To address the aforementioned issues, this invention aims to provide a biomimetic antithrombotic PMP gas exchange membrane based on zwitterionic gradient grafting. Through material and process innovation, it solves the following problems existing in traditional ECMO gas exchange membranes: easy detachment of the antithrombotic coating and insufficient long-term effectiveness; the risk of blood damage due to reliance on heparin or anticoagulants; and the damage to membrane pore structure and permeability caused by surface modification processes.

[0006] First, the present invention provides a biomimetic antithrombotic PMP gas exchange membrane based on zwitterionic gradient grafting, which includes a PMP membrane, wherein the surface of the PMP membrane has a gradient zwitterionic layer, the gradient zwitterionic layer comprising an inner sulfonate betaine (SBMA) layer and an outer phosphoric acid choline (PC) layer.

[0007] Preferably, the PMP membrane is grafted with the sulfonate betaine (SBMA) layer by forming a carboxyl-containing active layer through surface carboxylation treatment.

[0008] Secondly, the present invention also provides a method for preparing the above-mentioned biomimetic antithrombotic PMP gas exchange membrane based on zwitterionic gradient grafting, which includes the following steps:

[0009] (1) Substrate treatment

[0010] Clean and dry the PMP membrane;

[0011] (2) Plasma activation

[0012] The PMP membrane was placed in a plasma device and activated by passing acrylic acid gas to generate a carboxyl-containing active layer.

[0013] (3) SBMA grafting

[0014] The activated membrane was immersed in an SBMA monomer solution and subjected to ultraviolet light treatment to form a sulfonate betaine (SBMA) layer;

[0015] (4) PC grafting

[0016] The membrane treated in step (3) is further immersed in a PC monomer solution for a second ultraviolet irradiation treatment to form a sulfonate betaine (SBMA) layer;

[0017] (5) Post-processing

[0018] The grafted membrane is cleaned and dried to obtain the biomimetic antithrombotic PMP gas exchange membrane.

[0019] Preferably, in step (2), the plasma power is 40-80W, the activation time is 20-60s, and the acrylic acid gas flow rate is 5-10sccm.

[0020] Preferably, in step (3), the mass concentration of the SBMA monomer solution is 5-10 wt%, and the ultraviolet light intensity is 5-20 mW / cm². 2 The illumination time is 5-30 minutes.

[0021] Preferably, in step (4), the mass concentration of the PC monomer solution is 3-10 wt%, and the ultraviolet light intensity is 5-20 mW / cm². 2 The illumination time is 5-30 minutes.

[0022] Finally, the present invention relates to the application of the biomimetic antithrombotic PMP gas exchange membrane based on zwitterionic gradient grafting in the ECMO system.

[0023] Preferably, the biomimetic antithrombotic PMP gas exchange membrane is used to oxygenate the blood and remove excess CO2.

[0024] Compared with the prior art, the present invention has the following advantages:

[0025] First, this invention combines SBMA and PC using gradient grafting technology to achieve complementary and synergistic effects. Charge synergy: SBMA's strong negative charge repels platelets, while PC's neutral charge inhibits the activation of coagulation factors, forming a dual antithrombotic mechanism. Interface stability: SBMA provides chemical anchoring points, while PC enhances flexibility and reduces coating peeling. Long-lasting performance: The stability of SBMA combined with the dynamic hydration layer of PC extends the antithrombotic effect to over 30 days. While SBMA and PC achieve antithrombotic effects through charge repulsion and biomimetic mechanisms respectively, single materials have limitations (such as charge imbalance or insufficient mechanical strength). Through gradient grafting technology, their synergistic effect can cover a wider range of coagulation inhibition scenarios, while simultaneously improving interface stability and long-lasting performance. This design provides a safer and more durable blood contact material solution for medical devices such as ECMO and artificial wombs.

[0026] Secondly, the biomimetic antithrombotic PMP gas exchange membrane provided by this invention exhibits the following antithrombotic properties: a significant decrease in protein adsorption and a hemolysis rate of <1%.

[0027] Finally, the biomimetic antithrombotic PMP gas exchange membrane prepared by this invention has long-term stability: after continuous use, the grafted layer is retained and the contact angle changes only slightly; it does not rely on heparin coating and reduces the amount of anticoagulant used. Attached Figure Description

[0028] Figure 1 This is a graph showing the protein adsorption data for the original PMP membrane, SBMA+PC / PMP, SBMA / PMP, and PC / PMP.

[0029] Figure 2 The graph shows the hemolysis rates of PMP original membrane, SBMA+PC / PMP, SBMA / PMP, and PC / PMP.

[0030] Figure 3 These are contact angle data diagrams for PMP original film, SBMA+PC / PMP, SBMA / PMP, and PC / PMP.

[0031] Figure 4 This is a comparison chart of contact angle data before and after rinsing of SBMA+PC / PMP modified membranes. Detailed Implementation

[0032] The following embodiments further illustrate the content of the present invention, but should not be construed as limiting the present invention. Any modifications and substitutions made to the methods, steps, or conditions of the present invention without departing from the essence of the invention are within the scope of the present invention.

[0033] Example 1

[0034] (1) Substrate treatment

[0035] The PMP membrane was immersed in ethanol and ultrasonically cleaned for 10 minutes, then dried and placed in the plasma reaction chamber.

[0036] (2) Plasma activation

[0037] Acrylic acid gas is introduced at a flow rate of 5-10 sccm, a power of 60W, and a time of 40 seconds to generate an active layer containing carboxyl groups.

[0038] (3) SBMA grafting

[0039] The membrane was immersed in an 8% SBMA monomer solution and irradiated with ultraviolet light (8 mW / cm²). 2 In 10 minutes, the first layer will be formed;

[0040] (4) PC grafting

[0041] Replace with PC monomer solution (6% concentration), and perform secondary ultraviolet irradiation (8mW / cm²). 2 8 minutes, forming the second layer;

[0042] (5) Post-processing

[0043] Rinse with deionized water and vacuum dry at 60°C.

[0044] Example 2

[0045] (1) Substrate treatment

[0046] The PMP membrane was immersed in ethanol and ultrasonically cleaned for 10 minutes, then dried and placed in the plasma reaction chamber.

[0047] (2) Plasma activation

[0048] Acrylic acid gas is introduced at a power of 60W for 40 seconds to generate an active layer containing carboxyl groups.

[0049] (3) SBMA grafting

[0050] The membrane was immersed in an 8% SBMA monomer solution and irradiated with ultraviolet light (8 mW / cm²). 2 In 10 minutes, the first layer will be formed;

[0051] (4) Post-processing

[0052] Rinse with deionized water and vacuum dry at 60°C.

[0053] Example 3

[0054] (1) Substrate treatment

[0055] The PMP membrane was immersed in ethanol and ultrasonically cleaned for 10 minutes, then dried and placed in the plasma reaction chamber.

[0056] (2) Plasma activation

[0057] Acrylic acid gas is introduced at a power of 60W for 40 seconds to generate an active layer containing carboxyl groups.

[0058] (3) PC grafting

[0059] Replace with PC monomer solution (6% concentration), and perform secondary ultraviolet irradiation (8mW / cm²). 2 8 minutes, forming the second layer;

[0060] (4) Post-processing

[0061] Rinse with deionized water and vacuum dry at 60°C.

[0062] Related performance tests

[0063] Gas flux test:

[0064] 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.

[0065] 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:

[0066]

[0067] In the formula, J i The permeation rate of gas i is expressed in mL / (cm²). 2 ·min·bar), where v is the gas permeation rate (cm). 3 ), S m The effective area of ​​the membrane (cm²) 2 ), where t is the time (min) for the gas to pass through the membrane, and Δp is the pressure difference (bar) across the membrane.

[0068] Characterization results

[0069] Figure 1 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 51.7% compared with the original membrane. Figure 2 The hemolysis rate test results for PMP original membrane, SBMA+PC / PMP, SBMA / PMP, and PC / PMP are shown in sequence. The graph shows that the hemolysis rate is less than 5% for all of them, with PBMA+DA / PMP having the lowest hemolysis rate, less than 1%. Figure 3 The test results for the contact angle of the original PMP film, SBMA+PC / PMP, SBMA / PMP, and PC / PMP are shown. The contact angle decreased from 109° of the original film to 28° of the SBMA+PC / PMP modified film, a reduction of 74%. Figure 4 The contact angle of the SBMA+PC / 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.

[0070] 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 biomimetic antithrombotic PMP gas exchange membrane based on zwitterionic gradient grafting, characterized in that: It includes a PMP membrane, the surface of which has a gradient zwitterionic layer, the gradient zwitterionic layer comprising an inner sulfonate betaine (SBMA) layer and an outer phosphoric acid choline (PC) layer.

2. The biomimetic antithrombotic PMP gas exchange membrane according to claim 1, characterized in that, The PMP membrane is grafted with the sulfonate betaine (SBMA) layer by forming a carboxyl-containing active layer through surface carboxylation treatment.

3. A method for preparing a biomimetic antithrombotic PMP gas exchange membrane based on zwitterionic gradient grafting according to claim 1, characterized in that, Includes the following steps: (1) Substrate treatment Clean and dry the PMP membrane; (2) Plasma activation The PMP membrane was placed in a plasma device and activated by passing acrylic acid gas to generate a carboxyl-containing active layer. (3) SBMA grafting The activated membrane was immersed in an SBMA monomer solution and subjected to ultraviolet light treatment to form a sulfonate betaine (SBMA) layer; (4) PC grafting The membrane treated in step (3) is further immersed in a PC monomer solution for a second ultraviolet irradiation treatment to form a sulfonate betaine (SBMA) layer; (5) Post-processing The grafted membrane is cleaned and dried to obtain the biomimetic antithrombotic PMP gas exchange membrane.

4. The preparation method according to claim 1, characterized in that, In step (2), the plasma power is 40-80W, the activation time is 20-60s, and the acrylic acid gas flow rate is 5-10sccm.

5. The preparation method according to claim 1, characterized in that, In step (3), the mass concentration of the SBMA monomer solution is 5-10 wt%, and the ultraviolet light intensity is 5-20 mW / cm². 2 The illumination time is 5-30 minutes.

6. The preparation method according to claim 1, characterized in that, In step (4), the mass concentration of the PC monomer solution is 3-10 wt%, and the ultraviolet light intensity is 5-20 mW / cm². 2 The illumination time is 5-30 minutes.

7. The application of the biomimetic antithrombotic PMP gas exchange membrane based on zwitterionic gradient grafting as described in claim 1 in the ECMO system.

8. The application according to claim 9, characterized in that, The biomimetic antithrombotic PMP gas exchange membrane is used to oxygenate the blood and remove excess CO2.

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