A method for the preparation of a hollow fiber anti-coagulant coating for a membrane oxygenator
By loading dopamine and annular cavity-structured compounds onto the surface of hollow fiber membranes and combining them with anticoagulants, the problems of complexity and poor biocompatibility of existing anticoagulant coating methods are solved, achieving a simple and efficient anticoagulant effect, extending membrane operating time and reducing blood clotting.
Patent Information
- Application Number
- CN202410758161.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-06-13
- Publication Date
- 2025-12-12
- Estimated Expiration
- 2044-06-13
AI Technical Summary
Existing anticoagulant coating methods are complex, difficult to operate, require advanced equipment, have poor biocompatibility of intermediates, and vary greatly in anticoagulant operation methods, making it difficult to effectively solve the problem of thrombosis on the surface of hollow fiber membranes.
Dopamine and cyclic hollow structure compounds are used as linkers to load anticoagulants onto the surface of hollow fiber membranes. The preparation method is simple and requires low equipment. Cyclic polymers such as cyclodextrin and anticoagulant drugs such as warfarin and heparin are used. Hollow fiber membranes are treated with dopamine modification solution and anticoagulant solution.
It improves the anticoagulation properties of hollow fiber membranes, reduces blood clotting, extends operating time, and reduces protein adhesion, achieving a simple and efficient anticoagulation effect.
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Figure CN118846823B_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to a preparation method of a hollow fiber anticoagulant coating for a membrane oxygenator, more particularly to a hollow fiber membrane loaded with an anticoagulant coating, a preparation method and a membrane oxygenator, and belongs to the field of biomedical materials. BACKGROUND
[0002] As a medical emergency technology equipment, the membrane oxygenator provides short-term cardiopulmonary support for patients with severe heart and lung failure, and wins valuable time for the rescue of critical illness. The core material of the membrane oxygenator is a hollow fiber membrane, but blood often coagulates to form thrombus on the surface of the hollow fiber membrane during use. In order to solve this problem, the surface of the hollow fiber membrane is often modified to improve the blood compatibility of the membrane surface and reduce the formation of thrombus. However, the existing anticoagulant method often has the characteristics of complex process, high operation difficulty, poor biological compatibility of the intermediate reagent used, and large difference between different operation methods of anticoagulants. SUMMARY
[0003] The purpose of the present application is to provide a new preparation method of an anticoagulant coating applied to a hollow fiber membrane, to solve the problems of complex process, high operation difficulty, high equipment requirement, poor biological compatibility of the intermediate, and large difference between different operation methods of anticoagulants in the existing anticoagulant coating method. The dopamine and the compound with a ring-shaped cavity structure used in the present application are used as a linker between the hollow fiber membrane and the anticoagulant, without toxic and harmful reagents, and the preparation method is simple and the equipment requirement is low.
[0004] A hollow fiber membrane loaded with an anticoagulant coating, wherein the hollow fiber membrane is a porous polymer material, and a coating containing a ring-shaped cavity compound, polydopamine and an anticoagulant is further loaded on the surface of the hollow fiber membrane.
[0005] The ring-shaped cavity compound includes but is not limited to one or more of a mixture of cyclodextrin, cucurbituril, calixarene, and cyclophane.
[0006] The anticoagulant is a mixture of one or more of anticoagulant drugs such as warfarin, heparin, bivalirudin, and argatroban.
[0007] The preparation method of the hollow fiber membrane described above comprises the following steps:
[0008] Step 1: Dissolve dopamine and a ring-shaped cavity compound in a solution as a modification solution;
[0009] Step 2: Soak the hollow fiber membrane in the modification solution for treatment, and dry after taking out;
[0010] Step 3: Dissolve the anticoagulant in a solution as an anticoagulant solution, and then immerse the membrane filament obtained in Step 2 in the anticoagulant solution for treatment, and dry after taking out.
[0011] The solution in Step 1 refers to a Tris buffer solution.
[0012] The ratio of dopamine to the compound with a ring cavity structure is 1-0.1:20.
[0013] The soaking time is 0.1h-60h, and the temperature is 0-40℃.
[0014] The concentration of the anticoagulant solution is 0.1-10g / L.
[0015] A membrane oxygenator comprising the hollow fiber membrane described above is used for extracorporeal blood oxygenation.
[0016] Advantages
[0017] Cyclodextrin is a kind of compound in the shape of a conical ring, the outer edge is hydrophilic and the cavity is hydrophobic. After modifying it on the surface of the hollow fiber membrane, it can effectively improve the controlled release of drugs, achieve the purpose of anticoagulation and prevent protein adhesion in blood under long running time of the hollow fiber membrane. BRIEF DESCRIPTION OF DRAWINGS
[0018] Figure 1 is the surface SEM picture of commercial 3M hollow fiber membrane
[0019] Figure 2 is the surface SEM picture of the hollow fiber membrane prepared in Example 1
[0020] Figure 3 is the surface SEM picture of the hollow fiber membrane prepared in Example 2
[0021] Figure 4 is the surface SEM picture of the hollow fiber membrane prepared in Comparative Experiment 1
[0022] Figure 5 is the coagulation experiment result of PMP before and after modification
[0023] Figure 6 is the protein adsorption experiment result of PMP before and after modification
[0024] Figure 7 is the heparin release rate of the membrane filament within seven days DETAILED DESCRIPTION
[0025] The preparation process of the hollow fiber membrane in the present application can be prepared in the following manner in some typical embodiments:
[0026] Step 1: Dissolve dopamine and compounds with toroidal cavity structure in solution as modification solution;
[0027] Step 2: Soak the hollow fiber membrane filaments in the modification solution for treatment, and dry after taking out;
[0028] Step 3: Dissolve anticoagulant in solution as anticoagulant solution, soak the membrane filaments obtained in Step 2 in the anticoagulant solution for treatment, and dry after taking out.
[0029] The solution in Step 1 refers to Tris buffer solution.
[0030] The anticoagulant in Step 3 is selected from one or more mixtures of anticoagulant drugs such as warfarin, heparin, bivalirudin, argatroban, etc.
[0031] The mass ratio of dopamine to compounds with toroidal cavity structure is 1-0.1:20.
[0032] The soaking time is 0.1h-60h, and the temperature is 0-40℃.
[0033] The concentration of the anticoagulant solution is 0.1-10g / L.
[0034] The compounds with toroidal cavity structure include but are not limited to one or more mixtures of cyclodextrin, cucurbituril, calixarene, cyclophane, etc.
[0035] Example 1
[0036] 1) Mix dopamine and β-cyclodextrin according to the mass ratio of 1:1 into 100ml of tris (pH=8.5 50mmol / L) buffer solution, stir the solution for 10min, and dopamine and cyclodextrin are completely dissolved. Put the PMP hollow fiber membrane filaments into the solution and soak for 2h, so that dopamine and cyclodextrin fully react with the membrane filaments, then take out the membrane filaments, rinse with deionized water for 3 times, and dry.
[0037] 2) Dissolve 0.1g of heparin sodium in 0.9% NaCl solution, stir for 10min to fully dissolve heparin sodium, and immerse the membrane filaments obtained in Step (1) in the heparin sodium solution, take out the membrane filaments after 12h, rinse with deionized water for 3 times, and dry.
[0038] Example 2
[0039] 1) Dopamine and β-cyclodextrin were mixed according to the mass ratio of 1:1 and melted into 100 ml of tris (pH = 8.5 50 mmol / L) buffer solution. The solution was stirred for 10 min, and dopamine and cyclodextrin were completely dissolved. The PMP hollow fiber membrane filaments were immersed in the solution for 2 h, so that dopamine, cyclodextrin and the membrane filaments reacted sufficiently. The membrane filaments were taken out, washed with deionized water for 3 times and dried.
[0040] 2) 0.1 g of heparin sodium was dissolved in 0.9% NaCl solution, stirred for 10 min to completely dissolve heparin sodium. The membrane filaments obtained in step (1) were immersed in the heparin sodium solution, and after 24 h, the membrane filaments were taken out, washed with deionized water for 3 times and dried.
[0041] Example 3
[0042] 1) Dopamine and β-cyclodextrin were mixed according to the mass ratio of 1:1 and melted into 100 ml of tris (pH = 8.5 50 mmol / L) buffer solution. The solution was stirred for 10 min, and dopamine and cyclodextrin were completely dissolved. The PMP hollow fiber membrane filaments were immersed in the solution for 2 h, so that dopamine, cyclodextrin and the membrane filaments reacted sufficiently. The membrane filaments were taken out, washed with deionized water for 3 times and dried.
[0043] 2) 0.1 g of heparin sodium was dissolved in 0.9% NaCl solution, stirred for 10 min to completely dissolve heparin sodium. The membrane filaments obtained in step (1) were immersed in the heparin sodium solution, and after 24 h, the membrane filaments were taken out, washed with deionized water for 3 times and dried.
[0044] Example 4
[0045] 1) Dopamine and β-cyclodextrin were mixed according to the mass ratio of 1:1 and melted into 100 ml of tris (pH = 8.5 50 mmol / L) buffer solution. The solution was stirred for 10 min, and dopamine and cyclodextrin were completely dissolved. The PMP hollow fiber membrane filaments were immersed in the solution for 2 h, so that dopamine, cyclodextrin and the membrane filaments reacted sufficiently. The membrane filaments were taken out, washed with deionized water for 3 times and dried.
[0046] 2) 0.1 g of heparin sodium was dissolved in 0.9% NaCl solution, stirred for 10 min to completely dissolve heparin sodium. The membrane filaments obtained in step (1) were immersed in the heparin sodium solution, and after 24 h, the membrane filaments were taken out, washed with deionized water for 3 times and dried.
[0047] Example 5
[0048] 1) Dopamine and β-cyclodextrin were mixed in a mass ratio of 1:1 and dissolved in 100 ml of tris (pH = 8.5 50 mmol / L) buffer solution. The solution was stirred for 10 min until dopamine and cyclodextrin were completely dissolved. The PMP hollow fiber membrane was immersed in the solution for 2 h to allow dopamine and cyclodextrin to fully react with the membrane. The membrane was then taken out, washed with deionized water for 3 times, and dried.
[0049] 2) 0.1 g argatroban was dissolved in 0.9% NaCl solution and stirred for 10 min to fully dissolve argatroban. The membrane obtained in step (1) was immersed in the argatroban solution for 12 h. The membrane was then taken out, washed with deionized water for 3 times, and dried.
[0050] Example 6
[0051] 1) Dopamine and β-cyclodextrin were mixed in a mass ratio of 1:1 and dissolved in 100 ml of tris (pH = 8.5 50 mmol / L) buffer solution. The solution was stirred for 10 min until dopamine and cyclodextrin were completely dissolved. The PMP hollow fiber membrane was immersed in the solution for 2 h to allow dopamine and cyclodextrin to fully react with the membrane. The membrane was then taken out, washed with deionized water for 3 times, and dried.
[0052] 2) 0.1 g argatroban was dissolved in 0.9% NaCl solution and stirred for 10 min to fully dissolve argatroban. The membrane obtained in step (1) was immersed in the argatroban solution for 24 h. The membrane was then taken out, washed with deionized water for 3 times, and dried.
[0053] Comparative Experiment 1
[0054] The difference from Example 1 is that β-cyclodextrin is not added to the modification solution.
[0055] SEM characterization
[0056] Figure 1 is the surface scanning electron microscope image of the commercial 3M hollow fiber membrane.
[0057] Figure 2 is the surface scanning electron microscope image of the hollow fiber membrane prepared in Example 1. A layer of obvious coating is observed on the surface, indicating that heparin is successfully coated after 12 h.
[0058] Figure 3 is the surface scanning electron microscope image of the hollow fiber membrane prepared in Example 2. The surface coating is observed to be thicker, indicating that the surface defects are reduced and the surface is more uniform as the coating time is extended to 24 h.
[0059] Figure 4is the surface scanning electron microscope graph of the hollow fiber membrane prepared in Comparative Experiment 1. It is observed that the surface is uneven. When the surface is not added with cyclodextrin, the heparin coating effect on the membrane surface is poor, and the surface defects are many.
[0060] Experimental Example 1
[0061] The coagulation time experiment takes anticoagulant pig blood, and the modified membrane filaments prepared in Examples 1-6 and Comparative Experiment 1, and the 3M original membrane without modification are respectively put into the anticoagulant pig blood, and the membrane filaments are taken out after being placed in a 37℃ shaking bed for 10 min. The APTT and PT are detected by using an automatic coagulation instrument. The results are shown in Table 1 below. It can be seen that compared with the control sample, the APTT value of the modified coating is significantly increased, indicating that the modified coating has good anticoagulation performance, and the coating modified by cyclodextrin has better anticoagulation effect than the unmodified coating.
[0062] Table 1 Coagulation experiment results of PMP before and after modification
[0063]
[0064] Experimental Example 2
[0065] The protein adhesion experiment is carried out by putting the modified membrane filaments prepared in Examples 1-6 and Comparative Experiment 1, and the 3M original membrane without modification into a 0.1 mg / ml bovine serum protein solution, and taking out the membrane filaments after being placed in a 37℃ shaking bed for 2h. The remaining solution after soaking the membrane filaments is dyed by using a BCA kit, and the absorbance is detected by using an ultraviolet spectrophotometer to calculate the bovine serum protein adsorption amount. The results are shown in Table 2 below. It can be seen that compared with the control sample, the protein adsorption amount of the heparin coating is significantly reduced, and the protein adsorption amount of the membrane filaments modified by cyclodextrin is lower than that of the unmodified membrane filaments. It is indicated that the modified membrane filaments have good anti-protein adsorption capacity, and the anti-protein adsorption capacity of the membrane filaments modified by cyclodextrin is better than that of the unmodified membrane filaments.
[0066] Table 2 Protein adsorption experiment results of PMP before and after modification
[0067]
[0068] Experimental Example 3: Toluene blue heparin release detection
[0069] The content of heparin is calculated by using the toluidine blue method. The modified membrane filaments prepared in Examples 1-2 and Comparative Experiment 1, and the 3M original membrane without modification are placed in a phosphate buffer solution for a certain time, and the upper solution is taken out to detect the absorbance, and the content and release rate of heparin are calculated. The results are as follows Figure 7As shown, it can be seen that the heparin release rate of the cyclodextrin-modified membrane filament is slower than that of the unmodified membrane filament. The sustained-release ability of the experimental example 2 is the best, indicating that the cyclodextrin-modified membrane filament has better sustained-release ability than the unmodified membrane filament.
Claims
1. A hollow fiber membrane loaded with an anti-condensation coating, characterized in that, The hollow fiber membrane is a porous polymer material, and a coating containing annular cavity structure compound, polydopamine and anticoagulant is loaded on the surface of the hollow fiber membrane. The aforementioned annular cavity-like compound is β-cyclodextrin; The anticoagulant mentioned is bivalirudin or argatroban; The method for preparing the hollow fiber membrane with the anti-condensation coating includes the following steps: Step 1: Dopamine and a compound with a cyclic cavity structure are dissolved in a solution to serve as a modification solution; Step 2: Immerse the hollow fiber membrane fibers in the modification solution for treatment, then remove and dry them; Step 3: Dissolve the anticoagulant in a solution to form an anticoagulant solution. Immerse the membrane fibers obtained in Step 2 in the anticoagulant solution for treatment, and then remove and dry them. The solution mentioned in step 1 refers to Tris buffer solution; The mass ratio of dopamine to a compound with a cyclic cavity structure is 1–0.1:20; The soaking time is 0.1h to 60h, and the temperature is 0 to 40℃; The concentration of the anticoagulant solution is 0.1~10g / L.
2. A membrane oxygenator comprising the hollow fiber membrane of claim 1, for extracorporeal blood oxygenation.