CN113082301A - Anticoagulant and metal-organic framework compound double-modified coating for extracorporeal blood circulation pipeline and preparation method thereof - Google Patents
Anticoagulant and metal-organic framework compound double-modified coating for extracorporeal blood circulation pipeline and preparation method thereof Download PDFInfo
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- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
- A61L33/0005—Use of materials characterised by their function or physical properties
- A61L33/0011—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- A61L2300/606—Coatings
Abstract
The invention discloses an anticoagulant and a metal-organic framework compound double-modified extracorporeal blood circulation pipeline coating and a preparation method thereof, wherein the anticoagulant of the coating is selected from heparin, hirudin, citric acid or argatroban, and the metal-organic framework compound in the coating is MOF-Ag or MOF-Cu; the coating is obtained by fixing a metal-organic framework compound on the inner wall of an extracorporeal blood circulation pipeline through dopamine, and then fixing an anticoagulant on a dopamine layer with the metal-organic framework compound in a chemical grafting manner. The coating has high stability, improves the blood compatibility, has excellent anticoagulation and antibacterial effects, and the extracorporeal blood circulation pipeline with the coating can be applied to conventional hemodialysis, blood adsorption and continuous blood purification treatment.
Description
Technical Field
The invention relates to the technical field of blood purification, in particular to an anticoagulant and metal-organic framework compound double-modified coating for an extracorporeal blood circulation pipeline and a preparation method thereof.
Background
The blood circulation pipeline is used as a material which is contacted with blood for a long time, and the anticoagulant property of the material is always a focus of attention of the industry. When blood contacts with the tube, small molecules, plasma proteins and the like in the plasma are firstly adsorbed on the surface of the tube, so that thrombin is activated, fibrin is denatured, and platelet aggregation and thrombosis are caused. Therefore, the anticoagulation performance of the tubing is very important for blood circulation pipelines. At present, the main clinical method for preventing blood coagulation is to inject heparin solution through a heparin tube to achieve the effect of pipeline anticoagulation, but because the physique of patients is different, the dosage of heparin cannot be accurately controlled, and a few patients have low thrombocythemia, and the risk coefficient of heparin injection is high.
In addition to blood compatibility, the antibacterial property or anti-infection property of the material in contact with blood is an extremely important performance requirement, and during blood purification, inflammation reaction is caused by infection caused by bacteria adhered to the surface of the material, so that extremely serious consequences can be brought.
At present, the improvement of the blood compatibility of the tubing by modifying the surface of the circulation pipeline has become a hot point of research. The Chinese patent application for hemodialysis discloses an extracorporeal circulation pipeline and a preparation method thereof (application number is 201410171300.6). The extracorporeal circulation pipeline is coated with a macromolecular bionic coating containing sulfonic acid group poly (2-methoxyethyl acrylate) by a co-extrusion coating process, so that the blood coagulation and the thrombus are reduced to a great extent.
The utility model discloses an anticoagulation dialysis circulation pipeline (application number 201720375530.3) discloses an anticoagulation dialysis pipeline, and the material of pipeline has obtained anticoagulation tubular product through heparin and PVC blending for distributing PVC or TPU of heparin, nevertheless this utility model's coating can make the heparin inactivation through heparin and aggregate blending extrusion molding to can not reach the anticoagulation effect.
The blood circulation lines currently on the market have the following drawbacks: lack of anticoagulation coating, easy occurrence of side effects such as thrombus, hemagglutination, etc.; some pipelines realize anticoagulation by heparin injection, and have higher risk for low thrombocythemia; some pipelines realize anticoagulation by a granular heparin mixing extrusion molding mode, and heparin inactivation and lack of anticoagulation effect exist; some pipelines realize anticoagulation in a co-extrusion coating mode, relate to various organic solvents, are not environment-friendly and are easy to generate toxic and side effects on human bodies; meanwhile, the coating is thicker due to coating, and the thickness of the pipeline is influenced; the existing blood circulation lines generally do not take into account the antibacterial properties of the materials.
Disclosure of Invention
The invention aims to solve the problems and provide an extracorporeal blood circulation pipeline coating which has the advantages of improving blood compatibility and has anticoagulation and antibacterial effects and is doubly modified by anticoagulant and metal-organic framework compounds (MOFs).
In order to achieve the purpose, the invention adopts the technical scheme that:
an anticoagulant and metal-organic framework compound double-modified extracorporeal blood circulation pipeline coating, the anticoagulant of the coating is selected from heparin, hirudin, citric acid or argatroban, and the metal-organic framework compound in the coating is MOF-Ag or MOF-Cu; the coating is obtained by fixing a metal-organic framework compound on the inner wall of an extracorporeal blood circulation pipeline through dopamine, and then fixing an anticoagulant on a dopamine layer with the metal-organic framework compound in a chemical grafting manner;
preferably, the chemical grafting is carried out by electrostatically bonding polylysine and anticoagulant and then grafting the polylysine onto the dopamine layer.
The invention also provides a preparation method of the anticoagulant and metal-organic framework compound double-modified extracorporeal blood circulation pipeline coating, which comprises the following steps:
1) preparation of metal-organic framework compounds: preparing an organic solvent solution of trimesic acid, a silver nitrate aqueous solution or a copper nitrate aqueous solution, mixing and stirring the trimesic acid solution and the silver nitrate/copper nitrate solution uniformly to obtain MOF-Ag or MOF-Cu, and performing suction filtration and washing on a product for later use;
2) preparing a Tris buffer solution or a PBS buffer solution of dopamine, wherein the pH value is 5-12, and dissolving MOF-Ag or MOF-Cu in the dopamine solution to obtain a solution 1;
3) respectively preparing a polylysine solution and an anticoagulant solution by using normal saline or PBS buffer solution, and then mixing the anticoagulant solution and the polylysine solution to obtain a solution 2;
4) connecting an extracorporeal blood circulation pipeline with a solution 1, reacting at 10-30 ℃ for 1-24 h, introducing ultrapure water for cleaning for 1-3 times after the reaction is finished, then introducing a solution 2 into the pipeline, reacting at 10-30 ℃ for 1-24 h, introducing ultrapure water for cleaning for 1-3 times after the reaction is finished, and then drying the pipeline, wherein the inner surface of the pipeline is attached with a coating which is double modified by an anticoagulant and a metal-organic framework compound.
In the above technical scheme, the step 1) of preparing the metal-organic framework compound comprises the following specific steps:
preparing 0.05-0.5 g/ml of anhydrous ethanol solution of trimesic acid, preparing 0.05-0.5 g/ml of silver nitrate or copper nitrate solution by using ultrapure water, mixing the trimesic acid solution and the silver nitrate or copper nitrate solution in a volume ratio of 2-4: 1, mechanically stirring for 8-16 h, performing suction filtration on the obtained product, and repeatedly washing by using the anhydrous ethanol and the ultrapure water to obtain pure silver trimesate or copper trimesate for later use.
Preferably, the concentration of trimesic acid is equal to the concentration of the silver nitrate or copper nitrate solution, and the volume ratio of the trimesic acid solution to the silver nitrate or copper nitrate solution is 3: 1.
In the step 2), the concentration of the dopamine solution is 1 mg/ml-10 mg/ml, and the concentration of silver trimesate or copper trimesate in the solution 1 is 0.1-2 mg/ml;
preferably, the concentration of the dopamine solution is 2mg/ml, and the concentration of the silver trimesate or the copper trimesate in the solution 1 is 0.5-2 mg/ml.
In the step 3), 0.1-1 mg/ml polylysine solution is prepared, 5-10 mg/ml anticoagulant solution is prepared, and then the anticoagulant solution and the polylysine solution are mixed in a volume ratio of 1-3: 1 to obtain a solution 2, so that the solution can be used in the on-site preparation.
Preferably, in the step 3), 0.5mg/ml polylysine solution and 5-10 mg/ml anticoagulant solution are prepared, and then the anticoagulant solution and the polylysine solution are mixed at a volume ratio of 1: 1 to obtain the solution 2.
In the step 4), the extracorporeal blood circulation pipeline is made of PVC, and the solution 1 and the solution 2 are introduced and then react at 25 ℃ for 12-24 hours.
The invention also provides an external blood circulation pipeline doubly modified by the anticoagulant and the metal-organic framework compound, the inner wall of the external blood circulation pipeline is provided with the external blood circulation pipeline coating doubly modified by the anticoagulant and the metal-organic framework compound,
the coating is preferably applied to the inner wall surface of the pipeline by the method described above.
The extracorporeal blood circulation pipeline is made of polyvinyl chloride, polyurethane, silica gel or polytetrafluoroethylene, and preferably polyvinyl chloride.
The invention has the beneficial effects that:
1. the MOF-Ag and heparin double-modified extracorporeal circulation pipeline achieves an anticoagulation effect due to the grafting of heparin, can reduce the risk of rapid reduction of platelets of a patient with low thrombocythemia caused by anticoagulant injection, achieves an antibacterial effect due to the slow release of Ag ions in the MOF-Ag, and reduces the risk of bacterial infection of the patient; the problems that the surface of the PVC material is difficult to graft and heparin is inactivated due to the mixed extrusion molding of the heparin and the PVC granules are solved; the introduction of the metal organic framework compound ensures that the coating has good stability, is thin, does not introduce an organic solvent, has dual functions of antibiosis and anticoagulation, and improves the blood compatibility and the antibiosis performance of the pipeline material to a greater extent.
2. The heparin and MOF-Cu (capable of catalyzing and releasing NO) double-modified pipeline coating can reduce the risk of the rapid reduction of platelets caused by anticoagulant injection in a patient with low thrombocythemia; the problems that the surface of the PVC material is difficult to graft and heparin is inactivated due to the mixed extrusion molding of the heparin and the PVC granules are solved; because the slow release of Cu ions catalyzes an endogenous donor to generate NO and the heparin are combined to achieve an anticoagulation effect, the occurrence of thrombus and hemagglutination is reduced; due to the release of Cu ions, the adhesion of bacteria is inhibited, and the risk of bacterial infection is reduced. The coating is thin, NO organic solvent is introduced, the heparin and NO act together, the blood compatibility of the material is improved to a greater extent, the coating stability is high, and the antibacterial and anticoagulant effects are excellent.
Drawings
Fig. 1 is a graph showing the results of the platelet adsorption experiment of the extracorporeal blood circulation circuit of example 1, in which graph a is a control and graph B is a circuit modified with a coating of the present invention.
FIG. 2 is a graph showing the results of APTT (activated partial thromboplastin time) in the extracorporeal blood circulation circuit in example 1.
FIG. 3 shows the results of the antibacterial test in the extracorporeal blood circulation circuit in example 1.
Fig. 4 is a graph showing the results of the platelet adsorption experiment of the extracorporeal blood circulation circuit of example 2, in which graph a is a control and graph B is a circuit modified with a coating of the present invention.
FIG. 5 is a graph showing the results of APTT (activated partial thromboplastin time) in the extracorporeal blood circulation circuit in example 2.
Fig. 6 shows the results of the antibiotic test of the extracorporeal blood circulation circuit in example 2.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to be limiting.
The experimental procedures in the following examples are conventional unless otherwise specified.
The main reagents are as follows:
polylysine: CAS registry number 25988-63-0
Dopamine: CAS registry number 51-61-6
Heparin: CAS number: 9005-49-6
Trimesic acid: CAS registry number 554-95-0
The reagents are laboratory pure grade and are all obtained commercially. Unless otherwise specified, the remaining reagents used in the examples are conventional in the art and are commercially available.
Example 1 preparation of MOF-Ag and heparin double-modified in vitro blood circulation line coating
Firstly, preparing MOF-Ag and heparin double-modified coating on inner surface of extracorporeal blood circulation pipeline
The method comprises the following steps:
1) the trimesic acid was prepared as a 0.05g/ml absolute ethanol solution of trimesic acid. Silver nitrate was dissolved in ultrapure water to give a silver nitrate solution with a final concentration of 0.05 g/ml. The trimesic acid solution and the silver nitrate solution were mixed in a volume ratio of 3: 1 and mechanically stirred for 8 h. And then, carrying out suction filtration on the obtained product, and repeatedly washing the product by using absolute ethyl alcohol and ultrapure water to obtain pure silver trimesate for later use.
2) Tris buffer containing 2mg/ml dopamine (PH: 8.5), then dissolving the silver trimesate in the dopamine solution to obtain a solution 1 with the concentration of 0.5mg/ml, which is ready for use.
3) Preparing a polylysine solution with the concentration of 0.5mg/ml by using normal saline, preparing a heparin solution with the concentration of 5mg/ml by using the normal saline, and mixing the heparin solution and the polylysine solution in a volume ratio of 1: 1 to obtain a solution 2 for use.
4) Connecting an extracorporeal blood circulation pipeline made of PVC (polyvinyl chloride) material with a solution 1, reacting at 25 ℃ for 12h, introducing ultrapure water to clean for 3 times after the reaction is finished, removing physically adsorbed molecules for 3min each time, and repeating the process for three times to obtain a modified surface. And then introducing the solution 2 into the pipeline after the primary modification, reacting for 12 hours at 25 ℃, introducing ultrapure water for cleaning for 3 times after the reaction is finished, and removing the physically adsorbed molecules after 3 minutes each time. Then the pipeline is suspended and placed, ventilated and dried, and the extracorporeal circulation pipeline with the antibacterial and anticoagulant coatings (namely the modified extracorporeal circulation pipeline) is obtained.
Second, performance test
(1) Platelet adhesion test
The obtained extracorporeal circulation pipeline with the antibacterial and anticoagulant coatings is used for a platelet adhesion experiment, and meanwhile, a pipeline without the coating (namely, an unmodified extracorporeal circulation pipeline) is used as a control, and the experiment method comprises the following steps: cutting the extracorporeal circulation pipeline before and after modification into small blocks of 1cm x 1cm, placing the small blocks in a 24-hole plate, adding 500uL of platelet-rich plasma immersed samples into each hole, incubating the samples in a constant-temperature water bath at 37 ℃ in a dark place for 30min, and cleaning the surfaces of the samples by using normal saline. Then fixing with 2.5% glutaraldehyde, dehydrating and dealcoholizing, spraying gold, and observing platelet morphology by using a scanning electron microscope.
The scanning electron micrograph of the experiment (fig. 1) shows: the number of the platelets adhered to the surface of the control unmodified extracorporeal blood circulation pipeline is large; the external blood circulation pipeline with the antibacterial and anticoagulant coatings has small adhesion quantity of platelets on the surface. The result shows that the extracorporeal circulation pipeline with the antibacterial and anticoagulation coating reduces the adhesion of blood platelets and has anticoagulation effect.
(2) APTT (activated partial thromboplastin time) assay
The supernatant plasma was collected by centrifugation with venous blood and tested using APTT test kit (commercially available). Adding the activator in the kit into pre-warmed plasma containing sample pieces, incubating at 37 deg.C for 5min, and adding pre-warmed CaCl2Reagents, measured with a coagulometer, and the clotting time (seconds) was read.
The results of the APTT (activated partial thromboplastin time) experiment (figure 2) show: compared with an unmodified extracorporeal blood circulation pipeline, the activated partial thromboplastin time of the modified extracorporeal blood circulation pipeline is obviously improved, which shows that the extracorporeal blood circulation pipeline with the antibacterial and anticoagulant coating improves the blood compatibility of the material and obviously prolongs the blood coagulation time.
(3) Antibacterial experiments
The experimental method comprises the following steps: connecting the extracorporeal circulation pipeline before/after modification into a closed pipeline, introducing normal saline into the pipeline for circulation for 4 hours, taking out the normal saline to obtain a test solution, mixing the staphylococcus aureus liquid with the test solution in a ratio of 1: 10, adding 1ml of mixed solution onto an agar plate, culturing for 48 hours at 37 ℃, and then taking pictures for counting.
Staphylococcus aureus agar plate counts (fig. 3) show: the number of staphylococcus aureus colonies on the surface of an unmodified common PVC pipeline sample is obviously more than that on the surface of a PVC pipeline sample with the antibacterial and anticoagulant coating, and the result shows that the number of staphylococcus aureus colonies is reduced by an extracorporeal circulation pipeline with the antibacterial and anticoagulant coating, and the antibacterial and anticoagulant coating has a good antibacterial effect.
Example 2 preparation of MOF-Cu and heparin double modified in vitro blood circulation line modified coating of the invention
Firstly, preparing the MOF-Cu and heparin dual-modified coating of the invention on the inner surface of the extracorporeal blood circulation pipeline
The method comprises the following steps:
1) the trimesic acid was prepared as a 0.5g/ml absolute ethanol solution of trimesic acid. Copper nitrate was dissolved in ultrapure water to give a copper nitrate solution having a final concentration of 0.5 g/ml. The trimesic acid solution and the copper nitrate solution were mixed in a volume ratio of 3: 1 and mechanically stirred for 16 h. And then, carrying out suction filtration on the obtained product, and repeatedly washing the product by using absolute ethyl alcohol and ultrapure water to obtain pure copper trimesate for later use.
2) Tris buffer containing 2mg/ml dopamine (PH: 8.5), then dissolving copper trimesate in the dopamine solution to obtain a solution 1 with the concentration of 2mg/ml, and preparing for use.
3) Preparing a polylysine solution with the concentration of 0.5mg/ml by using normal saline, preparing a heparin solution with the concentration of 9mg/ml by using the normal saline, and mixing the heparin solution and the polylysine solution in a volume ratio of 1: 1 to obtain a solution 2 for use.
4) Connecting an extracorporeal blood circulation pipeline made of PVC material with a solution 1, reacting at 25 ℃ for 24h, introducing ultrapure water to clean for 3 times after the reaction is finished, 5min each time, removing physically adsorbed molecules, and repeating the process for two to three times to obtain a modified surface. And then introducing the solution 2 into the pipeline after the primary modification, reacting for 24 hours at 25 ℃, introducing ultrapure water for cleaning for 3 times after the reaction is finished, and removing physically adsorbed molecules after 5min each time. And then, hanging and placing the pipeline, ventilating and drying to obtain the antibacterial and anticoagulant dual-function coating with the MOF-Cu combined heparin capable of catalytically releasing NO.
Second, performance test
Specific procedures for platelet adhesion test, APTT (activated partial thromboplastin time) test and antibacterial test are as in example 1.
(1) Platelet adhesion test
The experimental scanning electron micrograph is shown in fig. 4, and the result shows that: compared with the unmodified common PVC pipeline, the blood platelet on the surface of the pipeline has a large adhesion amount and pseudosufficient blood platelets extending out, and is spread in a tree-like manner, and a few blood platelets are completely spread, so that the severe activation of the blood platelets is shown; the base material modified by the coating has small platelet adhesion quantity, is round and basically does not activate. The results show that the modified surface of NO in combination with heparin reduces platelet adhesion and activation, and has an anticoagulant effect.
(2) APTT (activated partial thromboplastin time) assay
The results of the APTT (activated partial thromboplastin time) experiment (figure 5) show: compared with an unmodified extracorporeal blood circulation pipeline, the activated partial thromboplastin time of the modified extracorporeal blood circulation pipeline is obviously improved, which shows that the extracorporeal blood circulation pipeline with the antibacterial and anticoagulant coating improves the blood compatibility of the material and obviously prolongs the blood coagulation time.
(3) Antibacterial experiments
Staphylococcus aureus agar plate counts (fig. 6) show: the number of staphylococcus aureus colonies on the surface of the unmodified common PVC pipeline is obviously more than that on the surface of the PVC pipeline with the antibacterial and anticoagulant coating, and the result shows that the number of staphylococcus aureus colonies is reduced by the extracorporeal circulation pipeline with the antibacterial and anticoagulant coating, and the antibacterial and anticoagulant coating has a good antibacterial effect.
Claims (10)
1. An anticoagulant and metal-organic framework compound double-modified coating of an extracorporeal blood circulation pipeline, which is characterized in that: the anticoagulant of the coating is selected from heparin, hirudin, citric acid or argatroban, and the metal organic framework compound in the coating is MOF-Ag or MOF-Cu; the coating is obtained by fixing a metal-organic framework compound on the inner wall of an extracorporeal blood circulation pipeline through dopamine, and then fixing an anticoagulant on a dopamine layer with the metal-organic framework compound in a chemical grafting manner;
preferably, the chemical grafting is carried out by electrostatically bonding polylysine and anticoagulant and then grafting the polylysine onto the dopamine layer.
2. The method of preparing an anticoagulant and metal-organic framework compound dual modified extracorporeal blood circulation line coating according to claim 1, comprising the steps of:
1) preparation of metal-organic framework compounds: preparing an organic solvent solution of trimesic acid, a silver nitrate aqueous solution or a copper nitrate aqueous solution, mixing and stirring the trimesic acid solution and the silver nitrate/copper nitrate solution uniformly to obtain MOF-Ag or MOF-Cu, and performing suction filtration and washing on a product for later use;
2) preparing a Tris buffer solution or a PBS buffer solution of dopamine, wherein the pH value is 5-12, and dissolving MOF-Ag or MOF-Cu in the dopamine solution to obtain a solution 1;
3) respectively preparing a polylysine solution and an anticoagulant solution by using normal saline or PBS buffer solution, and then mixing the anticoagulant solution and the polylysine solution to obtain a solution 2;
4) connecting an extracorporeal blood circulation pipeline with a solution 1, reacting at 10-30 ℃ for 1-24 h, introducing ultrapure water for cleaning for 1-3 times after the reaction is finished, then introducing a solution 2 into the pipeline, reacting at 10-30 ℃ for 1-24 h, introducing ultrapure water for cleaning for 1-3 times after the reaction is finished, and then drying the pipeline, wherein the inner surface of the pipeline is attached with a coating which is double modified by an anticoagulant and a metal-organic framework compound.
3. The method of claim 2, wherein: the step 1) of preparing the metal-organic framework compound comprises the following specific steps:
preparing 0.05-0.5 g/ml of anhydrous ethanol solution of trimesic acid, preparing 0.05-0.5 g/ml of silver nitrate or copper nitrate solution by using ultrapure water, mixing the trimesic acid solution and the silver nitrate or copper nitrate solution in a volume ratio of 2-4: 1, mechanically stirring for 8-16 h, performing suction filtration on the obtained product, and repeatedly washing by using the anhydrous ethanol and the ultrapure water to obtain pure silver trimesate or copper trimesate for later use.
4. The method of claim 3, wherein: the concentration of the trimesic acid is equal to that of the silver nitrate or copper nitrate solution, and the volume ratio of the trimesic acid solution to the silver nitrate or copper nitrate solution is 3: 1.
5. The method of claim 2, wherein: in the step 2), the concentration of the dopamine solution is 1 mg/ml-10 mg/ml, and the concentration of silver trimesate or copper trimesate in the solution 1 is 0.1-2 mg/ml;
preferably, the concentration of the dopamine solution is 2mg/ml, and the concentration of the silver trimesate or the copper trimesate in the solution 1 is 0.5-2 mg/ml.
6. The method of claim 2, wherein: in the step 3), 0.1-1 mg/ml polylysine solution is prepared, 5-10 mg/ml anticoagulant solution is prepared, and then the anticoagulant solution and the polylysine solution are mixed in a volume ratio of 1-3: 1 to obtain a solution 2, so that the solution can be used in the on-site preparation.
7. The method of claim 6, wherein: in the step 3), 0.5mg/ml polylysine solution is prepared, 5-10 mg/ml anticoagulant solution is prepared, and then the anticoagulant solution and the polylysine solution are mixed in a volume ratio of 1: 1 to obtain a solution 2.
8. The method of claim 2, wherein: in the step 4), the extracorporeal blood circulation pipeline is made of PVC, and the solution 1 and the solution 2 are introduced and then react at 25 ℃ for 12-24 hours.
9. An anticoagulant and metal-organic framework compound double-modified extracorporeal blood circulation pipeline, which is characterized in that: the extracorporeal blood circulation line having a coating according to claim 1 on an inner wall thereof,
preferably, the coating is applied to the inner wall surface of the pipeline by the method of any one of claims 2 to 8.
10. The extracorporeal blood circuit of claim 9, wherein: the extracorporeal blood circulation pipeline is made of polyvinyl chloride, polyurethane, silica gel or polytetrafluoroethylene, preferably polyvinyl chloride.
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