CN112089887A - Antithrombotic artificial blood vessel with excellent biocompatibility - Google Patents
Antithrombotic artificial blood vessel with excellent biocompatibility Download PDFInfo
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- CN112089887A CN112089887A CN202011037746.1A CN202011037746A CN112089887A CN 112089887 A CN112089887 A CN 112089887A CN 202011037746 A CN202011037746 A CN 202011037746A CN 112089887 A CN112089887 A CN 112089887A
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/507—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
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- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
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- C08G18/66—Compounds of groups C08G18/42, C08G18/48, or C08G18/52
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- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/68—Polyesters containing atoms other than carbon, hydrogen and oxygen
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- C08G63/6854—Polyesters containing atoms other than carbon, hydrogen and oxygen containing nitrogen derived from polycarboxylic acids and polyhydroxy compounds
- C08G63/6856—Dicarboxylic acids and dihydroxy compounds
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- D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
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- D01D5/0015—Electro-spinning characterised by the initial state of the material
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- D01D5/00—Formation of filaments, threads, or the like
- D01D5/0007—Electro-spinning
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- D01F6/58—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from homopolycondensation products
- D01F6/70—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from homopolycondensation products from polyurethanes
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- D04H1/00—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres
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- D04H1/728—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres characterised by the method of forming fleeces or layers, e.g. reorientation of fibres the fibres being randomly arranged by electro-spinning
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- D04H1/00—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres
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- D04H1/76—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres characterised by the method of forming fleeces or layers, e.g. reorientation of fibres otherwise than in a plane, e.g. in a tubular way
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- D04H3/00—Non-woven fabrics formed wholly or mainly of yarns or like filamentary material of substantial length
- D04H3/02—Non-woven fabrics formed wholly or mainly of yarns or like filamentary material of substantial length characterised by the method of forming fleeces or layers, e.g. reorientation of yarns or filaments
- D04H3/07—Non-woven fabrics formed wholly or mainly of yarns or like filamentary material of substantial length characterised by the method of forming fleeces or layers, e.g. reorientation of yarns or filaments otherwise than in a plane, e.g. in a tubular way
- D04H3/073—Hollow cylinder shaped
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/42—Anti-thrombotic agents, anticoagulants, anti-platelet agents
Abstract
The invention discloses an antithrombotic artificial blood vessel with excellent biocompatibility, which is characterized in that the preparation method of the antithrombotic artificial blood vessel comprises the following steps: preparation of poly 2,5 furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester, (di) antithrombotic modification of poly 2,5 furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester, (tri) preparation of vascular material, and (tetra) preparation of artificial blood vessel. The invention also discloses the antithrombotic artificial blood vessel prepared by the preparation method. The anti-thrombus artificial blood vessel prepared by the invention has excellent biocompatibility, anti-thrombus property, fatigue resistance, wear resistance, high elasticity, high strength and compliance, can ensure the long-time patency rate of the artificial blood vessel, and can prevent the artificial blood vessel from being bent into a dead angle.
Description
Technical Field
The invention relates to the technical field of artificial human organs, in particular to an anti-thrombus artificial blood vessel and a preparation method thereof.
Background
In recent years, with the pace of life increasing, the dual pressure from work and life increasing, the problem of environmental pollution becoming more and more serious, and the number of patients suffering from cardiovascular diseases increasing and the trend toward younger patients is also being presented. Cardiovascular diseases are one of the common diseases endangering human health, and one of the effective means for treating more serious cardiovascular diseases is blood vessel transplantation. In medicine, the dead artery blood vessel is generally replaced by the venous blood vessel, but the source of the blood vessel is limited, so that the artificial blood vessel is a substitute for a plurality of severely-narrow or occlusive blood vessels in clinic.
The artificial blood vessel is mainly used for replacing and repairing human tissue blood vessels. The artificial blood vessels which are used commercially at present mainly comprise terylene artificial blood vessels, expanded polytetrafluoroethylene artificial blood vessels and silk artificial blood vessels. The dacron artificial blood vessel is the earliest used blood vessel material, and is successfully used for replacing a large blood vessel for a long time due to high patency rate, but cannot completely meet the manufacturing requirement of a small-caliber artificial blood vessel. The expanded polytetrafluoroethylene artificial blood vessel has good biocompatibility and anticoagulation, but has poor compliance and extremely poor long-term patency rate. The silk artificial blood vessel is easy to shrink due to unstable spiral shrinkage, poor in shape retention and low in strength, so that the clinical application is limited. Polyurethane artificial blood vessels are developed in recent years, have excellent biocompatibility, fatigue resistance, wear resistance, high elasticity and high strength, but have aging degradation and calcification phenomena in vivo in the long-term use process, and have cracks or even complete damage, so the polyurethane artificial blood vessels cannot meet the high standard of artificial blood vessel clinical application at present.
Therefore, it is very important to develop an artificial blood vessel which has a simple preparation process, can ensure the patency of the artificial blood vessel for a long time, prevents the artificial blood vessel from being bent into a dead angle, and has good strength, biocompatibility, antithrombotic property and compliance.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides the antithrombotic artificial blood vessel and the preparation method thereof, and the preparation method is simple and feasible, has easily obtained raw materials and low preparation cost, and is suitable for commercial production; the prepared anti-thrombus artificial blood vessel has excellent biocompatibility, anti-thrombus property, fatigue resistance, wear resistance, high elasticity, high strength and compliance, can ensure the long-time patency rate of the artificial blood vessel, and can prevent the artificial blood vessel from being bent into a dead angle.
In order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows: a preparation method of an antithrombotic artificial blood vessel comprises the following steps:
preparation of poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester): dissolving 2, 5-furandicarboxylic acid in an organic solvent, adding oxalyl chloride, stirring and reacting for 4-6 hours at room temperature, then performing rotary evaporation to remove the solvent to obtain an intermediate product, adding the obtained intermediate product, a catalyst A and bis (2-hydroxyethyl) dimethylammonium chloride into tetrahydrofuran, stirring and reacting for 20-25 hours at 30-40 ℃, then adding tick anticoagulant peptide, continuing stirring for 3-5 hours, then precipitating in acetone, performing suction filtration, washing for 3-5 times by using dichloromethane, and then performing rotary evaporation to remove the dichloromethane to obtain poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride;
II, antithrombogenic modification of poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester): soaking the poly 2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester prepared in the step I in an anticoagulant aqueous solution with the mass fraction of 5-10% at 50-60 ℃ for 10-15 hours, taking out, washing with water for 3-5 times, and placing in a vacuum drying oven for drying at 90-100 ℃ for 10-15 hours to obtain the antithrombotic poly 2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester;
III, preparation of the vascular material: adding 2,2' -diphenylmethane diisocyanate and tetrafluorobutanediol into a three-neck flask with a stirring device, adding into a high-boiling-point solvent, stirring and reacting for 3.5-4.5 hours at 65-75 ℃ under the atmosphere of nitrogen or inert gas, then adding a catalyst B, heating to 85-95 ℃, stirring and reacting for 8-10 hours, then adding the antithrombotic poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium ester prepared by the step II, continuously stirring and reacting for 3-5 hours, cooling to room temperature after the reaction is finished, then precipitating in acetone, carrying out suction filtration, washing the product for 3-5 times with ethanol, and then carrying out rotary evaporation to remove the ethanol, thus obtaining the vascular material;
IV, preparation of artificial blood vessels: and (3) dissolving the vascular material prepared in the step (III) in hexafluoroisopropanol, stirring for 8-10 hours at 60-80 ℃ to obtain a spinning solution, injecting the spinning solution into electrostatic spinning equipment for spinning, ejecting formed fibers from a spinning nozzle of the electrostatic spinning equipment, adjusting a receiving device to obtain a polymer fiber layer, and taking the polymer fiber layer down from the receiving device to obtain the artificial blood vessel.
Preferably, the mass ratio of the 2, 5-furandicarboxylic acid, the organic solvent, the oxalyl chloride, the catalyst A, the bis (2-hydroxyethyl) dimethylammonium chloride, the tetrahydrofuran and the tick anticoagulant peptide in the step I is 1 (5-8):1.63:0.3:1.1 (5-8): 0.1.
Preferably, the organic solvent is selected from one or more of dichloromethane, tetrahydrofuran, acetone and acetonitrile.
Preferably, the catalyst A is selected from one or more of triethylamine, anhydrous pyridine and 4-dimethylaminopyridine.
Preferably, the mass ratio of the poly 2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester to the anticoagulant in the aqueous solution in the step II is 1 (10-20).
Preferably, the anticoagulant is one or more selected from ethylenediamine tetraacetic acid, sodium oxalate, heparin and sodium citrate.
Preferably, the mass ratio of the 2,2' -diphenylmethane diisocyanate, the tetrafluorobutanediol, the high-boiling point solvent, the catalyst B and the antithrombotic poly (2-hydroxyethyl) dimethyl ammonium salt of 2, 5-furandicarboxylic acid in the step III is 1:1.56 (10-15): 0.2-0.4: 2.
Preferably, the catalyst B is one or more selected from dibutyltin dilaurate, stannous octoate, triethylamine, ethylenediamine, triethanolamine and triethylenediamine.
Preferably, the high boiling point solvent is selected from one or more of dimethyl sulfoxide, N-dimethylformamide and N-methylpyrrolidone.
Preferably, the inert gas is selected from one or more of helium, neon and argon.
Preferably, the mass ratio of the blood vessel material to the hexafluoroisopropanol in the step IV is 1 (2.5-5).
Preferably, the parameters of the electrostatic spinning equipment during spinning are as follows: the voltage of a spinning nozzle is 15-25kV, and the flow rate of the solution is 3-8 mL/h; the receiving distance between the receiving device and the spinneret is 15-35 cm; double electrodes are prepared in the receiving device and used as receiving electrodes, the axes of the double electrodes are arranged in parallel on the same horizontal line, the diameter of each electrode in the double electrodes is 10-20mm, the distance between the double electrodes is 5-10cm, and the double electrodes synchronously rotate in the same direction; the method for adjusting the receiving device of the electrostatic spinning equipment and respectively obtaining the polymer fiber layers by double electrodes comprises the following steps: and connecting the double electrodes in the receiving device with 1-3kV negative pressure, and receiving for 10-40min to obtain the polymer fiber layer.
An antithrombotic artificial blood vessel is prepared by the preparation method of the antithrombotic artificial blood vessel.
Adopt the produced beneficial effect of above-mentioned technical scheme to lie in:
1) the anti-thrombus artificial blood vessel provided by the invention has the advantages of simple and feasible preparation method, easily available raw materials and low preparation cost, and is suitable for commercial production.
2) The anti-thrombus artificial blood vessel provided by the invention has excellent biocompatibility, thrombus resistance, fatigue resistance, wear resistance, high elasticity, high strength and compliance, can ensure the patency rate of the artificial blood vessel for a long time, and can prevent the artificial blood vessel from being bent into a dead angle.
3) The anti-thrombus artificial blood vessel provided by the invention combines the advantages of polyester, fluoropolymer and polyurethane, firstly prepares poly 2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester and fluorinated polyurethane through polycondensation, and then couples the poly 2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester and the fluorinated polyurethane through the coupling reaction of the end groups in the form of chemical bonds, thereby being beneficial to solving the problem of phase separation between blends; the introduction of the furan structure is favorable for improving the biocompatibility; cations are introduced into the main chain of the molecule, which is favorable for resisting thrombus; the introduction of fluorine structure is favorable for improving the comprehensive performance of blood vessels.
4) The anti-thrombus artificial blood vessel provided by the invention is added with tick anticoagulant peptide, and is connected with a macromolecular chain by a chemical reaction with the end group of the molecular chain, so that the effects of enhancing biocompatibility and resisting thrombus are achieved, and the structures have synergistic effect, so that the prepared artificial blood vessel has excellent comprehensive performance.
Detailed Description
In order to make the technical solutions of the present invention better understood and make the above features, objects, and advantages of the present invention more comprehensible, the present invention is further described with reference to the following examples. The examples are intended to illustrate the invention only and are not intended to limit the scope of the invention.
The starting materials described in the following examples of the invention are from Mobei (Shanghai) Biotech limited.
Example 1
A preparation method of an antithrombotic artificial blood vessel comprises the following steps:
preparation of poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester): dissolving 10g of 2, 5-furandicarboxylic acid in 50g of dichloromethane, adding 16.3g of oxalyl chloride, stirring and reacting at room temperature for 4 hours, performing rotary evaporation to remove dichloromethane to obtain an intermediate product, adding the obtained intermediate product, 3g of triethylamine and 11g of bis (2-hydroxyethyl) dimethylammonium chloride into 50g of tetrahydrofuran, performing rotary reaction at 30 ℃ for 20 hours, adding 1g of tick anticoagulant peptide, continuing stirring for 3 hours, precipitating in acetone, performing suction filtration, washing with dichloromethane for 3 times, and performing rotary evaporation to remove dichloromethane to obtain poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride;
II, antithrombogenic modification of poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester): soaking 10g of poly 2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester prepared in the step I in 100g of ethylenediaminetetraacetic acid aqueous solution with the mass fraction of 5% at 50 ℃ for 10 hours, taking out, washing with water for 3 times, and placing in a vacuum drying oven for drying at 90 ℃ for 10 hours to obtain antithrombotic poly 2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium salt ester;
III, preparation of the vascular material: adding 10g of 2,2' -diphenylmethane diisocyanate and 15.6g of tetrafluorobutanediol into a three-neck flask with a stirring device, adding 100g of dimethyl sulfoxide, stirring and reacting for 3.5 hours at 65 ℃ under a nitrogen atmosphere, then adding 2g of dibutyltin dilaurate, heating to 85 ℃, stirring and reacting for 8 hours, then adding 20g of antithrombotic poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethyl ammonium salt ester prepared in the step II, continuously stirring and reacting for 3 hours, cooling to room temperature after the reaction is finished, then precipitating in acetone, carrying out suction filtration, washing the product for 3 times by using ethanol, and then carrying out rotary evaporation to remove the ethanol, thus obtaining the vascular material;
IV, preparation of artificial blood vessels: dissolving 10g of the vascular material prepared in the step III in 25g of hexafluoroisopropanol, stirring for 8 hours at 60 ℃ to obtain a spinning solution, injecting the spinning solution into electrostatic spinning equipment for spinning, ejecting the formed fiber from a spinning nozzle of the electrostatic spinning equipment, adjusting a receiving device to obtain a polymer fiber layer, and taking down the polymer fiber layer from the receiving device to obtain the artificial blood vessel; the parameters of the electrostatic spinning equipment during spinning are set as follows: the voltage of a spinning nozzle is 15kV, and the flow rate of the solution is 3 mL/h; the receiving distance between the receiving device and the spinneret is 15 cm; double electrodes are prepared in the receiving device and used as receiving electrodes, the axes of the double electrodes are arranged on the same horizontal line in parallel, the diameter of each electrode in the double electrodes is 10mm, the distance between the double electrodes is 5cm, and the double electrodes rotate synchronously in the same direction; the method for adjusting the receiving device of the electrostatic spinning equipment and respectively obtaining the polymer fiber layers by double electrodes comprises the following steps: and connecting the double electrodes in the receiving device with 1kV negative pressure, and receiving for 10min to obtain the polymer fiber layer.
An antithrombotic artificial blood vessel is prepared by the preparation method of the antithrombotic artificial blood vessel.
Example 2
A preparation method of an antithrombotic artificial blood vessel comprises the following steps:
preparation of poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester): dissolving 10g of 2, 5-furandicarboxylic acid in 60g of tetrahydrofuran, adding 16.3g of oxalyl chloride into the tetrahydrofuran, stirring the mixture at room temperature for reaction for 4.5 hours, performing rotary evaporation to remove tetrahydrofuran to obtain an intermediate product, adding the obtained intermediate product, 3g of anhydrous pyridine and 11g of bis (2-hydroxyethyl) dimethylammonium chloride into 60g of tetrahydrofuran, stirring the mixture at 33 ℃ for reaction for 22 hours, adding 1g of tick anticoagulant peptide into the mixture, continuing stirring the mixture for 3.5 hours, precipitating the mixture in acetone, performing suction filtration, washing the mixture for 3 to 5 times by using dichloromethane, and performing rotary evaporation to remove the dichloromethane to obtain poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride;
II, antithrombogenic modification of poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester): soaking 10g of poly 2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester prepared in the step I in 120g of sodium oxalate aqueous solution with the mass fraction of 6% at 52 ℃ for 12 hours, taking out, washing with water for 4 times, and placing in a vacuum drying oven at 93 ℃ for drying for 12 hours to obtain antithrombotic poly 2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium salt ester;
III, preparation of the vascular material: adding 10g of 2,2' -diphenylmethane diisocyanate and 15.6g of tetrafluorobutanediol into a three-neck flask with a stirring device, adding 125g of N, N-dimethylformamide, stirring and reacting for 3.8 hours at 68 ℃ under helium atmosphere, then adding 2.5g of stannous octoate, heating to 87 ℃, stirring and reacting for 8.5 hours, then adding 20g of antithrombotic poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium ester prepared by the step II, continuing stirring and reacting for 3.5 hours, cooling to room temperature after the reaction is finished, then precipitating in acetone, carrying out suction filtration, washing a product for 4 times by using ethanol, and then carrying out rotary evaporation to remove the ethanol, thus obtaining the vascular material;
IV, preparation of artificial blood vessels: dissolving 10g of the vascular material prepared in the step III in 30g of hexafluoroisopropanol, stirring for 8.5 hours at 65 ℃ to obtain a spinning solution, injecting the spinning solution into electrostatic spinning equipment for spinning, ejecting the formed fiber from a spinning nozzle of the electrostatic spinning equipment, adjusting a receiving device to obtain a polymer fiber layer, and taking down the polymer fiber layer from the receiving device to obtain the artificial blood vessel; the parameters of the electrostatic spinning equipment during spinning are set as follows: the voltage of a spinning nozzle is 18kV, and the flow rate of the solution is 5 mL/h; the receiving distance between the receiving device and the spinneret is 19 cm; double electrodes are prepared in the receiving device and used as receiving electrodes, the axes of the double electrodes are arranged on the same horizontal line in parallel, the diameter of each electrode in the double electrodes is 13mm, the distance between the double electrodes is 6cm, and the double electrodes rotate synchronously in the same direction; the method for adjusting the receiving device of the electrostatic spinning equipment and respectively obtaining the polymer fiber layers by double electrodes comprises the following steps: and connecting the double electrodes in the receiving device with 1.5kV negative pressure, and receiving for 15min to obtain the polymer fiber layer.
An antithrombotic artificial blood vessel is prepared by the preparation method of the antithrombotic artificial blood vessel.
Example 3
A preparation method of an antithrombotic artificial blood vessel comprises the following steps:
preparation of poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester): dissolving 10g of 2, 5-furandicarboxylic acid in 70g of acetone, adding 16.3g of oxalyl chloride, stirring at room temperature for reaction for 5 hours, performing rotary evaporation to remove acetone to obtain an intermediate product, adding the obtained intermediate product, 3g of 4-dimethylaminopyridine and 11g of bis (2-hydroxyethyl) dimethylammonium chloride into 68g of tetrahydrofuran, stirring at 35 ℃ for reaction for 23 hours, adding 1g of tick anticoagulant peptide into the intermediate product, continuing stirring for 4 hours, precipitating in acetone, performing suction filtration, washing with dichloromethane for 4 times, and performing rotary evaporation to remove dichloromethane to obtain poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester;
II, antithrombogenic modification of poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester): soaking 10g of poly 2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester prepared in the step I in 150g of heparin aqueous solution with the mass fraction of 7% at the temperature of 55 ℃ for 13 hours, taking out the poly 2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester, washing the poly 2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester with water for 5 times, and placing the washed poly 2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester in a vacuum drying oven at the temperature of 95 ℃ for 13 hours;
III, preparation of the vascular material: adding 10g of 2,2' -diphenylmethane diisocyanate and 15.6g of tetrafluorobutanediol into a three-neck flask with a stirring device, adding 135g of N-methylpyrrolidone, stirring and reacting for 4 hours at 70 ℃ under the neon atmosphere, then adding 3g of triethylamine, heating to 90 ℃, stirring and reacting for 9 hours, then adding 20g of antithrombotic poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethyl ammonium salt ester prepared in the step II, continuously stirring and reacting for 4 hours, cooling to room temperature after the reaction is finished, then precipitating in acetone, carrying out suction filtration, washing the product for 5 times by using ethanol, and then carrying out rotary evaporation to remove the ethanol, thus obtaining the vascular material;
IV, preparation of artificial blood vessels: dissolving 10g of the vascular material prepared in the step III in 40g of hexafluoroisopropanol, stirring for 9 hours at 70 ℃ to obtain a spinning solution, injecting the spinning solution into electrostatic spinning equipment for spinning, ejecting formed fibers from a spinning nozzle of the electrostatic spinning equipment, adjusting a receiving device to obtain a polymer fiber layer, and taking down the polymer fiber layer from the receiving device to obtain the artificial blood vessel; the parameters of the electrostatic spinning equipment during spinning are set as follows: the voltage of a spinning nozzle is 20kV, and the flow rate of the solution is 6 mL/h; the receiving distance between the receiving device and the spinneret is 25 cm; double electrodes are prepared in the receiving device and used as receiving electrodes, the axes of the double electrodes are arranged on the same horizontal line in parallel, the diameter of each electrode in the double electrodes is 16mm, the distance between the double electrodes is 8cm, and the double electrodes rotate synchronously in the same direction; the method for adjusting the receiving device of the electrostatic spinning equipment and respectively obtaining the polymer fiber layers by double electrodes comprises the following steps: and connecting the double electrodes in the receiving device with 2kV negative pressure, and receiving for 25min to obtain the polymer fiber layer.
An antithrombotic artificial blood vessel is prepared by the preparation method of the antithrombotic artificial blood vessel.
Example 4
A preparation method of an antithrombotic artificial blood vessel comprises the following steps:
preparation of poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester): dissolving 10g of 2, 5-furandicarboxylic acid in 75g of an organic solvent, adding 16.3g of oxalyl chloride, stirring and reacting at room temperature for 5.5 hours, then performing rotary evaporation to remove the solvent to obtain an intermediate product, adding the obtained intermediate product, a catalyst A3g and 11g of bis (2-hydroxyethyl) dimethylammonium chloride into 75g of tetrahydrofuran, stirring and reacting at 38 ℃ for 24 hours, adding 1g of tick anticoagulant peptide into the intermediate product, continuing stirring for 4.5 hours, then precipitating in acetone, performing suction filtration, washing with dichloromethane for 4 times, and then performing rotary evaporation to remove dichloromethane to obtain poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride; the organic solvent is a mixture formed by mixing dichloromethane, tetrahydrofuran, acetone and acetonitrile according to a mass ratio of 1:2:1: 2; the catalyst A is a mixture formed by mixing triethylamine, anhydrous pyridine and 4-dimethylamino pyridine according to the mass ratio of 3:2: 3;
II, antithrombogenic modification of poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester): soaking 10g of poly 2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester prepared in the step I in 185g of anticoagulant aqueous solution with the mass fraction of 9% at 58 ℃ for 14.5 hours, taking out, washing with water for 5 times, and placing in a vacuum drying oven at 98 ℃ for drying for 14.5 hours to obtain antithrombotic poly 2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium salt ester; the anticoagulant is a mixture formed by mixing ethylene diamine tetraacetic acid, sodium oxalate, heparin and sodium citrate according to a mass ratio of 1:2:1: 3;
III, preparation of the vascular material: adding 10g of 2,2' -diphenylmethane diisocyanate and 15.6g of tetrafluorobutanediol into a three-neck flask with a stirring device, adding 145g of a high-boiling-point solvent, stirring and reacting for 4.4 hours at 73 ℃ under argon atmosphere, then adding 3.5g of a catalyst, heating to 94 ℃, stirring and reacting for 9.5 hours, then adding 20g of the antithrombotic poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium ester prepared in the step II, continuing stirring and reacting for 4.5 hours, cooling to room temperature after the reaction is finished, then precipitating in acetone, carrying out suction filtration, washing the product with ethanol for 5 times, and then carrying out rotary evaporation to remove the ethanol, thus obtaining the vascular material; the catalyst B is a mixture formed by mixing dibutyltin dilaurate, ethylenediamine, triethanolamine and triethylenediamine according to a mass ratio of 2:1:1: 3; the high-boiling-point solvent is a mixture formed by mixing dimethyl sulfoxide, N-dimethylformamide and N-methylpyrrolidone according to the mass ratio of 2:1: 4;
IV, preparation of artificial blood vessels: dissolving 10g of the vascular material prepared in the step III in 48g of hexafluoroisopropanol, stirring at 78 ℃ for 9.5 hours to obtain a spinning solution, injecting the spinning solution into electrostatic spinning equipment for spinning, ejecting the formed fiber from a spinning nozzle of the electrostatic spinning equipment, adjusting a receiving device to obtain a polymer fiber layer, and taking down the polymer fiber layer from the receiving device to obtain the artificial blood vessel; the parameters of the electrostatic spinning equipment during spinning are set as follows: the voltage of a spinning nozzle is 24kV, and the flow rate of the solution is 7 mL/h; the receiving distance between the receiving device and the spinneret is 34 cm; double electrodes are prepared in the receiving device and used as receiving electrodes, the axes of the double electrodes are arranged on the same horizontal line in parallel, the diameter of each electrode in the double electrodes is 18mm, the distance between the double electrodes is 9cm, and the double electrodes synchronously rotate in the same direction; the method for adjusting the receiving device of the electrostatic spinning equipment and respectively obtaining the polymer fiber layers by double electrodes comprises the following steps: and connecting the double electrodes in the receiving device with 2.5kV negative pressure, and receiving for 35min to obtain the polymer fiber layer.
An antithrombotic artificial blood vessel is prepared by the preparation method of the antithrombotic artificial blood vessel.
Example 5
A preparation method of an antithrombotic artificial blood vessel comprises the following steps:
preparation of poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester): dissolving 10g of 2, 5-furandicarboxylic acid in 80g of acetonitrile, adding 16.3g of oxalyl chloride, stirring at room temperature for reaction for 6 hours, carrying out rotary evaporation to remove the solvent to obtain an intermediate product, adding the obtained intermediate product, 3g of 4-dimethylaminopyridine and 11g of bis (2-hydroxyethyl) dimethylammonium chloride into 80g of tetrahydrofuran, stirring at 40 ℃ for reaction for 25 hours, adding 1g of tick anticoagulant peptide into the intermediate product, continuing stirring for 5 hours, precipitating in acetone, carrying out suction filtration, washing with dichloromethane for 5 times, and carrying out rotary evaporation to remove dichloromethane to obtain poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride;
II, antithrombogenic modification of poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester): soaking 10g of poly 2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester prepared in the step I in 200g of sodium citrate aqueous solution with the mass fraction of 10% at the temperature of 60 ℃ for 15 hours, taking out, washing with water for 5 times, and placing in a vacuum drying oven for drying at the temperature of 100 ℃ for 15 hours to obtain antithrombotic poly 2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium salt ester;
III, preparation of the vascular material: adding 10g of 2,2' -diphenylmethane diisocyanate and 15.6g of tetrafluorobutanediol into a three-neck flask with a stirring device, adding 150g of N, N-dimethylformamide, stirring and reacting for 4.5 hours at 75 ℃ under the nitrogen atmosphere, then adding 4g of triethylenediamine, heating to 95 ℃, stirring and reacting for 10 hours, then adding 20g of the antithrombotic poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium ester prepared by the step II, continuing stirring and reacting for 5 hours, cooling to room temperature after the reaction is finished, then precipitating in acetone, carrying out suction filtration, washing the product with ethanol for 5 times, and then carrying out rotary evaporation to remove the ethanol, thus obtaining the vascular material;
IV, preparation of artificial blood vessels: dissolving 10g of the vascular material prepared in the step III in 50g of hexafluoroisopropanol, stirring for 10 hours at 80 ℃ to obtain a spinning solution, injecting the spinning solution into electrostatic spinning equipment for spinning, ejecting the formed fiber from a spinning nozzle of the electrostatic spinning equipment, adjusting a receiving device to obtain a polymer fiber layer, and taking down the polymer fiber layer from the receiving device to obtain the artificial blood vessel; the parameters of the electrostatic spinning equipment during spinning are set as follows: the voltage of a spinning nozzle is 25kV, and the flow rate of the solution is 8 mL/h; the receiving distance between the receiving device and the spinneret is 35 cm; double electrodes are prepared in the receiving device and used as receiving electrodes, the axes of the double electrodes are arranged on the same horizontal line in parallel, the diameter of each electrode in the double electrodes is 20mm, the distance between the double electrodes is 10cm, and the double electrodes synchronously rotate in the same direction; the method for adjusting the receiving device of the electrostatic spinning equipment and respectively obtaining the polymer fiber layers by double electrodes comprises the following steps: and connecting the double electrodes in the receiving device with 3kV negative pressure, and receiving for 40min to obtain the polymer fiber layer.
An antithrombotic artificial blood vessel is prepared by the preparation method of the antithrombotic artificial blood vessel.
Comparative example
The invention discloses an artificial blood vessel, which is prepared by adopting an artificial blood vessel material prepared by a preparation method disclosed in Chinese patent CN 105294971A as a material and a preparation method in the embodiment 1 of the invention.
The artificial blood vessels prepared in examples 1 to 5 and comparative example were subjected to performance tests, the test results are shown in table 1, and the test methods are as follows:
(1) elongation at break, tensile strength: testing according to the test method of GB/T1039-1992;
(2) calcium recovery time: the test is carried out by referring to a test method of the calcium recovery time in Chinese invention patent CN 103087219B;
(3) hemolysis: tested according to the test method of ISO TR 7405.
TABLE 1
| Item | Elongation at Break (%) | Tensile Strength (MPa) | Recalcification time(s) | Hemolytic property (%) |
| Example 1 | 720 | 24 | 468 | 0.05 |
| Example 2 | 750 | 26 | 473 | 0.04 |
| Example 3 | 770 | 29 | 485 | 0.02 |
| Example 4 | 785 | 32 | 490 | 0.01 |
| Example 5 | 800 | 35 | 500 | 0.01 |
| Comparative example | 550 | 16 | 273 | 1.05 |
As can be seen from table 1, the antithrombotic artificial blood vessel disclosed in the embodiments of the present invention has more excellent mechanical properties, biocompatibility and antithrombotic properties.
The foregoing shows and describes the general principles, essential features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the invention, but that various changes and modifications may be made without departing from the spirit and scope of the invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (10)
1. An antithrombotic artificial blood vessel having excellent biocompatibility, characterized by comprising the steps of:
preparation of poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester): dissolving 2, 5-furandicarboxylic acid in an organic solvent, adding oxalyl chloride, stirring and reacting for 4-6 hours at room temperature, then performing rotary evaporation to remove the solvent to obtain an intermediate product, adding the obtained intermediate product, a catalyst A and bis (2-hydroxyethyl) dimethylammonium chloride into tetrahydrofuran, stirring and reacting for 20-25 hours at 30-40 ℃, then adding tick anticoagulant peptide, continuing stirring for 3-5 hours, then precipitating in acetone, performing suction filtration, washing for 3-5 times by using dichloromethane, and then performing rotary evaporation to remove the dichloromethane to obtain poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride;
II, antithrombogenic modification of poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester): soaking the poly 2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester prepared in the step I in an anticoagulant aqueous solution with the mass fraction of 5-10% at 50-60 ℃ for 10-15 hours, taking out, washing with water for 3-5 times, and placing in a vacuum drying oven for drying at 90-100 ℃ for 10-15 hours to obtain the antithrombotic poly 2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride ester;
III, preparation of the vascular material: adding 2,2' -diphenylmethane diisocyanate and tetrafluorobutanediol into a three-neck flask with a stirring device, adding into a high-boiling-point solvent, stirring and reacting for 3.5-4.5 hours at 65-75 ℃ under the atmosphere of nitrogen or inert gas, then adding a catalyst B, heating to 85-95 ℃, stirring and reacting for 8-10 hours, then adding the antithrombotic poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium ester prepared by the step II, continuously stirring and reacting for 3-5 hours, cooling to room temperature after the reaction is finished, then precipitating in acetone, carrying out suction filtration, washing the product for 3-5 times with ethanol, and then carrying out rotary evaporation to remove the ethanol, thus obtaining the vascular material;
IV, preparation of artificial blood vessels: and (3) dissolving the vascular material prepared in the step (III) in hexafluoroisopropanol, stirring for 8-10 hours at 60-80 ℃ to obtain a spinning solution, injecting the spinning solution into electrostatic spinning equipment for spinning, ejecting formed fibers from a spinning nozzle of the electrostatic spinning equipment, adjusting a receiving device to obtain a polymer fiber layer, and taking the polymer fiber layer down from the receiving device to obtain the artificial blood vessel.
2. The antithrombotic artificial blood vessel as claimed in claim 1, wherein the mass ratio of 2,5 furandicarboxylic acid, organic solvent, oxalyl chloride, catalyst A, bis (2-hydroxyethyl) dimethylammonium chloride, tetrahydrofuran, and tick anticoagulant peptide in step I is 1 (5-8):1.63:0.3:1.1 (5-8): 0.1.
3. The antithrombotic artificial blood vessel as claimed in claim 1, wherein the organic solvent is selected from one or more of dichloromethane, tetrahydrofuran, acetone, and acetonitrile; the catalyst A is selected from one or more of triethylamine, anhydrous pyridine and 4-dimethylamino pyridine.
4. The antithrombotic artificial blood vessel as claimed in claim 1, wherein the mass ratio of the poly (2, 5-furandicarboxylic acid bis (2-hydroxyethyl) dimethylammonium chloride) to the anticoagulant in the aqueous solution in step ii is 1 (10-20); the anticoagulant is one or more selected from ethylenediamine tetraacetic acid, sodium oxalate, heparin and sodium citrate.
5. The thrombus-resistant artificial blood vessel with excellent biocompatibility as claimed in claim 1, wherein the mass ratio of 2,2' -diphenylmethane diisocyanate, tetrafluorobutanediol, high boiling point solvent, catalyst B, and antithrombotic poly (2-hydroxyethyl) dimethylammonium 2, 5-furandicarboxylate in step III is 1:1.56 (10-15): 0.2-0.4: 2.
6. The antithrombotic artificial blood vessel as claimed in claim 1, wherein in step iii, the catalyst B is one or more selected from dibutyltin dilaurate, stannous octoate, triethylamine, ethylenediamine, triethanolamine, and triethylenediamine.
7. The antithrombotic artificial blood vessel as claimed in claim 1, wherein the high boiling point solvent is selected from one or more of dimethylsulfoxide, N-dimethylformamide, and N-methylpyrrolidone; the inert gas is selected from one or more of helium, neon and argon.
8. The antithrombotic artificial blood vessel as claimed in claim 1, wherein the mass ratio of the blood vessel material to hexafluoroisopropanol in step IV is 1 (2.5-5).
9. The antithrombotic artificial blood vessel as claimed in claim 1, wherein the parameters of the electrospinning device during spinning are as follows: the voltage of a spinning nozzle is 15-25kV, and the flow rate of the solution is 3-8 mL/h; the receiving distance between the receiving device and the spinneret is 15-35 cm; double electrodes are prepared in the receiving device and used as receiving electrodes, the axes of the double electrodes are arranged in parallel on the same horizontal line, the diameter of each electrode in the double electrodes is 10-20mm, the distance between the double electrodes is 5-10cm, and the double electrodes synchronously rotate in the same direction.
10. The anti-thrombotic artificial blood vessel according to claim 1, wherein the receiving device of the electrostatic spinning device is adjusted, and the polymer fiber layers are obtained by the double electrodes respectively: and connecting the double electrodes in the receiving device with 1-3kV negative pressure, and receiving for 10-40min to obtain the polymer fiber layer.
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