Disclosure of Invention
The invention aims to solve the technical problems that the mechanical property of the material of the artificial valve prepared by the existing artificial valve preparation method can not meet the application requirement, and the material is slowly endothelialized and easily generates thrombus.
The technical scheme adopted by the invention for solving the technical problems is to provide a preparation method of a prosthetic valve, which comprises the following steps: carrying out hot-pressing compounding on at least two layers of shaped thermoplastic polyurethane micro-nanofiber membranes to obtain a prosthetic valve; or, performing hot-pressing compounding on at least two layers of thermoplastic polyurethane micro-nanofiber membranes to obtain a thermoplastic polyurethane micro-nanofiber composite membrane; and shaping the thermoplastic polyurethane micro-nanofiber composite membrane to obtain the artificial valve.
Preferably, the thermoplastic polyurethane micro-nanofiber membrane is prepared by a solution electrospinning method, and the solution electrospinning method comprises the following steps: s11: obtaining a thermoplastic polyurethane spinning solution; s12: and (2) performing electrostatic spinning on the thermoplastic polyurethane spinning solution to form the thermoplastic polyurethane micro-nanofiber membrane, wherein in the electrostatic spinning process, the voltage is 20 kV-50 kV, and the injection rate of the thermoplastic polyurethane spinning solution is 2 mL/h-10 mL/h.
Preferably, the solvent of the thermoplastic polyurethane spinning solution is at least one of N-N dimethylformamide, dichloromethane, trichloromethane, tetrahydrofuran, dibutone, hexafluoroisopropanol, acetone and toluene.
Preferably, the solution electrospinning method is needle-less electrospinning, single-needle electrospinning or multi-needle electrospinning.
Preferably, the thermoplastic polyurethane micro-nanofiber membrane is prepared by a melt electrospinning method, and the melt electrospinning method comprises the following steps: s21: adding thermoplastic polyurethane particles and an additive into an electrostatic spinning device, and heating to a molten state at the temperature of 180-240 ℃ to form a melt, wherein the mass ratio of the additive to the thermoplastic polyurethane particles is 4-10%, and the additive is at least one of polyethylene glycol, polyester glycol and derivatives thereof, polyether glycol and derivatives thereof, and tetrahydrofuran ether glycol; s22: and (3) performing electrostatic spinning on the melt to form the thermoplastic polyurethane micro-nanofiber membrane, wherein in the electrostatic spinning process, the voltage is 30 kV-50 kV, and the flow rate of the melt is 150 g/min-180 g/min.
Preferably, at least one of heparin sodium, dipyridamole, warfarin, aspirin, a platelet receptor blocker, ticlopidine and clopidogrel is loaded on the thermoplastic polyurethane micro-nanofiber membrane.
Preferably, the artificial valve is obtained by hot-pressing and compounding 2-20 layers of thermoplastic polyurethane micro-nanofiber membranes.
Preferably, in the hot-pressing compounding process, the pressure is 0.1MPa to 20MPa, and the heating temperature is 80 ℃ to 200 ℃.
Preferably, the thermoplastic polyurethane micro-nanofiber composite membrane is shaped by using a valve type mold to obtain the artificial valve.
The invention also provides a prosthetic valve which is prepared by the preparation method.
Preferably, the artificial valve at least comprises three layers of thermoplastic polyurethane micro-nanofiber membranes, and the pores of the thermoplastic polyurethane micro-nanofiber membrane in the middle layer are smaller than the pores of the thermoplastic polyurethane micro-nanofiber membranes in the two layers of the surface.
Preferably, the artificial valve at least comprises three layers of thermoplastic polyurethane micro-nanofiber membranes, and the thermoplastic polyurethane micro-nanofiber membrane in the middle layer is loaded with the medicine.
Compared with the prior art, the invention has the following beneficial effects: according to the artificial valve and the preparation method thereof, the micro-nano fiber membrane preparation technology and the hot press molding technology are combined, the artificial valve with the multi-layer micro-nano structure is prepared, the mechanical property of the prepared artificial valve is greatly improved compared with that of a single-layer thermoplastic polyurethane micro-nano fiber membrane, the prepared artificial valve can be stretched circularly without deformation, and has high elasticity, high mechanical strength and fatigue resistance, and the service life of the artificial valve is prolonged; when the artificial valve is in a human blood environment, the micro-nano pores on the surface enable endothelial cells to be easily adhered, and accelerate the endothelialization process of the artificial valve, thereby achieving the effect of reducing and even avoiding thrombosis.
Detailed Description
The present invention will be further described with reference to the following examples.
Aiming at the problems that the mechanical property of the material of the artificial valve prepared by the existing artificial valve preparation method can not meet the application requirement and the material is slowly endothelialized and easily generates thrombus, the invention firstly adopts the spinning technology to prepare the thermoplastic polyurethane micro-nano fiber membrane. Then, aiming at the defect that the thermoplastic polyurethane micro-nano fiber film prepared by the existing spinning process has low tensile strength, a hot press molding technology is used for compounding multiple layers of thermoplastic polyurethane micro-nano fiber films so as to enhance the mechanical strength.
Therefore, the invention provides a prosthetic valve with a micro-nano structure, which is obtained by hot-pressing and compounding multiple layers of thermoplastic polyurethane micro-nano fiber membranes, and the compounded prosthetic valve has the characteristics of high elasticity, tensile resistance, fatigue resistance and the like. The micro-nano structure on the surface of the polyurethane micro-nano fiber membrane is basically reserved after hot-pressing compounding, the structure of the gap is beneficial to the adhesion of endothelial cells to the artificial valve, and the endothelialization process of the artificial valve is accelerated, so that the effect of reducing the generation of thrombus is achieved. The preparation method of the artificial valve mainly comprises the following steps:
carrying out hot-pressing compounding on at least two layers of shaped thermoplastic polyurethane micro-nanofiber membranes to obtain the artificial valve; or, performing hot-pressing compounding on at least two layers of thermoplastic polyurethane micro-nanofiber membranes to obtain a thermoplastic polyurethane micro-nanofiber composite membrane; and shaping the thermoplastic polyurethane micro-nanofiber composite membrane to obtain the artificial valve, wherein the shaping comprises but is not limited to cutting, heat shaping, mold shaping and the like to obtain the required shape of the artificial valve. Preferably, the artificial valve is obtained by hot-pressing and compounding 2-20 layers of thermoplastic polyurethane micro-nanofiber membranes. In the hot-pressing compounding process, the applied pressure can be 0.1-20 MPa, and is preferably applied along a direction perpendicular to the thermoplastic polyurethane micro-nanofiber membrane. The heating temperature can be 80-200 ℃, the heating is stopped and the cooling is carried out after the heating is carried out for 1-30 minutes, and the artificial valve or the thermoplastic polyurethane micro-nano fiber composite membrane is obtained.
In one embodiment, the method for preparing the thermoplastic polyurethane micro-nanofiber membrane by adopting solution electrostatic spinning comprises the following steps:
s11: and obtaining the thermoplastic polyurethane spinning solution. Specifically, thermoplastic polyurethane particles are dissolved in a solvent system to form a spinning solution; the solvent of the thermoplastic polyurethane spinning solution is preferably at least one of N-N dimethylformamide, dichloromethane, chloroform, tetrahydrofuran, dibutone, hexafluoroisopropanol, acetone and toluene. In a specific embodiment, N-N dimethylformamide and dichloromethane are mixed according to a volume ratio of 1: 1-4: 1, uniformly mixing to obtain a mixed solution, and adding a heparin sodium solution with the concentration of 1mg/mL-100mg/mL according to 0.1-4% of the volume of the mixed solution to prepare a solvent system; and dissolving the thermoplastic polyurethane particles in the solvent system to prepare the thermoplastic polyurethane spinning solution. And at least one of dipyridamole, warfarin, aspirin, a platelet receptor blocker, ticlopidine and clopidogrel can be further added into the solvent system to form a drug-loaded thermoplastic polyurethane micro-nanofiber; certainly, in other embodiments, the drugs may not be added to form the non-drug-loaded thermoplastic polyurethane micro-nanofiber, which is not particularly limited in the present invention, and a person skilled in the art may add appropriate drugs according to specific needs and purposes.
S12: and adding the thermoplastic polyurethane spinning solution into an injector, wherein the injector can be a needle cylinder, is connected with high-voltage static electricity of 20 kV-50 kV, and injects the thermoplastic polyurethane spinning solution at the speed of 2 mL/h-10 mL/h to form the thermoplastic polyurethane micro-nanofiber. The solution electrostatic spinning mode is needle-free electrostatic spinning, single-needle electrostatic spinning or multi-needle electrostatic spinning. The single-needle spinning is carried out through one needle; the multi-needle spinning is to carry out spinning after a plurality of needles are arranged in a certain way; the pinhead-free spinning does not need a pinhead and a needle cylinder, when the electric field intensity exceeds a critical value, a large amount of jet flow is directly formed from an open free liquid level, the problem of pinhead blockage is avoided, and the spinning efficiency and the fiber yield are improved.
After the thermoplastic polyurethane micro-nanofiber membrane is obtained, a receiving device can be used for receiving the thermoplastic polyurethane micro-nanofiber membrane, and the distance between the receiving device and an injector is preferably 13-30 cm. Further, the receiving device is a valve-shaped mold, a thermoplastic polyurethane micro-nanofiber membrane with a valve shape is obtained, at least two layers of thermoplastic polyurethane micro-nanofiber membranes with valve shapes are subjected to hot pressing compounding, and then the artificial valve can be directly obtained without secondary processing and forming.
In another embodiment, the thermoplastic polyurethane micro-nanofiber membrane is prepared by a melt electrospinning method, and comprises the following steps:
s21: adding thermoplastic polyurethane particles and an additive into a melt electrostatic spinning device, and heating to a molten state at the temperature of 180-240 ℃ to form a melt, wherein the mass ratio of the additive to the thermoplastic polyurethane particles is 4-10%, and the additive is at least one of polyethylene glycol, polyester glycol and derivatives thereof, polyether glycol and derivatives thereof, and tetrahydrofuran ether glycol; the polyethylene glycol is polyethylene glycol (PEG-10000), namely the average molecular weight of the polyethylene glycol is 10000. The additive can reduce the viscosity of the polyurethane melt and improve the spinnability of the polyurethane melt. And at least one of heparin sodium, dipyridamole, warfarin, aspirin, a platelet receptor blocker, ticlopidine and clopidogrel can be further added into the melt to form a drug-loaded thermoplastic polyurethane micro-nanofiber; certainly, in other embodiments, the drugs may not be added to form the non-drug-loaded thermoplastic polyurethane micro-nanofiber, which is not particularly limited in the present invention, and a person skilled in the art may add appropriate drugs according to specific needs and purposes.
S22: and forming a polyurethane micro-nanofiber membrane from the melt through electrostatic spinning, wherein in the electrostatic spinning process, the spinning voltage is 30 kV-50 kV, and the flow rate of the melt is 150 g/min-180 g/min.
After the thermoplastic polyurethane micro-nanofiber membrane is obtained, a receiving device can be used for receiving the thermoplastic polyurethane micro-nanofiber membrane, the distance between the receiving device and the melt electrostatic spinning device is preferably 10-20cm, the thermoplastic polyurethane micro-nanofiber membrane with the valve shape is obtained, at least two layers of thermoplastic polyurethane micro-nanofiber membranes with the valve shape are subjected to hot pressing and compounding, and then the artificial valve can be directly obtained without secondary processing and forming.
Furthermore, the thermoplastic polyurethane micro-nano fiber membranes with different pores and loaded with different drugs or without drugs can be obtained by the thermoplastic polyurethane micro-nano fiber membranes of different layers through an electrostatic spinning method, and further, the pore size and the mechanical strength of the artificial valve can be controlled, the controlled release of various drugs can be realized, and the like through the sequencing and compounding of the different thermoplastic polyurethane micro-nano fiber membranes. If in an embodiment, the artificial valve at least comprises three layers of thermoplastic polyurethane micro-nanofiber membranes, the pore size of the thermoplastic polyurethane micro-nanofiber membrane in the middle layer is smaller than the pore size of the thermoplastic polyurethane micro-nanofiber membranes in the two layers of the surface, taking the three layers of thermoplastic polyurethane micro-nanofiber membranes as an example, the pore size of the second layer of thermoplastic polyurethane micro-nanofiber membrane is smaller, the pore size of the first layer and the pore size of the third layer of plastic polyurethane micro-nanofiber membrane on the surface are larger, the artificial valve with higher mechanical strength can be obtained after compounding, and meanwhile, because the pore size of the two layers of thermoplastic polyurethane micro-nanofiber membranes on the surface is larger, human cells are easy to invade to form tissues. In a pair of proportions, the maximum breaking strength of the composite membrane obtained by hot-pressing and compounding five layers of thermoplastic polyurethane micro-nano fiber membranes with the porosity of 79.31% and the length and width of 50mm multiplied by 10mm is 6.3N; the thermoplastic polyurethane micro-nanofiber membranes with the porosity of 79.31% in two layers, the porosity of 73.24% in three layers and the length and width of 50 multiplied by 10mm are subjected to hot pressing compounding, and the membranes with high porosity are arranged on the first layer and the fifth layer, so that the maximum breaking strength of the obtained composite membrane is 15.42N, and the mechanical strength of the composite membrane is greatly improved. In another embodiment, the artificial valve comprises at least three layers of thermoplastic polyurethane micro-nanofiber membranes, and the thermoplastic polyurethane micro-nanofiber membrane in the middle layer is loaded with the drug. Different medicines or the same medicine can be loaded on the thermoplastic polyurethane micro-nanofiber membranes of different layers, or medicines are loaded on the thermoplastic polyurethane micro-nanofiber membranes of partial layers, and because the middle layer is positioned at the innermost part of the artificial valve, the release speed of the medicines is slower compared with other layers, the medicines which need to be slowly released in vivo can be loaded on the middle layer, and small-molecule antithrombotic medicines such as aspirin, warfarin and the like are preferably loaded on the middle layer. In a proportion, the cumulative release rate of aspirin after the aspirin-loaded single-layer drug-loaded thermoplastic polyurethane micro-nanofiber membrane is released for 14 hours is 50-60%; the composite film is obtained by compounding the three layers of thermoplastic polyurethane micro-nano fiber films, aspirin is loaded in the middle layer, and the cumulative release rate of the aspirin is 20-30% after 14 hours of release. The aspirin in the middle layer diffuses from the interior of the thermoplastic polyurethane micro-nanofiber composite membrane to the surface and then is released, so that the release speed is low. In this embodiment, when the number of layers of the thermoplastic polyurethane micro-nanofiber membrane constituting the prosthetic valve is odd, the middle layer refers to the middle layer, for example, the middle layer of 5 layers is the third layer; when the number of the layers of the thermoplastic polyurethane micro-nanofiber membrane constituting the artificial valve is even, the middle layer refers to the two or any one of the two layers at the middle, for example, the middle layer of 6 layers is the third layer or/and the fourth layer. The invention is not particularly limited by the specific structure of each layer of the multiple layers of thermoplastic polyurethane micro-nanofiber membranes and the compounding arrangement sequence among the multiple layers of thermoplastic polyurethane micro-nanofiber membranes, and a person skilled in the art can flexibly select different thermoplastic polyurethane micro-nanofiber membranes according to the pores, mechanical strength, drug effect, drug release speed and the like required by a prosthetic valve product and perform sequencing and compounding.
The artificial valve prepared by the invention is a thermoplastic polyurethane elastomer, has elasticity and wear resistance, and also has good biocompatibility. The molding mode of the artificial valve can be one or more of mold molding, heat setting and solution molding, the artificial valve can be directly molded into a required valve shape when the thermoplastic polyurethane micro-nanofiber membrane is prepared, and the artificial valve can be directly obtained after the multiple layers of thermoplastic polyurethane micro-nanofiber membranes with valve shapes are subjected to hot-pressing compounding; the thermoplastic polyurethane micro-nanofiber composite membrane after hot-pressing compounding can also be processed into a required valve shape for the second time, so that the artificial valve is obtained.
Example 1
First, in this embodiment, a solution electrospinning method is used to prepare a drug-loaded prosthetic valve: firstly, preparing a thermoplastic polyurethane spinning solution, completely dissolving thermoplastic polyurethane particles in a mixed solution of N-N dimethylformamide and dichloromethane, wherein the volume ratio of the N-N dimethylformamide to the dichloromethane is 1:1, and uniformly adding a heparin sodium water solution with the concentration of about 100mg/mL to prepare the spinning solution with the mass percent of the thermoplastic polyurethane of 8% and the mass percent of the heparin sodium of 0.04%; and then carrying out electrostatic spinning by using the prepared thermoplastic polyurethane spinning solution. The electrostatic spinning method comprises the following steps: adding the thermoplastic polyurethane spinning solution into a needle cylinder, connecting with high voltage static electricity of 50kV, injecting the spinning solution at the speed of 10mL/hour, and finally receiving by a receiving device, wherein the receiving distance between the receiving device and the needle cylinder is 30 cm.
And then compounding a plurality of thermoplastic polyurethane micro-nanofiber membranes obtained after electrostatic spinning, specifically, flatly overlapping three prepared thermoplastic polyurethane micro-nanofiber membranes together, applying a pressure of 20MPa in a direction vertical to the thermoplastic polyurethane micro-nanofiber membranes, and heating to 90 ℃.
And then, stopping heating after heating for 5 minutes, and cooling the compounded thermoplastic polyurethane micro-nanofiber membrane to obtain the thermoplastic polyurethane micro-nanofiber composite membrane.
Post-treatment of the thermoplastic polyurethane micro-nanofiber composite membrane: cutting the prepared thermoplastic polyurethane micro-nanofiber composite membrane according to a preset size, and processing the cut thermoplastic polyurethane micro-nanofiber composite membrane into a required shape at 50 ℃ by a shaping process to obtain the artificial valve.
Example 2
Firstly, in this embodiment, a melt electrostatic spinning method is used to prepare a thermoplastic polyurethane micro-nanofiber membrane: firstly drying thermoplastic polyurethane particles at 80 ℃ for 3 hours, then adding the thermoplastic polyurethane particles into a melt electrostatic spinning device, adding polyethylene glycol (PEG-10000) into the melt electrostatic spinning device, uniformly mixing the polyethylene glycol (PEG-10000) and the thermoplastic polyurethane particles according to the mass ratio of 10%, and heating the mixture to 180 ℃ for melting to form a melt. Then, electrostatic spinning was started, the spinning voltage was 30kV, the melt flow rate was 180g/min, and the spinning was received with a flap-type die, the receiving distance from the flap-type die to the electrostatic spinning device was 15 cm.
And then compounding the multilayer thermoplastic polyurethane micro-nanofiber membrane: overlapping two prepared thermoplastic polyurethane micro-nanofiber membranes together, applying 2MPa pressure in the direction perpendicular to the thermoplastic polyurethane micro-nanofiber membranes, heating to 125 ℃, and compounding the two layers of thermoplastic polyurethane micro-nanofiber membranes together.
And then, stopping heating after heating for 2 minutes, and cooling the compounded thermoplastic polyurethane micro-nanofiber membrane to obtain the thermoplastic polyurethane micro-nanofiber composite membrane.
Post-treatment of the thermoplastic polyurethane micro-nanofiber composite membrane: and cutting the prepared thermoplastic polyurethane micro-nanofiber composite membrane into a required shape to obtain the artificial valve.
Therefore, according to the artificial valve and the preparation method thereof provided by the invention, the micro-nano fiber membrane preparation technology and the hot press molding technology are combined to prepare the artificial valve with the micro-nano structure, and the artificial valve has the following advantages:
firstly, the tensile strength of the thermoplastic polyurethane micro-nanofiber composite membrane is obviously improved compared with that of a single-layer thermoplastic polyurethane micro-nanofiber membrane, the elasticity is good, and the requirement on the mechanical property of the artificial valve can be met. Particularly, the multiple layers of thermoplastic polyurethane micro-nanofiber membranes with different pores are combined and arranged, the pores of the two layers of thermoplastic polyurethane micro-nanofiber membranes on the surface are larger, and human cells are easy to invade to form tissues; the thermoplastic polyurethane micro-nanofiber membrane with small pores is placed in the middle layer, and the mechanical strength of the artificial valve can be improved.
Secondly, the surface of the thermoplastic polyurethane micro-nano fiber composite membrane presents a micro-nano porous structure which is similar to human tissues, so that the endothelialization process of the artificial valve in the body can be accelerated, and the risk of thrombosis can be reduced.
In addition, the thermoplastic polyurethane micro-nano fiber membrane can load antithrombotic drugs in the fibers according to needs in the preparation process and slowly release the antithrombotic drugs in blood. Namely, the artificial valve has the potential of a drug slow-release carrier. Especially, the multilayer structure can load different medicines on the thermoplastic polyurethane micro-nanofiber membranes on different layers, and the medicines needing to be slowly released are placed in the middle layer, so that the treatment effect of the artificial valve can be further improved.
Finally, the preparation process of the artificial valve provided by the invention is simple and is easy to realize batch production.
Although the present invention has been described with respect to the preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.