CN108837182B

CN108837182B - Preparation method of polytetrafluoroethylene multichannel intravascular stent and coating liquid used by preparation method

Info

Publication number: CN108837182B
Application number: CN201810355994.7A
Authority: CN
Inventors: 张琪; 张超; 叶开天; 张依; 张华�
Original assignee: Sichuan Zhijiang Advanced Materials Co ltd
Current assignee: Sichuan Zhijiang Advanced Materials Co ltd
Priority date: 2018-04-19
Filing date: 2018-04-19
Publication date: 2021-04-27
Anticipated expiration: 2038-04-19
Also published as: CN108837182A

Abstract

The invention discloses a coating liquid for the surface of an intravascular stent, which is prepared by the following steps: adding fluorinated graphene into perfluoroalkane as a solvent, performing ultrasonic treatment at normal temperature, adding polytetrafluoroethylene, and stirring at 300-400 ℃ for 12-24 h to obtain a polytetrafluoroethylene solution as a coating solution. The invention also provides a preparation method of the polytetrafluoroethylene multichannel intravascular stent by using the coating liquid, which comprises the following steps: selecting a metal mould or a vascular stent matched with the shape of the blood vessel as a frame body; and injecting the coating liquid into an injector which is controlled by a micro-injection pump and has the capacity of 5-10 ml in the electrostatic spinning device, spraying the coating liquid from the needle point of the injector under the action of electrostatic force, and carrying out electrostatic spinning on the frame body to attach a polytetrafluoroethylene membrane on the surface of the frame body, thereby obtaining the polytetrafluoroethylene multichannel intravascular stent. The method of the invention can obtain the high-elasticity multi-channel intravascular stent.

Description

Preparation method of polytetrafluoroethylene multichannel intravascular stent and coating liquid used by preparation method

Technical Field

The invention relates to a preparation method of a polytetrafluoroethylene multichannel intravascular stent and coating liquid used by the preparation method, in particular to a method for preparing the polytetrafluoroethylene multichannel intravascular stent by an electrostatic spinning method.

Background

Along with the improvement of the living standard of people, the incidence rate of cardiovascular diseases is higher and higher. Is one of the important causes of death. It is reported that 300 million people worldwide receive cardiovascular stent implantation surgery every year. With the development of intravascular treatment technology, intravascular stent implantation has become one of the main methods for treating cardiovascular diseases, and a series of complications after stent implantation, such as acute/subacute thrombosis, stent restenosis and the like, are attracting more and more attention, and in particular, stent restenosis becomes an unavoidable problem.

After the stent is implanted into a human body, the stent is in a blood environment, and the metal stent has two main problems of thrombus and corrosion when being used in the blood environment for a long time. One of the key factors determining the quality of the intravascular stent is the stent material. At present, the materials used for manufacturing the intravascular stent mainly comprise metal, high polymer materials and the like. Coronary stents which are widely applied clinically are made of metal materials, the excellent mechanical properties of the metal materials can meet the requirements of the environment, but the corrosion of the metal stents in blood and the problem of induced thrombus can damage the matrix performance and the physiological environment. Compared with a metal bare stent, the covered stent has the characteristics of light injury to blood vessels and stimulation to intima of the blood vessels, small thrombogenesis, slight inflammatory reaction, less intimal hyperplasia and the like, and reduces the restenosis rate of the blood vessels.

CN104383608A discloses a multi-channel blood vessel stent with a membrane and a preparation method thereof, wherein the multi-channel blood vessel stent is coated with a membrane and comprises a stent body, the surface of the stent body is coated with a polytetrafluoroethylene membrane, and the polytetrafluoroethylene membrane is prepared by electrospinning polytetrafluoroethylene solution on the surface of the stent body; the polytetrafluoroethylene solution comprises polytetrafluoroethylene and perfluoroalkane, and the concentration of the polytetrafluoroethylene is 1-30 g/ml. The multi-channel intravascular stent is characterized in that a polytetrafluoroethylene layer is coated on the surface of a stent body, the performance of a coating film is similar to that of expanded polytetrafluoroethylene, and the multi-channel intravascular stent can be processed into various shapes such as a cylinder shape, a circular shape and a curved surface, so that the multi-channel intravascular stent is suitable for treating complicated aneurysms and the success rate of operations is improved.

CN1568907A discloses an artificial endovascular stent and a preparation method thereof, which adopts an expanded polytetrafluoroethylene vascular membrane and a nickel-titanium alloy stent to prepare a domestic artificial endovascular stent for the intra-luminal treatment of aneurysms by a membrane pressure integration method. The method improves the performance of the existing artificial intravascular stent, has small caliber, is suitable for the bending running of the artery, and improves the flexibility and the biocompatibility. The stent has no toxicity, no tissue irritation, no pyrogenicity, no sensitization and no teratogenicity, can not induce thrombosis in the artery, and reduces direct damage to the aortic wall. The stent can greatly reduce the price of the products, so that more patients with aneurysm have the opportunity to receive the intracavity treatment, and the stent is also helpful for promoting the academic level of the endovascular treatment in China.

CN104436319A discloses a multichannel blood vessel stent with a membrane and a preparation method thereof, wherein the multichannel blood vessel stent with the membrane comprises a stent body, and a polytetrafluoroethylene membrane is coated on the surface of the stent body. The multi-channel intravascular stent is characterized in that a polytetrafluoroethylene layer is coated on the surface of a stent body, the performance of the coating film is similar to that of expanded polytetrafluoroethylene, and the coating film can be processed into various shapes such as a cylinder shape, a circular shape and a curved surface, so that the multi-channel intravascular stent is suitable for treating complicated aneurysms and the success rate of operations is improved.

CN201798829U discloses an intravascular stent, comprising: a nickel-titanium alloy tubular stent with a hollow inner part; an expanded polytetrafluoroethylene outer layer membrane laid on the outer surface of the nickel-titanium alloy tubular stent through membrane pressing; and an expanded polytetrafluoroethylene inner layer membrane which is laid on the inner surface of the nickel-titanium alloy tubular stent by membrane pressing. The intravascular stent main body is supported by memory nickel-titanium alloy, and smooth and flexible expanded polytetrafluoroethylene membranes are respectively stuck inside and outside the nickel-titanium alloy stent, so that the intravascular stent has strong support and good flexibility, can avoid the friction loss of the tissues in a patient body, and is convenient to be introduced into the diseased artery of the patient; and the expanded polytetrafluoroethylene membrane can induce the endothelial cells of the blood vessels to grow in, so that the circulating blood keeps a flowing state, and the expanded polytetrafluoroethylene has electronegativity, thereby preventing platelet aggregation, preventing thrombosis and keeping good long-term permeability. Is especially suitable for patients with advanced age and aneurysm with more basic diseases.

US4767418(a) discloses a method of making a vascular prosthesis consisting of a moulded article of Polytetrafluoroethylene (PTFE) having a polished planar surface, a synthetic vascular material being cast onto the PTFE mould to form blind grooves in the interior of the synthetic blood vessel, the grooves having a predetermined uniform cross-section and being present in a predetermined uniform shape. The surface of the intravascular stent is coated with polytetrafluoroethylene material.

KR20130013206(a) discloses a non-vascular drug releasing stent membrane and a method for manufacturing the same to inhibit tumor growth. The method comprises the following steps: a drug-eluting membrane for manufacturing a non-vascular stent includes a drug coating solution prepared by dissolving an anticancer drug in polyurethane and an organic solvent, a first layer of a metallic stent formed by coating the metallic stent with a silicon tube or polytetrafluoroethylene, and a coating layer applied to the metallic stent.

WO2013015495(a1), RU2552875(C1) disclose a non-vascular drug eluting stent membrane prepared using electrospinning. The non-vascular drug eluting stent film is covered on a polytetrafluoroethylene tube metal stent, then a rotating roller or an inserted metal stent is implanted into a polytetrafluoroethylene tube and a silicon tube or polytetrafluoroethylene tube to form a metal stent primary coating layer, and then the metal stent is manufactured by one rotation, and the electrostatic spinning solution drug coating layer comprises polyurethane and an anticancer agent, in order to obtain a uniform surface, the influence on the uniformity of the thickness is uniform, and compared with the stable control, the drug eluting stent is continuously eluted by a dipping process film making method, the growth of tumors is obviously limited, and the weight of the tumors is obviously reduced. Thus, it can be used to enlarge luminal stenosis, inhibit tumor growth, or prevent luminal restenosis.

The fluorinated graphene has the characteristics of reduced surface energy, enhanced hydrophobicity, high temperature resistance, stable chemical property and the like, can be used as a tunnel barrier or a high-quality insulator or barrier material, can also be used for a light-emitting diode and a display, and has wide application prospects in the fields of interfaces, novel nano electronic devices, lubricating materials and the like.

The fluorinated graphene serving as a novel derivative of graphene not only maintains the high-strength performance of graphene, but also brings novel interface and physicochemical properties such as surface energy reduction, hydrophobicity enhancement, band gap broadening and the like due to the introduction of fluorine atoms. Meanwhile, the fluorinated graphene is high-temperature resistant, stable in chemical property, similar to polytetrafluoroethylene in property, and called as two-dimensional Teflon.

The fluorinated graphene can be easily transferred to different substrates, particularly the Young modulus and the continuous strain of the fluorinated graphene can be respectively as high as 100N/m and 15%, and if the fluorinated graphene is transferred to a flexible substrate, a flexible photoelectric detection device with the characteristics of flexibility, impact resistance, light weight and the like can be realized.

However, at present, there is no report that fluorinated graphene is used for surface coating of intravascular stents.

Disclosure of Invention

The invention aims to provide a high-elasticity multi-channel intravascular stent, a preparation method thereof and a coating liquid used by the same.

In order to solve the technical problems, the invention provides a coating liquid for the surface of an intravascular stent (namely, a polytetrafluoroethylene solution for coating the surface of the intravascular stent), and the preparation method of the coating liquid comprises the following steps:

adding fluorinated graphene into perfluoroalkane serving as a solvent, performing ultrasonic treatment (400-600 w) for 15-30 h at normal temperature (10-30 ℃), then adding polytetrafluoroethylene, and stirring for 12-24 h at 300-400 ℃ (so that the polytetrafluoroethylene is dissolved in the perfluoroalkane) to obtain a coating solution (polytetrafluoroethylene solution);

the feed-liquid ratio of the fluorinated graphene to the perfluoroalkane is 0.1-0.6 g/ml, and the feed-liquid ratio of the polytetrafluoroethylene to the perfluoroalkane is 1-30 g/ml.

The improvement of the coating liquid for the surface of the intravascular stent is as follows:

the perfluoroalkane is perfluorohexane, perfluorocyclohexane, or perfluoroheptane.

The number of layers of the fluorinated graphene is less than or equal to 20, the thickness of the fluorinated graphene is 0.8-5.0 nm, the particle size of the fluorinated graphene is 2.0-5.0 mu m, and the fluorine content of the fluorinated graphene is 20-40 wt.%.

The invention also provides a preparation method of the polytetrafluoroethylene multichannel intravascular stent (high-elasticity multichannel intravascular stent) by using the coating liquid (polytetrafluoroethylene solution), which comprises the following steps:

(1) selecting a frame body;

the frame body is a metal mould or a blood vessel bracket which is matched with the blood vessel in shape;

(2) preparing the vascular stent:

injecting a coating liquid (polytetrafluoroethylene solution) into an injector which is controlled by a micro-injection pump and has a capacity of 5-10 ml in an electrostatic spinning device, spraying the coating liquid (polytetrafluoroethylene solution) from a needle point of the injector under the action of electrostatic force, and carrying out electrostatic spinning on a frame body (a metal mold or a blood vessel support) to attach a polytetrafluoroethylene membrane on the surface of the frame body, thereby obtaining the polytetrafluoroethylene multichannel intravascular stent (namely, a multichannel blood vessel support with the membrane).

The improvement of the preparation method of the polytetrafluoroethylene multi-channel intravascular stent (high-elasticity multi-channel intravascular stent) is as follows:

the electrostatic spinning process conditions in the step (2) are as follows: controlling the micro-injection pump to enable the flow rate of the polytetrafluoroethylene solution sprayed out of the needle point to be 1-5 ml/h (at the moment, the rotating speed of a motor of the micro-injection pump is about 1500-2000 r/min); the voltage of a power supply is controlled to be 10-25 KV, the receiving distance (the distance from the needle point to the frame body) is 10-25 cm, the temperature is 10-30 ℃, and the relative humidity is 20-40%.

The preparation method of the polytetrafluoroethylene multichannel intravascular stent is further improved as follows:

the metal mold or the vascular stent is obtained by 3D printing.

The volume of the injector is 5-10 ml.

The invention has the following technical effects:

(1) the invention can carry out surface coating on vascular stents (metal dies) with various shapes by utilizing the electrostatic spinning device; the process is simple and easy to operate;

(2) after the surface of the blood vessel stent (metal mold) is covered with the polytetrafluoroethylene film containing the fluorinated graphene, the mechanical property of the blood vessel stent can be improved.

(3) The polytetrafluoroethylene film containing the fluorinated graphene can be used for covering blood vessel stents and can also be used as covering materials of various heart and blood vessel implanting instruments.

Detailed Description

The present invention is further described below with reference to examples. It should be noted that the following examples are not intended to limit the scope of the present invention, and any modifications made on the basis of the present invention do not depart from the spirit of the present invention.

Example 1, a method for preparing a polytetrafluoroethylene multi-channel intravascular stent (diameter 8mm, length 30mm) sequentially comprises the following steps:

(1) a blood vessel stent with the diameter of 8mm and the length of 30mm is selected as a stent body.

(2) Preparation of polytetrafluoroethylene solution:

adding 0.2g of fluorinated graphene (the number of layers of the fluorinated graphene is less than or equal to 20, the thickness of the fluorinated graphene is 0.8-5.0 nm, the particle size of the fluorinated graphene is 2.0-5.0 mu m, and the fluorine content of the fluorinated graphene is 20-40 wt.%) into 1ml of perfluorohexane, carrying out ultrasonic treatment (500w) for 20 hours at normal temperature, then adding 5g of polytetrafluoroethylene, stirring for 20 hours at 320 ℃, and dissolving the polytetrafluoroethylene in the perfluorohexane to obtain a polytetrafluoroethylene solution serving as a coating solution.

(3) Preparing the vascular stent:

a conventional electrostatic spinning device is selected and used, the device comprises an injector which is controlled by a micro-injection pump and has the capacity of 5-10 ml, the anode output end of a power supply is connected with a needle head of the injector, the cathode output end of the power supply is connected with a metal receiving shaft, and a frame body (a metal mold or a blood vessel support) is arranged on the metal receiving shaft.

3ml of polytetrafluoroethylene solution (coating solution) is injected into a 5ml injector of an electrostatic spinning device, the flow rate of the polytetrafluoroethylene solution sprayed from a needle point is 5ml/h (at the moment, the rotating speed of a motor of a micro-injection pump is about 2000r/min) by controlling the micro-injection pump, the environmental temperature is controlled to be 10-30 ℃, and the relative humidity is controlled to be 20-40%; the voltage of the power supply is controlled to be 10KV, and the receiving distance is set to be 10 cm.

The polytetrafluoroethylene solution is sprayed out from the needle tip under the action of electrostatic force, and electrostatic spinning is carried out on the metal mould or the vascular stent through the needle head of the injector, so that a layer of uniform membrane is formed on the surface of the vascular stent, and the multi-channel vascular stent with the membrane is obtained.

Example 2, a method for preparing a polytetrafluoroethylene multi-channel intravascular stent (diameter of 3mm, length of 10mm) sequentially comprises the following steps:

(1) a blood vessel stent with the diameter of 3mm and the length of 10mm is selected as a stent body.

(2) Preparation of polytetrafluoroethylene solution:

adding 0.3g of fluorinated graphene into 1ml of perfluorocyclohexane, carrying out ultrasonic treatment (400w) at normal temperature for 30h, then adding 10g of polytetrafluoroethylene, and stirring at 300 ℃ for 12h to dissolve the polytetrafluoroethylene in the perfluorocyclohexane to obtain a polytetrafluoroethylene solution serving as a coating liquid.

(3) Preparing the vascular stent:

3ml of polytetrafluoroethylene solution (coating solution) is injected into a 5ml injector of an electrostatic spinning device, the flow rate of the polytetrafluoroethylene solution sprayed out of a needle point is 2ml/h by controlling a micro injection pump, the environmental temperature is controlled to be 10-30 ℃, and the relative humidity is 20-40%; the voltage of the power supply is controlled to be 10KV, and the receiving distance is set to be 10 cm. Thereby obtaining the multi-channel blood vessel stent with the membrane.

Example 3, a method for preparing a polytetrafluoroethylene multi-channel intravascular stent (diameter of 10mm, length of 20mm) sequentially comprises the following steps:

(1) a blood vessel stent with the diameter of 10mm and the length of 20mm is selected as a stent body.

(2) Preparation of polytetrafluoroethylene solution:

adding 0.6g of fluorinated graphene into 1ml of perfluoroheptane, carrying out ultrasonic treatment (600w) at normal temperature for 25h, then adding 30g of polytetrafluoroethylene, and stirring at 350 ℃ for 16h to dissolve the polytetrafluoroethylene in the perfluoroheptane, thereby obtaining a polytetrafluoroethylene solution serving as a coating liquid.

(3) Preparing the vascular stent:

injecting 6ml of polytetrafluoroethylene solution (coating solution) into a 10ml injector of an electrostatic spinning device, and controlling a micro injection pump to ensure that the flow rate of the polytetrafluoroethylene solution sprayed from a needle point is 5ml/h, the environmental temperature is controlled to be 10-30 ℃, and the relative humidity is 20-40%; the voltage of the power supply is controlled to be 25KV, and the receiving distance is set to be 25 cm. Thereby obtaining the multi-channel blood vessel stent with the membrane.

Example 4, a method for preparing a polytetrafluoroethylene multi-channel intravascular stent (diameter 6mm, length 10mm) sequentially comprises the following steps:

(1) a blood vessel stent with the diameter of 6mm and the length of 10mm is selected as a stent body.

(2) Preparation of polytetrafluoroethylene solution:

adding 0.5g of fluorinated graphene into 1ml of perfluorocyclohexane, carrying out ultrasonic treatment (500w) at normal temperature for 20h, then adding 15g of polytetrafluoroethylene, and stirring at 400 ℃ for 12h to dissolve the polytetrafluoroethylene in the perfluorocyclohexane to obtain a polytetrafluoroethylene solution serving as a coating liquid.

(3) Preparing the vascular stent:

injecting 5ml of polytetrafluoroethylene solution (coating solution) into a 10ml injector of an electrostatic spinning device, and controlling a micro-injection pump to ensure that the flow rate of the polytetrafluoroethylene solution sprayed from a needle point is 3ml/h, the environmental temperature is controlled to be 10-30 ℃, and the relative humidity is 20-40%; the voltage of the power supply is controlled to be 15KV, and the receiving distance is set to be 15 cm. Thereby obtaining the multi-channel blood vessel stent with the membrane.

Comparative example 1-1, the use of fluorinated graphene in step (2) of example 1 was eliminated, i.e., the amount of fluorinated graphene used was 0; the rest is equivalent to embodiment 1.

Comparative examples 1-2, the amount of "fluorinated graphene" in step (2) of example 1 was changed from 0.2g to 1 g; the rest is equivalent to embodiment 1.

Comparative example 2-1, the fluorinated graphene in step (2) of example 1 was changed to carbon nanotubes with the same amount; the rest is equivalent to embodiment 1.

Comparative example 2-2, the fluorinated graphene in step (2) of example 1 was changed to carbon fiber with the same amount; the rest is equivalent to embodiment 1.

Comparative example 3, step (2) of example 1 was changed to: 0.2g of fluorinated graphene and 5g of polytetrafluoroethylene are added into 1ml of perfluorohexane and stirred for 20h at 320 ℃ to obtain a polytetrafluoroethylene solution.

The rest is equivalent to embodiment 1.

The first experiment, the mechanical property experiment,

the experimental method comprises the following steps: the intravascular stent material is cut into a rectangle with the length of 10mm and the width of 6mm, and a unidirectional tensile experiment is carried out on an electronic universal tester (CMT8502, Shenzhen) at the tensile speed of 5mm/min until a sample is broken, and the test temperature is normal temperature.

The results obtained were: see table 1.

TABLE 1

Therefore, when the breaking strength and the elongation at break of table 1 are analyzed, table 1 shows that the breaking strength and the elongation at break of the above comparative examples are far inferior to those of the present invention, and thus it is proved that the stent material prepared by the above comparative examples is brittle and has poor elastic properties.

Note: the elastic modulus of example 1 was specifically 3.75. + -. 1.5MPa, the elastic modulus of example 2 was specifically 4.65. + -. 0.9MPa, the elastic modulus of example 3 was specifically 8.98. + -. 0.5MPa, and the elastic modulus of example 4 was specifically 11.23. + -. 0.5 MPa.

The prior art discloses that the modulus of elasticity of the rubber is 0.0078GPa, i.e. 78 MPa.

In conclusion, the mechanical property of the blood vessel stent (metal mold) can be improved after the surface of the blood vessel stent (metal mold) is covered with the polytetrafluoroethylene film containing the fluorinated graphene.

Finally, it is also noted that the above-mentioned lists merely illustrate a few specific embodiments of the invention. It is obvious that the invention is not limited to the above embodiments, but that many variations are possible. All modifications which can be derived or suggested by a person skilled in the art from the disclosure of the present invention are to be considered within the scope of the invention.

Claims

1. The preparation method of the polytetrafluoroethylene multichannel intravascular stent by using the coating liquid is characterized by comprising the following steps of:

(1) selecting a frame body;

(2) and (3) preparation:

injecting a coating liquid into an injector which is controlled by a micro-injection pump and has a capacity of 5-10 ml in an electrostatic spinning device, spraying the coating liquid from a needle point of the injector under the action of electrostatic force, and carrying out electrostatic spinning on the frame body to attach a polytetrafluoroethylene film on the surface of the frame body, thereby obtaining the polytetrafluoroethylene multichannel intravascular stent;

the preparation method of the coating liquid comprises the following steps:

adding fluorinated graphene into perfluoroalkane serving as a solvent, performing ultrasonic treatment for 15-30 hours at normal temperature, then adding polytetrafluoroethylene, and stirring at 300-400 ℃ for 12-24 hours to obtain a polytetrafluoroethylene solution serving as a coating liquid;

the feed-liquid ratio of the fluorinated graphene to the perfluoroalkane is 0.1-0.6 g/ml, and the feed-liquid ratio of the polytetrafluoroethylene to the perfluoroalkane is 1-30 g/ml;

the perfluoroalkane is perfluorohexane, perfluorocyclohexane or perfluoroheptane;

2. The method for preparing a polytetrafluoroethylene multichannel intravascular stent as claimed in claim 1, wherein the method comprises the following steps:

the electrostatic spinning process conditions in the step (2) are as follows: controlling the micro-injection pump to enable the flow rate of the polytetrafluoroethylene solution sprayed out of the needle point to be 1-5 ml/h; the voltage of a power supply is controlled to be 10-25 KV, the receiving distance is 10-25 cm, the temperature is 10-30 ℃, and the relative humidity is 20-40%.

3. The method for preparing a polytetrafluoroethylene multichannel intravascular stent as claimed in claim 2, wherein the method comprises the following steps:

the metal mold or the vascular stent is obtained by 3D printing.

4. The preparation method of the polytetrafluoroethylene multichannel intravascular stent as claimed in claim 1, wherein the following steps are sequentially carried out:

(1) selecting a blood vessel stent with the diameter of 3mm and the length of 10mm as a stent body;

(2) preparation of polytetrafluoroethylene solution:

adding 0.3g of fluorinated graphene into 1ml of perfluorocyclohexane, carrying out ultrasonic treatment at normal temperature for 30h at 400w, then adding 10g of polytetrafluoroethylene, and stirring at 300 ℃ for 12h to dissolve the polytetrafluoroethylene in the perfluorocyclohexane to obtain a polytetrafluoroethylene solution serving as a coating solution;

(3) preparing the vascular stent:

3ml of polytetrafluoroethylene solution serving as coating liquid is injected into a 5ml injector of an electrostatic spinning device, the flow rate of the polytetrafluoroethylene solution sprayed out of a needle point is controlled to be 2ml/h by controlling a micro injection pump, the environmental temperature is controlled to be 10-30 ℃, and the relative humidity is controlled to be 20-40%; controlling the voltage of a power supply to be 10KV, and setting the receiving distance to be 10 cm; thereby obtaining the multi-channel blood vessel stent with the membrane.