WO2017101583A1 - Method for preparing membrane-covered intravascular stent - Google Patents

Abstract

Disclosed is a method for preparing a membrane-covered intravascular stent. The method comprises: (1) designing a processing mold core according to a blood vessel structure needing an intravascular stent to be implanted; (2) processing a first layer stent membrane covering on the mold core; (3) sheathing a stent skeleton on the mold core processed with the first layer stent membrane covering; (4) processing a second layer membrane covering on the mold core which is sheathed with the stent skeleton and processed with the first layer stent membrane covering so that the second layer stent membrane covering is bonded to the first layer stent membrane covering and thus the stent skeleton is at least partly coated in the membrane covering, wherein when the first layer stent membrane covering and/or the second layer stent membrane covering are processed, a polyvinylidene fluoride resin solution is used for a membrane forming process. The preparation method can obtain the stent membrane covering through simple operations and saves on cost. The obtained membrane-covered intravascular stent has good mechanical properties and biological properties.

Description

Preparation method of covered vascular stent Technical field

The invention relates to the field of interventional therapeutic medical devices, in particular to a method for preparing a covered blood vessel stent.

Background technique

Interventional treatment of vascular stents is widely used in the treatment of cardiovascular and cerebrovascular diseases such as vascular occlusion. For example, it is often necessary to implant a stent graft, a metal stent of other small blood vessels, and the like in a large blood vessel such as an aorta. The stent graft not only retains the support function of the common stent, but also effectively improves the abnormal hemodynamics of the diseased vessel. At present, the coated stent is generally coated with a PTFE resin, and the polytetrafluoroethylene resin is melted by high temperature, and then the film is bonded to the stent substrate under pressure. Under the action of heat, the middle of the film is easy to form suspension, which causes the film to be uneven, and the whole process consumes a large amount of energy, which makes the existing film-covered stent costly.

Summary of the invention

The object of the present invention is to provide a method for preparing a covered vascular stent, which overcomes the defect that the conventional polytetrafluoroethylene resin coating is subjected to high temperature treatment to cause uneven film formation.

In order to achieve the above object, the present invention provides a method for preparing a covered vascular stent, which comprises: (1) designing a processing core according to a vascular structure of a vascular stent to be implanted; and (2) processing the core. The first layer of the stent is coated; (3) the stent skeleton is placed on the core on which the first layer of the stent is processed; and (4) the sleeve is coated and the first layer of the stent is processed. Processing a second layer of the film on the core, and bonding the second layer of the stent film to the first layer of the stent film such that the stent frame is at least partially coated in the film; wherein When the first layer of the stent is coated and/or when the second layer of the stent is coated, the film is formed using a polyvinylidene fluoride resin solution. Reason.

Preferably, the weight ratio of the polyvinylidene fluoride resin to the organic solvent in the polyvinylidene fluoride resin solution is 1: (4-100).

Preferably, the polyvinylidene fluoride resin has a melt mass flow rate of from 1 to 20 g/10 min.

Preferably, the organic solvent is at least one of dimethylformamide, dimethylacetamide, dimethyl sulfoxide, and methyl ethyl ketone.

Preferably, the film forming treatment includes a casting film forming treatment, an electrospinning film forming treatment, a controlled deposition film forming treatment, and a spray coating film forming treatment.

Preferably, the temperature of the film forming treatment by the spray coating is from 10 to 90 °C.

Preferably, the scaffold skeleton is a metal scaffold skeleton and/or a polymer scaffold skeleton.

Preferably, the metal in the metal stent skeleton comprises stainless steel and/or nickel titanium alloy.

Preferably, the method further comprises, in step (4), removing the core such that the first layer of stent film forms a cavity.

Preferably, the material obtained by processing the core comprises a saccharide material, and the operation of removing the core comprises removing the core using a liquid capable of dissolving the core; the saccharide substance comprises a monosaccharide, At least one of a disaccharide and a water-soluble polysaccharide.

According to the above technical solution, the present invention dissolves the polyvinylidene fluoride resin in a solvent such as dimethylformamide to obtain a coating film, and solves the problem that the conventional polytetrafluoroethylene resin material needs to be subjected to high temperature treatment when it is used as a coating material. The operation is simple and cost-effective, and the obtained coated vascular stent has good mechanical properties and biological properties.

Other features and advantages of the invention will be described in detail in the detailed description which follows.

detailed description

Specific embodiments of the present invention will be described in detail below. It is to be understood that the specific embodiments described herein are merely illustrative and not restrictive.

The invention provides a preparation method of a covered blood vessel stent, which comprises: (1) designing a processing core according to a blood vessel structure to be implanted into a blood vessel stent; and (2) processing a first layer stent covering on the core a film; (3) a stent skeleton is placed on the core on which the first layer of the stent is processed; and (4) a processing on the core in which the stent frame is formed and the first layer of the stent is processed. Laminating the second layer and bonding the second layer of the stent to the first layer of the stent so that the stent is at least partially coated in the coating; wherein the first stent is processed When the film is coated and/or the second layer of the stent is processed, a film formation treatment is performed using a polyvinylidene fluoride resin solution.

In a preferred embodiment of the invention, in order to obtain a core that is compatible with the vascular structure in a precise and convenient manner, preferably, in step (1), the core is processed by a 3D printing technique. Specifically, when designing the core, the blood vessel structure with the implanted stent portion can be obtained by medical means such as angiography, such as CT angiography, and then the vascular structure can be constructed in the computer according to the vascular structure of the stent to be implanted. The 3D model is then processed by a 3D printer. It should be noted that, since the finally obtained vascular stent needs to be adapted to the inner wall of the blood vessel, the size of the core can be adjusted according to the doctor's requirements while ensuring that the outer surface structure of the core is adapted to the inner wall structure of the blood vessel. The error precision is designed, and the processing methods for different error precision should fall within the protection scope of the present invention. That is, since the stent graft is manufactured on the basis of the outer surface of the core, the stent graft needs to be implanted on the inner wall of the blood vessel, and therefore, when processing the core, it is necessary to design the core according to the doctor's request. The outer surface dimension is less than the size of the inner wall of the blood vessel with the required error so that the final stent graft accommodates the inner wall of the blood vessel. Wherein, the core may be a hollow structure or a solid structure, and the invention is not limited thereto. Among them, the core is preferably a solid structure in consideration of convenient processing.

In order to complete the processing of the covered vascular stent, it is necessary to combine the stent skeleton and the stent coating on the core. In order to facilitate the combination of the two, the first layer of the stent film is first processed on the core, and then the stent skeleton is placed on the core on which the first layer of the stent is processed, and then the second is processed on the stent skeleton. The layer carrier is coated and the second layer of the stent is bonded to the first layer of the stent to achieve a combination of the coating material and the stent skeleton. That is, it will be supported by two layers of film before and after The frame skeleton is firmly sandwiched to achieve a stable combination of the two.

According to the invention, the stent coating is obtained by a film forming treatment using a polyvinylidene fluoride resin solution. The weight ratio of the polyvinylidene fluoride resin to the organic solvent in the polyvinylidene fluoride resin solution can function to dissolve the polyvinylidene fluoride resin in a wide range, for example, the polyvinylidene fluoride resin and the organic solvent. The weight ratio can be 1: (4-100).

According to the present invention, the polyvinylidene fluoride resin (PVDF) mainly refers to a vinylidene fluoride homopolymer or a copolymer of vinylidene fluoride and other small amount of fluorine-containing vinyl monomer. For the same kind of high polymer, the molecular weight can be compared by the melt mass flow rate (MFR). The larger the degree of polymerization, that is, the larger the molecular weight, the smaller the melt mass flow rate, and the smaller the molecular weight, the larger the melt flow rate. The melt flow rate of the polyvinylidene fluoride resin of the present invention may be from 1 to 20 g/10 min.

The solubility of the polyvinylidene fluoride resin in the solvent varies depending on the polymerization process and formulation of the polyvinylidene fluoride resin. Conventional solvents are acetone, tetrahydrofuran, methyl ethyl ketone, dimethylformamide, dimethylacetamide, tetramethylurea, dimethyl sulfoxide, trimethyl phosphate, N-methylpyrrolidone, butyrolactone, and isophora. Ketone, carbitol acetate, methyl isobutyl ketone, butyl acetate, cyclohexanone, diisobutyl ketone, ethyl acetoacetate and triethyl phosphate. According to the invention, the solvent is preferably at least one of dimethylformamide, dimethylacetamide, dimethyl sulfoxide and methyl ethyl ketone.

According to the present invention, the film forming treatment may employ a polymer film forming treatment method commonly used in the art, such as a casting method, an electrospinning method, a controlled deposition method, or a spray coating method. The casting method refers to a method in which a polymer solution is uniformly cast on a dry, smooth, and clean substrate, and then dried to form a film in a constant temperature oven. The electrospinning method is to generate a charged jet by overcoming the surface tension under a high-voltage electrostatic field, and the jet stream is refined and split, and the finally solid polymer fiber falls on the substrate to form a fiber membrane. The controlled deposition method refers to a method of depositing a film-forming material on a carrier to control conditions to form a film. Spraying method refers to a method of atomizing a solution by using a high pressure air by using a pneumatic spray gun, and the droplets are pushed by the load gas to reach the substrate for deposition and drying to form a film; when the film forming process of the present invention is carried out by spraying, the film is lower. The film can be sprayed on the core to form a film at a temperature. Preferably, the temperature of the film forming process by the spraying method is 10-90 ° C.

According to the present invention, the scaffold skeleton may be selected from conventional framework materials in the art, and may be, for example, a metal scaffold skeleton and/or a polymer scaffold skeleton. The metal in the metal stent skeleton may include stainless steel and/or nickel titanium alloy. The bracket frame may be a single-ring ring member, and the bracket ring of different specifications is selected according to the specification of the core to be combined with the film after being applied to the core. In addition, the stent skeleton may also be a whole wire to be wrapped on the outer surface of the core by wrapping and wrapping, thereby obtaining a suitable stent skeleton.

According to the invention, the method further comprises, in step (4), removing the core such that the first layer of stent film forms a cavity. The core is designed and formed according to the structure of the human blood vessel to be implanted into the stent. After the stent graft is processed on the core, the core and the stent graft are separated, thereby obtaining a covered vessel stent having a cavity structure.

In order to facilitate the processing of the core, a core can be processed with a dissolvable material, for example, a core processed with a water-soluble material. More specifically, the core can be processed using a saccharide material, so that a solid core can be conveniently obtained. Preferably, the saccharide substance may include at least one of a monosaccharide, a disaccharide, and a water-soluble polysaccharide; further preferably, the saccharide may be maltose, sucrose, and fructose, and the maltose, sucrose, and fructose are The mass ratio can be 1: (1-5): (1-5). In addition, it is important to use a liquid-soluble material to process the core in order to better achieve the separation of the core and the manufactured stent. Preferably, in order to quickly separate the core from the stent graft, the core may be removed using a liquid capable of dissolving the core to separate the core from the stent graft. In other embodiments, the core may also be made of a meltable material, as long as the core is melted by a heating device when the core is separated, and such deformation is also within the scope of the present invention.

The following examples are further described, but the invention is not limited thereby.

Example 1

Obtaining the vascular structure of the stent portion to be implanted by CT angiography, and then according to the stent to be implanted The vascular structure of the site is constructed in a computer to form a three-dimensional model that fits the vascular structure, and then the core is processed by a 3D printer. The core is mixed with maltose, sucrose and fructose at a mass ratio of 1:1:1.

The polyvinylidene fluoride resin FR901 (purchased from Shanghai San Aifu, melt mass flow rate 16g/10min) and dimethylformamide were mixed at a weight ratio of 1:10, stirred for 4 hours, and then defoamed to obtain a polyethylene bias. Fluoroethylene resin solution.

When the distance between the nozzle and the core surface is 150 mm at a pressure of 0.3 MPa and 30 ° C using a pneumatic spray gun, the obtained polyvinylidene fluoride resin solution is sprayed on the surface of the core to form a continuous first layer of the stent film.

The stainless steel stent frame is placed on the core coated with the first layer of the stent film, and then the polyvinylidene fluoride resin solution is sprayed again along the surface of the stainless steel stent frame under the same working conditions to form a discontinuity by using a pneumatic spray gun. The second layer of the stent is coated, and the second layer of the stent is combined with the first layer of the stent to form a stent film having a thickness of 0.1 mm, and the stainless steel stent skeleton is coated therein.

The core was dissolved with water to obtain a covered vascular stent prepared by the present invention.

The obtained stent graft was implanted into the aorta of experimental animals (rabbit), and arterial angiography was performed after 4 weeks, 12 weeks, and 24 weeks. The vascular patency of the stent graft was observed, the stent adherence performance, and the presence or absence of migration. Bit and so on.

Animal implantation experiments showed that all experimental animals (rabbits) survived well during the follow-up period, and the vessels at the site of stent implantation remained unobstructed without thrombosis. There is no shrinkage, rupture, etc. of the film, no complications, blood leakage, stent displacement, and the stent graft is well attached and has good biocompatibility.

Example 2

The vascular structure of the part to be implanted is obtained by CT angiography, and then a three-dimensional model of the vascular structure is constructed in the computer according to the vascular structure of the part to be implanted, and then the core is processed and manufactured by a 3D printer. Using maltose, sucrose and glucose by mass ratio Mix for 1:2:5.

The polyvinylidene fluoride resin FR921 (purchased from Shanghai San Aifu, melt mass flow rate 2g/10min) and dimethylacetamide were mixed at a weight ratio of 1:80, stirred for 4 hours, and then defoamed to obtain a polyethylene bias. Fluoroethylene resin solution.

The obtained polyvinylidene fluoride resin solution is cast into a mold in which a core is placed, and the polyvinylidene fluoride resin solution is cast on the surface of the core to form a continuous first layer of the stent film.

The nickel-titanium alloy support skeleton is set on the core which is cast into the film with the first layer of the stent film, and then placed in the mold again, and the polyvinylidene fluoride resin solution is cast again to form the second layer of the stent film. The two-layer stent film is combined with the first layer of the stent film to form a stent film having a thickness of 0.2 mm, and the nickel-titanium alloy stent skeleton is coated therein.

The core was dissolved with water to obtain a covered vascular stent prepared by the present invention.

The obtained stent graft was implanted into the aorta of experimental animals (rabbit), and arterial angiography was performed after 4 weeks, 12 weeks, and 24 weeks. The vascular patency of the stent graft was observed, the stent adherence performance, and the presence or absence of migration. Bit and so on.

Animal implantation experiments showed that all experimental animals (rabbits) survived well during the follow-up period, and the vessels at the site of stent implantation remained unobstructed without thrombosis. There is no shrinkage, rupture, etc. of the film, no complications, blood leakage, stent displacement, and the stent graft is well attached and has good biocompatibility.

Claims (10)

A method for preparing a covered vascular stent, characterized in that the preparation method comprises: (1) designing a processing core according to the vascular structure of the stent to be implanted; (2) processing the first layer of the stent film on the core; (3) arranging the scaffold skeleton on the core body processed with the first layer of the stent film; (4) processing a second layer of the film on the core having the stent frame and processing the first layer of the stent film, and bonding the second layer of the stent film to the first layer of the stent film, So that the scaffold skeleton is at least partially coated in the coating film; wherein, when the first layer of the stent coating is processed and/or the second layer of the stent is processed, the polyvinylidene fluoride resin solution is used for forming Membrane treatment. The method according to claim 1, wherein a weight ratio of the polyvinylidene fluoride resin to the organic solvent in the polyvinylidene fluoride resin solution is 1: (4-100). The method according to claim 1 or 2, wherein the polyvinylidene fluoride resin has a melt mass flow rate of from 1 to 20 g/10 min. The method according to claim 2, wherein the organic solvent is at least one selected from the group consisting of dimethylformamide, dimethylacetamide, dimethyl sulfoxide, and methyl ethyl ketone. The method according to claim 1, wherein the film forming treatment comprises a casting film forming treatment, an electrospinning film forming treatment, a controlled deposition film forming treatment, and a spray coating film forming treatment. The method according to claim 5, wherein the temperature of the film forming treatment by the spray coating is from 10 to 90 °C. The method of claim 1 wherein the scaffold skeleton is a metal scaffold skeleton and/or a polymeric scaffold skeleton. The method of claim 7 wherein the metal in the metal stent skeleton comprises stainless steel and/or nickel titanium alloy. The method of claim 1 wherein the method further comprises, in step (4), removing the core such that the first layer of stent film forms a cavity. The method of claim 9 wherein the material from which the core is processed comprises a saccharide material, and the removing the core comprises removing the core using a liquid capable of dissolving the core; The saccharide substance includes at least one of a monosaccharide, a disaccharide, and a water-soluble polysaccharide.