WO2017197849A1

WO2017197849A1 - Blood vessel stent and manufacturing method thereof

Info

Publication number: WO2017197849A1
Application number: PCT/CN2016/104403
Authority: WO
Inventors: 刘牧龙; 许文超
Original assignee: 深圳生命谷科技研究院有限公司
Priority date: 2016-05-16
Filing date: 2016-11-03
Publication date: 2017-11-23
Also published as: CN107376035B; CN107376035A

Abstract

A blood vessel stent and manufacturing method thereof. The blood vessel stent comprises: a blood vessel stent body, and a coating applied on the surface thereof. The coating comprises a copper(II). The blood vessel stent can promptly release copper(II) ions at a region of a blood vessel injured when placing the stent, thereby facilitating effective repair and regeneration of the blood vessel.

Description

Vascular stent and preparation method thereof

Technical field

The invention relates to the medical field, in particular to a blood vessel stent and a preparation method thereof.

Background technique

With the changes in human diet and work habits and the aging of the population, vascular diseases have become a huge problem for humans. About 17 million people worldwide die from the disease every year. It is estimated that by 2020, the global annual cardiovascular and cerebrovascular diseases The number of deaths from the disease will reach 25 million.

Clinical medical research has found that the use of vascular stents can effectively treat cardiovascular and cerebrovascular diseases such as vascular stenosis and intraluminal obstruction. Since the invention of the vascular stent widely used in coronary arteries in the 1980s, vascular stent technology has received more and more attention. The industrialization of vascular stent technology provides an effective solution for vascular patients.

In the research and practice of the prior art, the inventors of the present invention found that before and during the placement of the stent, the periphery of the embolization or the narrow blood vessel may have different degrees of necrotic damage due to the blood supply problem, causing secondary damage to the blood vessel. Damage, therefore, need to repair vascular damage or promote vascular regeneration at the site of ischemic injury.

technical problem

The embodiment of the invention provides a blood vessel stent and a preparation method thereof, and aims to solve the problem that the embolization or the narrow blood vessel may have different degrees of necrotic damage due to blood supply problems before and during the placement of the blood vessel stent, and cause secondary damage to the blood vessel. There is a need to repair vascular damage or promote vascular regeneration at the site of ischemic injury.

Technical solution

The embodiment of the invention is achieved by a blood vessel stent, the blood vessel stent comprising:

Vascular stent base;

a coating disposed on a surface of the vascular stent substrate, the coating comprising a divalent copper element.

Embodiments of the present invention also provide a method of preparing a blood vessel stent, the method comprising the steps of:

Preparing a coating material comprising a divalent copper element;

The coating material is applied to the surface of the vascular stent substrate by spraying, modifying or electroplating to form a coating on the surface of the vascular stent substrate.

Beneficial effect

In the embodiment of the present invention, by coating a surface of the base of the blood vessel stent with a coating comprising a divalent copper element, after the blood vessel stent is placed in the blood vessel, the blood vessel stent can release the blood vessel repair and regeneration which is damaged by the blood vessel placement in time. Divalent copper ions, and the release position is highly accurate, thus allowing the blood vessels to be repaired in a timely and effective manner.

DRAWINGS

1 to 15 are graphs showing changes in the concentration of divalent copper ions in a normal human plasma sample solution according to an embodiment of the present invention.

Embodiments of the invention

The present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It is understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

In the embodiment of the present invention, a coating comprising a divalent copper element is coated on the surface of the vascular stent base, so that after the blood vessel stent is placed in the blood vessel, the vascular stent can release the divalent copper ions, and the divalent copper ions promote the migration of the endothelial cells. It regulates the extracellular matrix, participates in the formation and maintenance of the vascular lumen, and promotes the proliferation of endothelial cells, and the release position is accurate, thus enabling timely and effective repair of blood vessels.

The blood vessel stent provided by the embodiment of the invention comprises a blood vessel stent base and a coating disposed on the surface of the blood vessel stent base, the coating comprising a divalent copper element. Wherein, the vascular stent matrix may be composed of a degradable material such as polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), polyanhydride, poly-β-hydroxybutyrate, polydioxane ring a copolymer of hexanone, poly DTH iminocarbonic acid, polypropylene, fumaric acid, polyethylene terephthalate, polyamide, polyurethane, degradable iron alloy, degradable magnesium alloy, or the like or The mixture may be composed of a non-degradable material, such as a metal ruthenium, a medical stainless steel, a nickel-titanium alloy, a cobalt-chromium alloy, or the like, which is not limited herein.

As an embodiment of the present invention, the compound containing a divalent copper element in the blood vessel stent may be added not as a coating, but may be added as a scaffold constituent material in the process of preparing the blood vessel stent to make the divalent copper element The compound is present throughout the vascular stent.

As an embodiment of the present invention, in order to better control the coating effect and release rate of divalent copper ions, the coating includes an auxiliary material and a compound containing divalent copper. The auxiliary material may be one of a natural high molecular polymer and a synthetic high molecular polymer, a mixture or a copolymer. Further, the natural high molecular polymer may be one of a mixture, a mixture or a copolymer of collagen, chitosan or cellulose, and the synthetic high molecular polymer may be a polyamic acid anhydride, a polydioxanone or a poly DTH. One of a mixture, a mixture or a copolymer of iminocarbonic acid, polypropylene, polyfumaric acid, polyethylene terephthalate, polyamide, polyurethane, polyamino acid, aliphatic polyester. Wherein, the aliphatic polyester may be, for example, a polylactic acid-glycolic acid copolymer (PLGA), a polylactic acid (PLA), a polyglycolic acid (PGA), a polycaprolactone (PCL) or a poly-β-hydroxybutyrate. For one, copolymer or mixture, the polyanhydride may be, for example, 1,3-bis(p-carboxyphenoxy)propane-sebacic acid (P(CPP:SA)), polyfumaric acid-sebacic acid (P( FA:SA)), the polyamino acid may be, for example, polyalanine, polytyrosine or the like, which is not limited herein.

In the embodiment of the present invention, in order to enable the divalent copper element to be directly released or converted into copper ions by the divalent copper ions in the human body, the copper element in the copper-containing compound is a complex of Cu2+, copper-containing protein or Cu2+. Form exists. The amount of the copper element in the divalent copper-containing compound may be 1.4 to 2.6 μmol, preferably 1.7 to 2.3 μmol, and the ratio of the amount of the compound containing the divalent copper to the amount of the auxiliary material is 9:1 to 81. Controlling the total amount of release of divalent copper ions and the release rate, so that the concentration of divalent copper ions in the blood does not have a significant impact on the normal physiological activities of the human body due to excessive or too low, such as by adjusting the hydrophobicity of 1,3- The ratio of bis(p-carboxyphenoxy)propane (CPP) in the polyanhydride P (CPP-SA) to sebacic acid (SA) is controlled to regulate the release of divalent copper ions from a few days to several months.

In the embodiment of the present invention, in order to further enhance the effect of the vascular stent to promote vascular repair and regeneration, the vascular stent base or the coating may further contain other functional components for anticoagulant, angiogenesis inhibition, stem cell capture antibody, etc., such as Heparin, aspirin, etc.

The vascular stent described above can be prepared by preparing a coating material and then applying the coating material to the surface of the vascular stent substrate by spraying, modifying or electroplating to form a coating, for example, when When the layer material includes the auxiliary material and the compound containing divalent copper, the auxiliary material and the compound containing divalent copper may be uniformly mixed, and then the coating material is sprayed on the vascular stent base by a spray coater, or the auxiliary material and the divalent copper-containing material are used. The compound is added to the plating solution, and then the vascular stent substrate is placed in the plating solution to plate the coating material onto the surface of the vascular stent substrate.

The technical solutions and technical effects of the present invention will be further described below by way of specific examples. It should be noted that the concentration of copper ions in the solution in the following examples is determined by the method of dicyclohexanone oxalyl dihydrazide.

Example 1

In the embodiment of the present invention, copper chloride (CuCl2) is used as a source of divalent copper element, and polylactic acid-glycolic acid copolymer (PLGA) is used as an auxiliary material, and the ratio of copper chloride to polylactic acid-glycolic acid copolymer material is 9:1, wherein the amount of the divalent copper element is 1.7 μmol, the copper chloride and the polylactic acid-glycolic acid copolymer are mixed and sprayed on the vascular stent base, and then the vascular stent is placed in an 80 ml normal human plasma sample solution. In order to determine the concentration of divalent copper ions, the concentration of divalent copper ions is as shown in FIG.

Example 2

In the embodiment of the present invention, citric acid chelated copper is used as a source of divalent copper element, and poly DTH iminocarbonic acid, polyethylene terephthalate and poly-β-hydroxybutyrate are used as auxiliary materials, and citric acid chelation is used. The ratio of the amount of the copper substance to the sum of the amounts of the three auxiliary materials of poly DTH iminocarbonic acid, polyethylene terephthalate, and poly-β-hydroxybutyrate is 9:1, wherein the divalent copper element The amount of the substance is 1.9 μmol, and the citrate chelated copper is mixed with poly DTH iminocarbonic acid, polyethylene terephthalate, and poly-β-hydroxybutyrate, and then modified on the vascular stent base, and then the vascular stent is placed. It was placed in an 80 ml normal human plasma sample solution to determine the concentration of divalent copper ions, and the concentration of divalent copper ions is shown in FIG.

Example 3

In the embodiment of the present invention, copper chloride (CuCl2) is used as a source of divalent copper element, and polyfumaric acid is used as an auxiliary material, and the ratio of copper chloride to polyfumaric acid is 19:1, wherein divalent copper The amount of the elemental substance is 1.4 μmol, and the copper chloride is mixed with the polyfumaric acid, and then plated on the vascular stent base, and then the vascular stent is placed in an 80 ml normal human plasma sample solution to determine the concentration of the divalent copper ion, and the valence is determined. The copper ion concentration is shown in Figure 3.

Example 4

In the embodiment of the present invention, citrate chelated copper is used as a source of divalent copper element, and 1,3-bis(p-carboxyphenoxy)propane-sebacic acid (P(CPP:SA)) is used as an auxiliary material, citric acid. The amount ratio of chelated copper to 1,3-bis(p-carboxyphenoxy)propane-sebacic acid (P(CPP:SA)) material is 7:3, wherein the amount of the divalent copper element substance is 1.5 μmol The citrate chelated copper is mixed with 1,3-bis(p-carboxyphenoxy)propane-sebacic acid (P(CPP:SA)) and sprayed onto the vascular stent base, and then the vascular stent is placed in 80 ml normal. In the human plasma sample solution, the concentration of divalent copper ions is determined, and the concentration of divalent copper ions is as shown in FIG.

Example 5

In the embodiment of the present invention, cuprous oxide is used as a source of copper element, and collagen is used as an auxiliary material. The ratio of cuprous oxide to collagen material is 7:3, wherein the amount of copper element is 2.0 μmol, which will be oxidized. The copper was mixed with collagen and sprayed onto the vascular stent base, and then the vascular stent was placed in an 80 ml normal human plasma sample solution to determine the concentration of the divalent copper ions. The concentration of the divalent copper ions is shown in FIG.

Example 6

In the embodiment of the present invention, a copper-containing iron alloy is used as a source of copper element, and a copolymer of collagen and polypropylene is used as an auxiliary material, and a ratio of a substance containing a copolymer of copper-iron alloy and collagen and polypropylene is 7:3, wherein The amount of the copper element is 2.0 μmol. The copper-containing iron alloy is mixed with the copolymer of collagen and polypropylene and sprayed on the vascular stent base, and then the vascular stent is placed in an 80 ml normal human plasma sample solution to determine the bivalent value. The copper ion concentration and the divalent copper ion concentration are shown in Fig. 6.

Example 7

In the embodiment of the present invention, copper sulfate (CuSO4) is used as a source of divalent copper, and polyethylene terephthalate is used as an auxiliary material, and the amount of copper sulfate (CuSO4) and polyethylene terephthalate is used. The ratio is 1:1, wherein the amount of the divalent copper element is 2.6 μmol, and copper sulfate (CuSO4) is mixed with polyethylene terephthalate and sprayed on the vascular stent substrate, and then the blood vessel stent is placed. In a normal human plasma sample solution of 80 ml, the concentration of divalent copper ions was measured, and the concentration of divalent copper ions was as shown in FIG.

Example 8

In the embodiment of the present invention, citrate chelated copper is used as a source of divalent copper element, and a copolymer of polyethylene terephthalate and polypropylene is used as an auxiliary material, and citric acid chelated copper and polyethylene terephthalate The amount ratio of the copolymer of the glycol ester and the polypropylene is 1:1, wherein the mass of the divalent copper element is 1.8 μmol, and the citric acid is chelated with copper and polyethylene terephthalate and polypropylene. The copolymer was mixed and plated on a vascular stent base, and then the vascular stent was placed in an 80 ml normal human plasma sample solution to determine the concentration of divalent copper ions. The concentration of the divalent copper ions is shown in FIG.

Example 9

In the embodiment of the present invention, hemocyanin is used as a source of divalent copper, and chitosan-cellulose copolymer is used as an auxiliary material, and the ratio of hemocyanin to chitosan-cellulose copolymer is 1:1. Wherein the amount of the divalent copper element substance is 2.4 μmol, the hemocyanin and the chitosan-cellulose copolymer are mixed and modified on the vascular stent base, and then the vascular stent is placed in an 80 ml normal human plasma sample solution to The concentration of divalent copper ions was measured, and the concentration of divalent copper ions was as shown in FIG.

Example 10

In the embodiment of the present invention, hemocyanin is used as a source of divalent copper element, and polyamide is used as an auxiliary material, and the ratio of hemocyanin to polyamide is 3:7, wherein the amount of divalent copper element is 2.3 μmol. The limpet hemocyanin and the polyamide are mixed and plated on the vascular stent base, and then the vascular stent is placed in an 80 ml normal human plasma sample solution to determine the concentration of the cupric ion, and the concentration of the cupric ion is as shown in FIG.

Example 11

In the embodiment of the present invention, citrate chelated copper is used as a source of divalent copper element, and polylactic acid is used as an auxiliary material, and the ratio of chelating copper chelating copper to polylactic acid is 3:7, wherein the divalent copper element material The amount of 2.2 μmol was mixed with lactic acid chelated copper and polylactic acid and sprayed on the vascular stent substrate, and then the vascular stent was placed in an 80 ml normal human plasma sample solution to determine the concentration of divalent copper ions and the concentration of divalent copper ions. As shown in Figure 11.

Example 12

In the embodiment of the present invention, the adjacent phenanthrene

Copper complexes as a source of divalent copper, using polyamide and collagen mixtures as excipients, phenanthrene

The ratio of the amount of the copper complex material to the sum of the amounts of the polyamide and the collagen material is 3:7, wherein the amount of the divalent copper element is 2.0 μmol, and the phenanthrene

The copper complex, the polyamide and the collagen are mixed and electroplated on the vascular scaffold substrate, and then the vascular scaffold is placed in an 80 ml normal human plasma sample solution to determine the concentration of the divalent copper ion, and the concentration of the divalent copper ion is as shown in FIG. Show.

Example 13

In the embodiment of the present invention, a copper-containing titanium alloy is used as a source of copper, and a polyurethane is used as an auxiliary material, and the ratio of the content of the copper-containing titanium alloy to the polyurethane material is 1:9, wherein the amount of the copper element is 2.5 μmol, the copper-containing titanium alloy and polyurethane were mixed and electroplated on the vascular stent substrate, and then the vascular stent was placed in an 80 ml normal human plasma sample solution to determine the concentration of divalent copper ions, and the concentration of divalent copper ions was as follows. Figure 13 shows.

Example 14

In the embodiment of the present invention, copper chloride (CuCl2) is used as a source of divalent copper, and polyglycolic acid (PGA) is used as an auxiliary material, and the ratio of copper chloride (CuCl2) to polyglycolic acid (PGA) is 1: 9. The amount of the divalent copper element is 2.6 μmol. The copper chloride (CuCl 2 ) and the polyglycolic acid (PGA) are mixed and plated on the vascular stent substrate, and then the vascular stent is placed in an 80 ml normal human plasma sample solution. In order to determine the concentration of divalent copper ions, the concentration of divalent copper ions is as shown in FIG.

Example 15

In the embodiment of the present invention, citric acid chelated copper is used as a source of divalent copper element, and polydioxanone is used as an auxiliary material, and the ratio of chelating copper chelating copper to polydioxanone is 1: 9, wherein the amount of the divalent copper element is 2.1 μmol, the citrate chelate copper is mixed with the polydioxanone and modified on the vascular stent base, and then the vascular stent is placed in an 80 ml normal human plasma sample solution. In order to determine the concentration of divalent copper ions, the concentration of divalent copper ions is as shown in FIG.

The above is only the preferred embodiment of the present invention, and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection of the present invention. Within the scope.

Claims

A blood vessel stent, characterized in that the blood vessel stent comprises:

Vascular stent base;

a coating disposed on a surface of the vascular stent substrate, the coating comprising a divalent copper element.
The blood vessel stent according to claim 1, wherein said coating comprises an excipient and a compound containing a divalent copper element.
The blood vessel stent according to claim 2, wherein the excipient comprises one of a natural high molecular polymer and a synthetic high molecular polymer, a mixture or a copolymer.
The blood vessel stent according to claim 3, wherein said natural high molecular polymer comprises one, a mixture or a copolymer of collagen, chitosan or cellulose, said synthetic high molecular polymer comprising poly Anhydride, polydioxanone, poly DTH iminocarbonate, polypropylene, polyfumaric acid, polyethylene terephthalate, polyamide, polyurethane, polyamino acid, aliphatic polyester One of them, a copolymer or a mixture.
The blood vessel stent according to claim 4, wherein the aliphatic polyester comprises polylactic acid-glycolic acid copolymer (PLGA), polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone ( One of PCL) or poly-β-hydroxybutyrate, a copolymer or a mixture.
The blood vessel stent according to claim 2, wherein the divalent copper element in the divalent copper element-containing compound exists as a complex of Cu2+, a copper-containing protein or Cu2+.
The blood vessel stent according to any one of claims 2 to 6, wherein a ratio of the amount of the divalent copper element-containing compound to the auxiliary material is from 9:1 to 81.
A method of preparing a blood vessel stent according to any one of claims 1 to 7, wherein the method comprises the following steps:

Preparing a coating material comprising a divalent copper element;

The coating material is applied to the surface of the vascular stent substrate by spraying, modifying or electroplating to form a coating on the surface of the vascular stent substrate.