CN108852572B

CN108852572B - Multilayer intravascular stent and preparation method thereof

Info

Publication number: CN108852572B
Application number: CN201810798485.1A
Authority: CN
Inventors: 王刚; 王亮; 邹雪
Original assignee: Sichuan Xingtai Pollock Medical Technology Co Ltd
Current assignee: Lepu Shenzhen International Development Center Co ltd
Priority date: 2018-07-19
Filing date: 2018-07-19
Publication date: 2019-12-06
Anticipated expiration: 2038-07-19
Also published as: CN108852572A

Abstract

The invention discloses a multilayer intravascular stent which comprises a stent body, wherein the stent body is provided with an inner tube, an outer tube and a plurality of supporting bars, the inner tube is sleeved on the outer tube, the supporting bars are radially arranged on the outer wall of the inner tube, one end of each supporting bar is connected with the outer wall of the inner tube, the other end of each supporting bar is connected with the inner wall of the outer tube, the inner wall of the inner tube is coated with a first coating, and the outer wall of the outer tube is coated with a second coating. The preparation method of the multilayer vascular stent comprises (a) extruding polylactic acid out of a pipe, cutting by laser, and preparing a support strip on the outer wall of an inner pipe; coating rapamycin on the outer surface of the supporting strip, and drying; manufacturing an outer pipe at one end of the supporting bar far away from the inner pipe; (b) coating heparin drugs and alumina hydrogel on the inner surface of the inner tube, and coating the alumina hydrogel on the surface of the first coating; (c) and (4) performing electrostatic spinning on the outer surface of the outer tube for 1-2h to form a second coating of 5-10 um.

Description

Multilayer intravascular stent and preparation method thereof

Technical Field

The invention belongs to the technical field of medical equipment, and particularly relates to a multilayer intravascular stent and a preparation method thereof.

Background

polylactic acid is mostly adopted as a matrix material for polymer intravascular stents, but the polylactic acid can promote the formation of thrombus in blood vessels; after most of the existing vascular stents are placed in blood vessels, the drug coating loaded on the stents is usually released within 1 month, the intima of the blood vessels can not be completely repaired, and after the drug is released, no drug exists in the stents, so that the probability of thrombosis is further increased.

Antithrombotic stents in the prior art are mostly formed by coating antithrombotic drugs on stents, for example, patent CN201320855841.1 discloses a new antithrombotic stent, which comprises a first antithrombotic drug layer and a second antithrombotic drug layer, and the antithrombotic drugs are loaded on the two layers of coatings to realize antithrombotic; however, the blood vessel stent in the patent also has low biological activity, which may cause foreign body reaction of the stent in vivo, and the stent has single function and does not have the function of repairing blood vessels.

Disclosure of Invention

The invention aims to: the defects in the prior art are overcome, and the multilayer vascular stent and the method for preparing the multilayer vascular stent are provided.

in order to achieve the purpose, the invention adopts the technical scheme that: the utility model provides a multilayer vascular support, includes the support body, the support body has inner tube, outer tube and a plurality of support bar, inner tube suit in the outer tube, the support bar is radially located the outer wall of inner tube, the one end of support bar has the outer wall connection of inner tube, the other end of support bar with the interior wall connection of outer tube, the inner wall coating of inner tube has first coating, the outer wall coating of outer tube has the second coating.

Further, a plurality of the supporting strips are distributed on the outer surface of the inner pipe in a radial mode.

Furthermore, the wall thickness of the inner tube is 0.10-0.2mm, the inner diameter of the inner tube is 2.50-4.50mm, the wall thickness of the outer tube is 0.05-0.1mm, the distance between adjacent support bars is 0.10-0.50mm, and the diameter of each support bar is 0.01-0.1 mm.

The method for preparing the multilayer vascular stent comprises the following steps:

(a) The support body: adding polylactic acid into an extruder, extruding a pipe, cutting the pipe by laser to obtain an inner pipe, placing the inner pipe in a corresponding mould, adding a shape memory polymer in a molten state into the mould, cooling to room temperature, drying, and preparing a support strip on the outer wall of the inner pipe; coating the rapamycin-loaded solution on the outer surface of the supporting strip, and drying; placing the inner tube in a corresponding mould, adding the shape memory polymer into the mould, cooling to room temperature, drying, and preparing an outer tube at one end of the support bar far away from the inner tube;

(b) A first coating layer: uniformly mixing heparin medicines and alumina hydrogel, ultrasonically spraying the mixture on the inner surface of the inner tube of the stent body prepared in the step (a), drying the mixture at the temperature of 20-25 ℃ to prepare a first coating, coating the alumina hydrogel on the surface of the first coating, and drying the coated alumina hydrogel at the temperature of 20-25 ℃ to prepare a gel coating; wherein, the thickness of the first coating is 1-3um, and the thickness of the gel coating is 2-5 um;

(c) And (3) second coating: adding GRGD-spidroin, gelatin and polycaprolactone into a container, stirring uniformly, adding formic acid and chloroform into the container in sequence, stirring uniformly to obtain an electrospinning solution, and performing electrostatic spinning on the outer surface of the outer tube of the stent body in the step (a) for 1-2 hours to form a second coating of 5-10um on the outer surface of the stent body.

Furthermore, the weight part ratio of the GRGD-spider silk protein to the gelatin to the polycaprolactone is 0.1-0.5:1-10: 1-10.

Further, the heparin medicine is one of enoxaparin sodium, nadroparin calcium or dalteparin sodium.

Further, the preparation method of the alumina water-soluble gel comprises the following steps: adding aluminum isopropoxide into water with the temperature of 20 ℃, uniformly stirring, adding a chloroform solution, heating a solution system to 60-80 ℃, uniformly stirring, standing at the temperature of 60-80 ℃, extracting an inorganic phase after liquid is layered, ultrasonically stirring the inorganic phase for 1-3h, and cooling to room temperature to obtain the alumina hydrogel.

Furthermore, the weight ratio of the heparin medicine to the alumina hydrogel in the first coating is 1: 5-10.

Further, in the step (c), the voltage of electrostatic spinning is 5-20KV, the distance between a spray head of the electrostatic spinning and the support body is 20-50cm, and the rotating speed of the support body is 10-100 rpm.

due to the adoption of the technical scheme, the invention has the beneficial effects that:

The multilayer intravascular stent consists of an inner tube, an outer tube and a supporting strip, wherein the inner tube is sleeved in the outer tube, the supporting strip is arranged between the inner tube and the outer tube, and the supporting strip and the outer tube are both shape memory polymers and can radially expand in a blood vessel to open the blood vessel; when the stent is expanded, the stent does not retract axially, so that the damage of the stent to a blood vessel is reduced. Coating a first coating on the inner wall of the inner tube, wherein the first coating contains heparin medicines, and an alumina hydrogel layer is coated outside the first coating, so that the heparin medicines can prevent thrombosis; rapamycin is coated on the supporting bars, the rapamycin is firstly released in blood vessels, and the heparin medicine is released later due to the protection of the alumina hydrogel layer, so that the antithrombotic time of the stent is prolonged and the formation of thrombus is reduced; the outer wall of the tube is coated with a second coating which is a GRGD-spidroin protein, gelatin and polycaprolactone coating, so that the biological activity of the stent can be increased, the foreign body reaction of the polymer stent in the body can be reduced, and meanwhile, the surface layer material has the effect of promoting healing and can promote the formation of the vascular intima, thereby achieving the purpose of repairing the blood vessel.

Drawings

FIG. 1 is a left side view of the stent of the present invention

FIG. 2 is a front view of the inner tube and the support strip of the stent of the present invention

Reference numerals: 1-inner tube, 2-support bar, 3-outer tube.

Detailed Description

Embodiments of the present invention will be described in detail with reference to the accompanying fig. 1-2.

Example 1:

(a) Adding polylactic acid with the molecular weight of 90 ten thousand Da into an extruder, extruding a pipe with the wall thickness of 0.2mm, cutting the pipe by laser, cutting the wall of the pipe into a net-shaped structure to obtain an inner pipe 1, wherein the inner diameter of the inner pipe 1 is 4mm, placing the inner pipe 1 into a mould for preparing support strips 2, adding shape memory polymers in a molten state into the mould, cooling to room temperature, drying, preparing the support strips 2 on the outer wall of the inner pipe 1, wherein a plurality of the support strips 2 are radially distributed on the outer surface of the inner pipe 1, the diameter of each support strip 2 is 0.05mm, and the distance between every two adjacent support strips 2 is 0.5 mm; then coating the rapamycin-loaded solution on the outer surface of the support strip 2 and drying; then placing the inner tube 1 in a mold for preparing the outer tube 3, adding the shape memory polymer into the mold, cooling to room temperature, drying, and preparing the outer tube 3 at one end of the supporting bar 2 far away from the inner tube 1, wherein the wall thickness of the outer tube 3 is 0.05mm, and the outer diameter of the outer tube 3 is 7 mm; the two ends of the supporting bar 2 are respectively connected with the inner tube 1 and the outer tube 3 to form a whole.

(b) a first coating layer: uniformly mixing 1 part of enoxaparin sodium and 5 parts of alumina water-soluble gel, ultrasonically spraying the mixture on the inner surface of the inner tube 1 of the stent body prepared in the step (a), drying the mixture at 25 ℃ to prepare a first coating, coating the alumina water-soluble gel on the surface of the first coating, and drying the coated alumina water-soluble gel at 25 ℃ to prepare a gel coating; wherein, the thickness of the first coating is 3um, and the thickness of the gel coating is 2 um;

(c) And (3) second coating: adding 0.1 part of GRGD-spider silk protein, 1 part of gelatin and 1 part of polycaprolactone into a container, uniformly stirring, adding formic acid and chloroform into the container in sequence, uniformly stirring to obtain an electrospinning solution, and performing electrostatic spinning on the outer surface of the outer tube 3 of the stent body in the step (a) for 2 hours to form a second coating of 2um on the outer surface of the stent body. Wherein the working voltage of the electrostatic spinning is 5KV, the distance between the spray head and the bracket body is 20cm, and the rotating speed of the bracket body is 50 rpm. The prepared stent is compressed in a delivery pipe, and the outer diameter of the outer pipe 3 of the compressed stent is 2 mm.

In this example, the method for preparing an alumina hydrogel was: adding aluminum isopropoxide into water with the temperature of 20 ℃, uniformly stirring, adding a chloroform solution, heating a solution system to 60 ℃, uniformly stirring, standing at the temperature of 60 ℃, extracting an inorganic phase after liquid is layered, ultrasonically stirring the inorganic phase for 3 hours, and cooling to room temperature to obtain the alumina hydrogel.

The support of this embodiment preparation has inner tube 1, outer tube 3 and a plurality of support bar 2, and 1 suit in inner tube 3, a plurality of support bar 2 radially locate the outer wall of inner tube 1, a plurality of support bar 2 are radial distribution, and the wall of inner tube 1 is the netted framework of fretwork, the one end of support bar 2 has the outer wall connection of inner tube 1, the other end of support bar 2 with the interior wall connection of outer tube 3, the inner wall coating of inner tube 1 has first coating, the outer wall coating of outer tube 3 has the second coating.

Example 2:

(a) Adding polylactic acid with the molecular weight of 100 ten thousand Da into an extruder, extruding a pipe with the wall thickness of 0.2mm, cutting the pipe by laser to obtain an inner pipe 1, wherein the inner diameter of the inner pipe 1 is 4mm, placing the inner pipe 1 into a mold for preparing support strips 2, adding shape memory polymers in a molten state into the mold, cooling to room temperature, drying, preparing the support strips 2 on the outer wall of the inner pipe 1, radially distributing a plurality of the support strips 2 on the outer surface of the inner pipe 1, wherein the diameter of each support strip 2 is 0.01mm, and the distance between every two adjacent support strips 2 is 0.4 mm; then coating the rapamycin-loaded solution on the outer surface of the support strip 2 and drying; then placing the inner tube 1 in a mold for preparing the outer tube 3, adding the shape memory polymer into the mold, cooling to room temperature, drying, and preparing the outer tube 3 at one end of the supporting bar 2 far away from the inner tube 1, wherein the wall thickness of the outer tube 3 is 0.1 mm; the external diameter of outer tube 3 is 7mm, and the both ends of support bar 2 are connected with inner tube 1 and outer tube 3 respectively, form a whole.

(b) A first coating layer: uniformly mixing 1 part of nadroparin calcium and 8 parts of alumina water-soluble gel, ultrasonically spraying the mixture on the inner surface of the inner tube 1 of the stent body prepared in the step (a), drying the mixture at the temperature of 20 ℃ to prepare a first coating, coating the surface of the first coating with the alumina water-soluble gel, and drying the coated gel at the temperature of 20 ℃ to prepare a gel coating; wherein the thickness of the first coating is 2um, and the thickness of the gel coating is 5 um;

(c) and (3) second coating: adding 0.3 part of GRGD-spider silk protein, 3 parts of gelatin and 5 parts of polycaprolactone into a container, uniformly stirring, adding formic acid and chloroform into the container in sequence, uniformly stirring to obtain an electrospinning solution, and performing electrostatic spinning on the outer surface of the outer tube 3 of the stent body in the step (a) for 2 hours to form a second coating of 2um on the outer surface of the stent body. Wherein the working voltage of the electrostatic spinning is 10KV, the distance between the spray head and the bracket body is 30cm, and the rotating speed of the bracket body is 10 rpm.

Example 3:

(a) adding polylactic acid with the molecular weight of 90 ten thousand Da into an extruder, extruding a pipe with the wall thickness of 0.1mm, cutting the pipe by laser to obtain an inner pipe 1, wherein the inner diameter of the inner pipe 1 is 3mm, placing the inner pipe 1 into a mold for preparing support strips 2, adding shape memory polymers in a molten state into the mold, cooling to room temperature, drying, preparing the support strips 2 on the outer wall of the inner pipe 1, radially distributing the support strips 2 on the outer surface of the inner pipe 1, wherein the diameter of each support strip 2 is 0.1mm, and the distance between every two adjacent support strips 2 is 0.5 mm; then coating the rapamycin-loaded solution on the outer surface of the support strip 2 and drying; then placing the inner tube 1 in a mold for preparing the outer tube 3, adding the shape memory polymer into the mold, cooling to room temperature, drying, and preparing the outer tube 3 at one end of the supporting bar 2 far away from the inner tube 1, wherein the wall thickness of the outer tube 3 is 0.1 mm; the two ends of the supporting bar 2 are respectively connected with the inner tube 1 and the outer tube 3 to form a whole.

(b) a first coating layer: uniformly mixing 1 part of dalteparin sodium and 10 parts of alumina hydrogel, ultrasonically spraying the mixture on the inner surface of the inner tube 1 of the stent body prepared in the step (a), drying at 23 ℃ to prepare a first coating, coating the surface of the first coating with the alumina hydrogel, and drying at 23 ℃ to prepare a gel coating; wherein the thickness of the first coating is 1um, and the thickness of the gel coating is 3 um;

(c) and (3) second coating: adding 0.5 part of GRGD-spider silk protein, 10 parts of gelatin and 5 parts of polycaprolactone into a container, uniformly stirring, adding formic acid and chloroform into the container in sequence, uniformly stirring to obtain an electrospinning solution, and performing electrostatic spinning on the outer surface of the outer tube 3 of the stent body in the step (a) for 2 hours to form a second coating of 6um on the outer surface of the stent body. Wherein the working voltage of the electrostatic spinning is 20KV, the distance between the spray head and the bracket body is 50cm, and the rotating speed of the bracket body is 100 rpm.

Example 4:

(a) Adding polylactic acid with the molecular weight of 120 ten thousand Da into an extruder, extruding a pipe with the wall thickness of 0.2mm, cutting the pipe by laser to obtain an inner pipe 1, placing the inner pipe 1 into a mold for preparing support strips 2, adding shape memory polymers in a molten state into the mold, cooling to room temperature, drying, preparing the support strips 2 on the outer wall of the inner pipe 1, radially distributing the support strips 2 on the outer surface of the inner pipe 1, wherein the diameter of each support strip 2 is 0.05mm, and the distance between every two adjacent support strips 2 is 0.5 mm; then coating the rapamycin-loaded solution on the outer surface of the support strip 2 and drying; then placing the inner tube 1 in a mold for preparing the outer tube 3, adding the shape memory polymer into the mold, cooling to room temperature, drying, and preparing the outer tube 3 at one end of the supporting bar 2 far away from the inner tube 1, wherein the wall thickness of the outer tube 3 is 0.05 mm; the two ends of the supporting bar 2 are respectively connected with the inner tube 1 and the outer tube 3 to form a whole.

(b) A first coating layer: uniformly mixing 1 part of enoxaparin sodium and 10 parts of alumina hydrogel, ultrasonically spraying the mixture on the inner surface of the inner tube 1 of the stent body prepared in the step (a), drying the mixture at 25 ℃ to prepare a first coating, coating the alumina hydrogel on the surface of the first coating, and drying the coated alumina hydrogel at 25 ℃ to prepare a gel coating; wherein the thickness of the first coating is 1um, and the thickness of the gel coating is 5 um;

(c) And (3) second coating: adding 0.5 part of GRGD-spider silk protein, 3 parts of gelatin and 10 parts of polycaprolactone into a container, uniformly stirring, adding formic acid and chloroform into the container in sequence, uniformly stirring to obtain an electrospinning solution, and performing electrostatic spinning on the outer surface of the outer tube 3 of the stent body in the step (a) for 2 hours to form a second coating of 5um on the outer surface of the stent body. Wherein the working voltage of the electrostatic spinning is 20KV, the distance between the spray head and the bracket body is 20cm, and the rotating speed of the bracket body is 10 rpm.

In this example, the method for preparing an alumina hydrogel was: adding aluminum isopropoxide into water with the temperature of 20 ℃, uniformly stirring, adding a chloroform solution, heating a solution system to 80 ℃, uniformly stirring, standing at 80 ℃, extracting an inorganic phase after liquid is layered, ultrasonically stirring the inorganic phase for 3 hours, and cooling to room temperature to obtain the alumina hydrogel.

comparative test example 1: this comparative test example is different from the above example 1 in that the inner wall of the inner tube 1 and the supporting strip 2 are not coated with the drug, and the rest is the same as example 1.

Comparative test example 2: this comparative test example is different from example 1 in that the inner wall of the inner tube 1 is not coated with the drug, and is the same as example 1.

comparative test example 3: the difference from example 2 is that the outer wall of the outer tube 3 was not coated with the second coating layer, and the rest was the same as example 2.

The vascular stents of the above examples 1 to 4 and comparative test examples 1 to 2 were subjected to an antithrombotic examination: taking fresh blood, adding a small amount of anticoagulant into the blood, dripping the blood on the stent to enable the blood to smoothly flow along the wall of the inner tube 1, the inner light and the outer tube 3, repeating dripping for 15 times, observing the surface of the stent, and obtaining the result shown in table 1:

TABLE 1

as can be seen from Table 1, the vascular stents of examples 1-4 were good in antithrombotic property, and had no blood and protein deposition on the stents.

the vascular stents of the above examples 1 to 4 and comparative test examples 1 to 3 were implanted into the blood vessels of normal rabbits, and the minimum diameter of the blood vessels at the stents, the stent degradation condition, the thrombosis condition and the inflammatory response were observed by imaging at different times after the implantation, respectively, and the results showed that the stents of the examples 1 to 4 began to degrade after 1 year, and no thrombus or severe inflammatory response appeared during the 1 year period, indicating that the stents of the examples 1 to 4 have good antithrombotic property and biocompatibility; the stent of comparative test example 1 began to appear thrombus 1 month after implantation, and at month 3, the blood vessel at the stent had been completely blocked. At month 2.5 after the stent of experimental example 2 was implanted, thrombus began to appear, and at month 5, the blood vessel was completely occluded and blood did not flow smoothly. The stent of comparative test example 3 exhibited a severe inflammatory reaction at month 8 and a small amount of thrombus at month 10. Comparing example 1, comparative test example 1 and comparative test example 2, it can be seen that the stent of the present invention has better biocompatibility, the stent is not easy to generate inflammatory reaction in blood vessels, meanwhile, rapamycin on the stent is released first, and heparin drugs in the first coating are released later, so that the release time of antithrombotic drugs is prolonged, and thrombus is reduced. Comparing example 2 and comparative test example 3, it can be seen that the inventive stent is biocompatible and is less likely to cause inflammatory reactions.

Claims

1. The multilayer intravascular stent is characterized by comprising a stent body, wherein the stent body is provided with an inner tube (1), an outer tube (3) and a plurality of supporting bars (2), the inner tube (1) is sleeved on the outer tube (3), the supporting bars (2) are radially arranged on the outer wall of the inner tube (1), one end of each supporting bar (2) is connected with the outer wall of the inner tube (1), the other end of each supporting bar (2) is connected with the inner wall of the outer tube (3), the inner wall of the inner tube (1) is coated with a first coating, and the outer wall of the outer tube (3) is coated with a second coating;

The preparation method of the multilayer vascular stent comprises the following steps:

(a) The support body: adding polylactic acid into an extruder, extruding a pipe, cutting the pipe by laser to obtain an inner pipe (1), placing the inner pipe (1) into a corresponding mould, adding a shape memory polymer in a molten state into the mould, cooling to room temperature, drying, and preparing a support strip (2) on the outer wall of the inner pipe (1); coating the rapamycin-loaded solution on the outer surface of the support strip (2), and drying; placing the inner pipe (1) in a corresponding mould, adding a shape memory polymer into the mould, cooling to room temperature, drying, and preparing an outer pipe (3) at one end of the support bar (2) far away from the inner pipe (1);

(b) a first coating layer: uniformly mixing heparin medicines and alumina hydrogel, ultrasonically spraying the mixture on the inner surface of the inner tube (1) of the stent body prepared in the step (a), drying the mixture at 20-25 ℃ to prepare a first coating, coating the alumina hydrogel on the surface of the first coating, and drying the coated alumina hydrogel at 20-25 ℃ to prepare a gel coating; wherein, the thickness of the first coating is 1-3um, and the thickness of the gel coating is 2-5 um;

(c) And (3) second coating: adding GRGD-spidroin, gelatin and polycaprolactone into a container, stirring uniformly, adding formic acid and chloroform into the container in sequence, stirring uniformly to obtain an electrospinning solution, and performing electrostatic spinning on the outer surface of the outer tube (3) of the stent body in the step (a) for 1-2 hours to form a second coating of 5-10um on the outer surface of the stent body.

2. the multilayered vascular stent of claim 1, wherein: the supporting strips (2) are distributed on the outer surface of the inner tube (1) in a radial mode.

3. The multilayered vascular stent of claim 1, wherein: the wall thickness of the inner tube (1) is 0.10-0.2mm, the inner diameter of the inner tube (1) is 2.50-4.50mm, the wall thickness of the outer tube (3) is 0.05-0.1mm, the distance between the adjacent support bars (2) is 0.10-0.50mm, and the diameter of the support bars (2) is 0.01-0.1 mm.

4. The method for preparing a multilayered vascular stent according to claim 1, wherein: the mass ratio of the GRGD-spidroin protein to the gelatin to the polycaprolactone is 0.1-0.5:1-10: 1-10.

5. The method for preparing a multilayered vascular stent according to claim 1, wherein: the heparin medicine is one of enoxaparin sodium, nadroparin calcium or dalteparin sodium.

6. the method for preparing a multilayered vascular stent according to claim 1, wherein: the preparation method of the alumina water-soluble gel comprises the following steps: adding aluminum isopropoxide into water with the temperature of 20 ℃, uniformly stirring, adding a chloroform solution, heating a solution system to 60-80 ℃, uniformly stirring, standing at the temperature of 60-80 ℃, extracting an inorganic phase after liquid is layered, ultrasonically stirring the inorganic phase for 1-3h, and cooling to room temperature to obtain the alumina hydrogel.

7. the method for preparing a multilayered vascular stent according to claim 1, wherein: the weight ratio of the heparin medicine to the alumina hydrogel in the first coating is 1: 5-10.

8. The method for preparing a multilayered vascular stent according to claim 1, wherein: in the step (c), the voltage of electrostatic spinning is 5-20KV, the distance between a spray head of the electrostatic spinning and the bracket body is 20-50cm, and the rotating speed of the bracket body is 10-100 rpm.