KR102590225B1 - Method of manufacturing hydrophobic stent using electron beam pulse and hydrophobic stent manufactured by the method - Google Patents

Abstract

A method of manufacturing a water-repellent stent is disclosed in which the stent surface is modified to be water-repellent by irradiating an electron beam pulse to the stent. A method for manufacturing a water-repellent stent according to an embodiment of the present invention includes the steps of (a) preparing a stent; and modifying the surface of the stent to be water-repellent by electron beam treatment of repeatedly applying electron beam pulses to the stent multiple times.

Description

Method of manufacturing a water-repellent stent using electron beam pulse and a water-repellent stent manufactured thereby {Method of manufacturing hydrophobic stent using electron beam pulse and hydrophobic stent manufactured by the method}

The present invention relates to a method of manufacturing a water-repellent stent for implantation in the body, and more specifically, to a method of manufacturing a water-repellent stent in which the surface of the stent is modified to be water-repellent by applying an electron beam pulse to the stent.

Myocardial infarction, one of the cardiovascular diseases, is a systemic disease in which cholesterol builds up inside the blood vessel walls and narrows the blood vessels. One of the treatment methods for this is stenting, which is a technique that normalizes blood flow by inserting a stent into a narrowed or blocked blood vessel to physically expand the narrowed blood vessel.

This surgical procedure is very effective in dilating narrowed blood vessels and is a relatively simple surgical method compared to methods such as vascular bypass surgery. However, in some cases, symptoms of restenosis at the stent insertion site occur within 3 to 6 months after the procedure, causing damage to the blood vessel wall. There is a problem that the narrowing phenomenon occurs again.

To solve this problem, regular checkups and periodic intake of thrombolytic drugs are implemented after stent surgery. However, regular use of thrombolytic drugs has limitations in that it creates resistance to the drug and makes it difficult to perform emergency surgery in the event of an unexpected accident.

To overcome these problems, drug-coated stents (drug eluting stents) coated with drugs on the surface were developed. However, because the amount of the coated drug is small, the coated drug is consumed 2-3 weeks after stent insertion, so it has the disadvantage of having to take the drug again afterwards. In addition, stents attached with substances such as peptides and heparin have been developed, but commercialization is difficult due to difficulties such as clinical trials in various environments, and there are problems with the complexity of the process and stent storage methods.

Recently, instead of drug-centered restenosis solutions, research has been conducted to minimize restenosis through stent surface modification. This method can reduce restenosis by minimizing the degree of adsorption of protein-based plasma present in blood vessels to the stent surface. In addition, research was conducted to change the surface roughness of the stent strut using a femtosecond laser and to minimize restenosis by coating it with a drug. Because the surface is reprocessed using a laser, there are problems with process complexity and increased stent costs. In addition, research has been conducted to reduce restenosis by changing the surface energy through nitrogen ion injection into the surface of a metal stent, but practical application is difficult due to low water repellency and limited biocompatibility of the ion-implanted material.

Meanwhile, there is a technology that reduces the surface roughness of the stent to prevent the inner wall of the blood vessel from being torn by friction with the stent when inserting the stent into the blood vessel. This method requires an additional electro-chemical polishing step after processing the material into a stent shape. However, it is difficult to secure the water-repellent properties of the stent simply by reducing the surface roughness.

The present invention is intended to provide a method for manufacturing a water-repellent stent by applying an electron beam pulse to the stent to modify the surface of the stent to be water-repellent, and a water-repellent stent manufactured thereby.

In addition, by modifying the surface of the stent to be water-repellent, the present invention prevents stenosis of proteins such as plasma and cholesterol within blood vessels and cell growth such as neointima, thereby lowering the restenosis rate of blood vessels and increasing the use cycle of the stent. The purpose is to provide a method of manufacturing a water-repellent stent that can solve the inconvenience caused by the operator's regular checkups and periodic taking of thrombolytics.

In addition, the present invention is intended to provide a method of manufacturing a water-repellent stent that can modify the stent to be water-repellent by irradiating an electron beam pulse to the surface of the stent and at the same time reduce the surface roughness of the stent.

A method for manufacturing a water-repellent stent according to an embodiment of the present invention includes (a) preparing the stent; and (b) modifying the surface of the stent to be water-repellent by electron beam treatment in which electron beam pulses are repeatedly applied to the stent multiple times.

The step (b) includes (b1) applying an electron beam pulse to the stent by an electron beam pulse application device for a set pulse application time; and (b2) after the electron beam pulse is applied, resting for a set pause time so that the surface of the stent is cooled, wherein the steps (b1) and (b2) are sequentially repeated a plurality of times. It may include a method of modifying the surface of the stent.

Step (b) may further include a method of modifying the surface of the stent by repeating the electron beam pulse 3 to 5 times.

The pulse application time can be set within 1 μsec to 3 μsec, and the pause time can be set within 3 seconds to 7 seconds.

The pause time may be set to 1*10 ⁶ times to 7*10 ⁶ times the pulse application time.

In step (b), the electron beam pulse may be applied by plasma in an oxygen atmosphere.

The method for manufacturing a water-repellent stent according to an embodiment of the present invention is: setting the cathode voltage to 20 kV to 30 kV, setting the anode voltage to 3 kV to 5 kV, and setting the solenoid voltage to 1 kV to 1.5 kV, It may include a method of applying the electron beam pulse by setting the distance between the electron beam pulse gun and the stent to 20 mm to 40 mm.

Step (b) includes polishing the stent to reduce surface roughness of the stent; and modifying the surface of the stent to be water-repellent by repeatedly applying the electron beam pulse to the stent with reduced surface roughness a plurality of times.

The stent may be a metal stent containing CoCr.

Step (b) may include a method of modifying the surface of the stent to be water-repellent by changing Cr(OH)3 formed on the surface of the metal stent into Cr2O3 by the electron beam pulse.

The water-repellent stent according to an embodiment of the present invention is manufactured by the water-repellent stent manufacturing method, and includes a stent body for implantation into the body; and an oxidation layer formed on the surface of the stent body by multiple electron beam pulses, and a contact angle with water of 120° to 150°.

The stent body may be a metal stent containing CoCr, the oxidation layer may contain Cr2O3, and the oxidation layer may serve as a protective layer to prevent the interior of the stent body from being oxidized.

According to an embodiment of the present invention, a method for manufacturing a water-repellent stent is provided by applying an electron beam pulse to the stent to modify the surface of the stent to be water-repellent, and a water-repellent stent manufactured thereby.

In addition, according to an embodiment of the present invention, by modifying the surface of the stent to be water-repellent, it is possible to reduce protein stenosis such as plasma and cholesterol present in blood vessels and inhibit cell growth such as neointima. Accordingly, the restenosis rate of blood vessels can be lowered and the cycle of stent use can be increased, and the inconvenience of the operator's regular checkups and periodic taking of thrombolytics can also be resolved.

In addition, the present invention can irradiate the surface of the stent with an electron beam pulse to modify the surface of the stent to be water-repellent and at the same time reduce the stent surface roughness. Therefore, the surface polishing process, which involves processing the material into a stent shape and then performing an additional electro-chemical polishing step to lower the surface roughness, can be omitted.

1 is a flowchart of a method for manufacturing a water-repellent stent according to an embodiment of the present invention.
FIG. 2 is a flowchart specifically showing step S20 of FIG. 1.
Figure 3 is a graph regarding the application and pause time of an electron beam pulse according to an embodiment of the present invention.
Figure 4 is a cross-sectional view schematically showing the configuration of the electron beam irradiation device.
Figure 5 is a contact angle analysis table of a water-repellent stent according to an embodiment of the present invention.
Figure 6 is an SEM of a stent before and after applying an electron beam pulse to the stent.
Figure 7 shows the XPS results of the CoCr alloy stent surface before and after electron beam pulse application.
Figure 8 is a graph showing the radial force value of the expanded stent after irradiation with an electron beam pulse.
Figure 9 shows the results of a cardiac muscle cell growth experiment on the CoCr surface 310 before the application of the electron beam pulse and on the CoCr surface 300 after the application of the electron beam pulse and images taken with a metal microscope.

The advantages and/or features of the present invention and methods for achieving them will become clear by referring to the embodiments described in detail below in conjunction with the accompanying drawings. However, the present invention is not limited to the embodiments disclosed below and will be implemented in various different forms, but the present embodiments only serve to ensure that the disclosure of the present invention is complete and are within the scope of common knowledge in the technical field to which the present invention pertains. It is provided to fully inform those who have the scope of the invention, and the present invention is only defined by the scope of the claims. Like reference numerals refer to like elements throughout the specification. Hereinafter, embodiments of the present invention will be described in detail with reference to the attached drawings.

The method for manufacturing a water-repellent stent according to an embodiment of the present invention is to reduce the re-adsorption rate of blood vessels by making it difficult to narrow proteins such as plasma and cholesterol present in blood vessels after a stent insertion procedure, and thereby increase the use cycle of the stent. Electron beam By applying a pulse (electron beam pulse) to change the surface roughness and energy of the stent through recrystallization of the material, the stent surface is modified to be water-repellent. Surface treatment using a large-area electron beam is a very simple process, has the advantage of enabling effective surface modification even within a short process time, and has the advantage of maintaining high water-repellent properties for a long period of time. In addition, electron beam treatment is suitable for surface treatment of stents with complex three-dimensional shapes because the entire surface of the sample is modified using a reactive gas in a vacuum atmosphere.

1 is a flowchart of a method for manufacturing a water-repellent stent according to an embodiment of the present invention. FIG. 2 is a flowchart specifically showing step S20 of FIG. 1. Figure 3 is a graph regarding the application and pause time of an electron beam pulse according to an embodiment of the present invention. Figure 4 is a cross-sectional view schematically showing the configuration of the electron beam irradiation device.

1 to 4, the method for manufacturing a water-repellent stent according to an embodiment of the present invention includes manufacturing a stent with a fine wire mesh structure by laser processing (S10), and repeatedly applying an electron beam pulse to the manufactured stent multiple times. It may include a step (S20) of modifying the surface of the stent to be water-repellent by electron beam treatment. For example, the stent may be a metal stent made of a biocompatible material such as CoCr (Cobalt-Chromium) alloy or stainless steel (SUS303, SUS319, etc.). For example, the step of manufacturing a stent by laser processing (S10) may include laser processing a round bar-shaped CoCr tube into a stent shape. In step S20, the electron beam treatment for the stent includes applying an electron beam pulse to the stent by plasma in an oxygen atmosphere by an electron beam pulse application device for a set pulse application time (T1) (S22), and after the electron beam pulse is applied, the stent. It may include a step (S24) of resting for a rest time (T2) set to allow the surface to cool. At this time, the step of applying the electron beam pulse (S22) and the rest step (S24) are sequentially repeated a set number of times (N) (S26), and thus the process of modifying the surface of the stent to be water-repellent can be completed.

The electron beam pulse application treatment may be performed under a gas other than an oxygen atmosphere. As an example, electron beam processing creates a plasma based on gases such as oxygen, argon, and nitrogen in a low vacuum atmosphere (e.g., 0.05 Pa), and uses a DC of 30 KeV or This can be performed through RF-based field emission, thereby changing the surface of the stent to water-repellent properties. Metal has a hydrophilic nature, making it very easy to adsorb proteins such as plasma and cholesterol present in blood vessels. However, according to an embodiment of the present invention in which electron beam pulse application treatment is performed on a stent, restenosis is prevented even when a metal stent is applied. Occurrence can be prevented.

In an embodiment of the present invention, the repetition number (N) of the electron beam pulse is set to 3 to 5 times, the pulse application time (T1) is set to within 1 μsec (microsecond) to 3 μsec, and the pause time (T2) is set to 3 to 5 times. It can be set within seconds to 7 seconds. The pause time (T2) can be set to 1*10 ⁶ times to 7*10 ⁶ times the pulse application time (T1).

The reason why it is desirable to set the repetition number (N) of the electron beam pulse to 3 to 5 times is that if the repetition number (N) of the electron beam pulse is set to 1 or 2, it is difficult to obtain the water repellency modification effect by the electron beam pulse, and it is difficult to obtain the water repellency modification effect by the electron beam pulse 5 times. This is because a sufficient water repellency modification effect can be obtained with pulses, and the water repellency modification effect is saturated by electron beam pulses exceeding 5 times, so the increase in water repellency is not significant.

The reason why it is desirable to limit the pulse application time (T1) of the electron beam pulse to the range of 1 μsec to 3 μsec is that if the pulse application time (T1) is less than 1 μsec, the surface material of the stent does not melt, making surface treatment impossible or insufficient water repellency modification effect. It is difficult to expect, and if it exceeds 3μsec, the surface of the stent may be damaged or the rest period (T2) may need to be set longer, which may lower productivity.

The reason for setting the pause time (T2) within 3 to 7 seconds is that if the pause time (T2) is shorter than 3 seconds, the surface material of the stent dissolved by the electron beam pulse may not be cooled sufficiently and may not solidify. This is because the water-repellent modification effect decreases with repeated application, and the stent surface can be sufficiently cooled with a pause time (T2) of 7 seconds or less.

In an embodiment of the present invention, electron beam pulse processing for a stent may be performed by setting the cathode 110 voltage to 20 kV to 30 kV. This is because if the cathode 110 voltage is lower than 20 kV, surface treatment is not possible, and if it is higher than 30 kV, stent damage may occur. Additionally, in order to treat the surface of the stent and simultaneously prevent damage to the stent, electron beam pulse treatment may be performed by setting the anode 120 voltage to 3 kV to 5 kV.

Electron beam pulse processing for the stent can be performed by setting the solenoid 130 voltage to 1 kV to 1.5 kV. This is because if the voltage of the solenoid 130 is lower than 1 kV, treatment of the side of the stent is impossible, and if the voltage is higher than 1.5 kV, stent damage may occur. Additionally, electron beam pulse processing can be performed by setting the distance between the electron beam pulse gun and the stent to 20 mm to 40 mm. If the distance between the electron beam pulse gun and the stent is less than 20 mm, damage to the stent may occur, and if it exceeds 40 mm, surface treatment may not be possible.

When an electron beam pulse is applied to the surface of a stent under these conditions, the effect of lowering the surface roughness of the stent and the effect of modifying the stent to be water-repellent can be obtained at the same time. Because of this, when inserting a stent into a blood vessel of the human body, it is possible to prevent the inner wall of the blood vessel from being torn due to friction with the stent. Therefore, according to an embodiment of the present invention, the process of lowering surface roughness through electro-chemical polishing can be replaced with an electron beam process, and water-repellent functionality can be additionally provided along with surface polishing. Therefore, polishing treatment (surface polishing process) to reduce the surface roughness of the stent before applying the electron beam pulse can be omitted. If necessary, before applying the electron beam pulse to the stent, a separate polishing treatment is performed to primarily lower the surface roughness of the stent, and then the surface roughness of the stent is subjected to water-repellent treatment using the electron beam pulse and at the same time, the surface roughness of the stent is improved. It can also be secondaryly reduced to a lower level.

Below, an experiment to verify the performance of the water-repellent stent manufacturing method according to an embodiment of the present invention will be described. Electron beam pulse treatment was performed by surface treating the CoCr metal stent with plasma in an oxygen (O) atmosphere, and the resulting contact angle analysis, stent surface analysis (SEM), stent bond configuration analysis (XPS), shear force (radial force) analysis, and Cardiac cell culture assays were performed. The length of the CoCr metal stent used in the experiment was 15 mm, the thickness of the strut was 75 μm, and the diameter before expansion was 1 mm and the diameter after expansion was 3 mm.

Figure 5 is a contact angle analysis table of a water-repellent stent according to an embodiment of the present invention. More specifically, since restenosis of blood vessels occurs intensively between 2 and 3 months after stent surgery, the change in contact angle of a metal stent with modified water repellency to water droplets over a period of 2 months is shown.

Figure 6 is a scanning electron microscope (SEM) view of a stent before and after applying an electron beam pulse to the stent.

Referring to Figures 5 and 6, the water-repellent stent according to an embodiment of the present invention is a water-repellent stent manufactured by the water-repellent stent manufacturing method according to Figures 1 to 4, and includes a stent body 200 and a stent body for implantation into the body. It includes an oxide layer 210 formed on the surface of 200 by multiple electron beam pulses. The water-repellent stent manufactured by the method according to the embodiment of the present invention has water-repellent (or super-hydrophobic) properties with a contact angle of 120° to 150° with respect to water droplets.

The stent body 200 may be a metal stent containing CoCr. The oxide layer 210 may include Cr ₂ O ₃ formed by electron beam pulses. The oxidation layer 210 may serve as a passivation layer to prevent the interior of the stent body 200 from being oxidized.

The oxidation layer 210 may be created by changing Cr(OH) ₃ formed on the surface of the stent body 200 to Cr ₂ O ₃ by an electron beam pulse during the process of manufacturing a stent by laser processing, and thus the stent. The surface can be modified to be water-repellent.

Figure 7 shows the results of X-ray photoelectron spectroscopy (XPS) of the surface of a CoCr alloy stent before and after applying an electron beam pulse. In the case of alloys containing Cr, the surface energy is lowered and chemical stability can be achieved by the chromium oxide formed on the surface, so the surface energy and chemical resistance are determined by the type of oxide formed on the surface.

Figure 7-(a) shows Cr-2p XPS results on the stent surface before (Bare) and after (EB) application of the electron beam pulse.

Figure 7-(b) shows Cr-2p XPS results under the stent surface before (Bare) and after (EB) application of the electron beam pulse.

Figure 7-(c) shows the O-1s XPS results of the stent before (Bare) and after (EB) application of the electron beam pulse.

Referring to Figure 7-(a), in the case of the stent surface (Bare) before electron beam pulse irradiation, although Cr ₂ O ₃ compounds are mainly formed, a high proportion of Cr(OH) ₃ structures are formed, and CrO ₃ compounds are formed. It is analyzed that some form of oxide is present.

However, in the case of the stent surface (EB) after irradiation of the electron beam pulse, it is mostly present in the form of Cr ₂ O ₃ and it is analyzed that Cr metal is present in a high proportion. This is because in the process of irradiating electron beam pulses to the stent, the plasmaized oxygen and molten layer quickly and stably form Cr ₂ O ₃ due to the high energy, and the remaining Cr metal remains in the form of pure metal without any additional oxidation reaction. It can be analyzed as

In addition, after irradiation of the electron beam pulse, the stent surface (EB) was analyzed to have a reduced proportion of bonded structures containing -OH functional groups, and Cr ₂ O ₃ having a stable structure was formed. A decrease in the -OH functional group, which has hydrophilic properties, affects a decrease in surface energy and an increase in contact angle.

Referring to Figure 7-(b), in the Cr-2p graph on the subsurface after etching, it can be seen that almost no oxide is formed inside the material due to electron beam surface treatment. Electron beam pulse irradiation using oxygen gas can be analyzed to form a faster and more stable oxide layer (Cr ₂ O ₃ ) than electron beam irradiation using conventional argon plasma gas, and a protective layer on the surface formed through electron beam surface treatment. It is analyzed that silver plays the role of protecting the material from chemical reactions such as oxidation and corrosion by increasing the chemical resistance on the surface of the material and plays the role of a protective layer to prevent additional oxidation from occurring inside the material. A decrease in the oxide ratio inside the material can also be analyzed as the cause of the effect of reducing surface energy and increasing contact angle.

Referring to Figure 7-(c), in the O-1s graph, the ratio of -OH bonds was found to be significantly reduced after the application of the electron beam pulse. Through this, the surface energy of the stent was reduced and the contact angle was improved by the application of the electron beam pulse. And chemical resistance can be confirmed through the formation of a stable oxidation layer.

Figure 8 is a graph showing the shear force (radial force) value of the expanded stent after irradiating an electron beam pulse. A stent inserted into a blood vessel is expanded using a balloon catheter, and one of the factors that evaluates whether it can support the wall of the expanded blood vessel is the radial force value.

Referring to FIG. 8, in the case of a stent that is not irradiated with an electron beam pulse, the radial force value shows a maximum value of 2.53 ± 0.27 N, and in the case of a stent that is irradiated with an electron beam pulse, the radial force value has a maximum value of 3.03 ± 0.22 N. The radial force value of the stent irradiated with electron beam pulses is approximately 0.5 N higher. This is due to the creation of a surface oxide film, reduction of -OH functional groups, and change in surface strength due to surface heat treatment.

Figure 9 shows the results of a cardiac muscle cell growth experiment on the CoCr surface 310 before the application of the electron beam pulse and on the CoCr surface 300 after the application of the electron beam pulse and images taken with a metal microscope.

Referring to FIG. 9, it can be seen that cardiac muscle cells 320 do not grow on the CoCr surface 300 after applying the electron beam pulse. The specific conditions of the experiment were to isolate neonatal rat cardiomyocytes (320) from the heart of a 1- to 3-day-old rat, and then incubate them in 1×ADS buffer solution (NaCl 120mM, HEPES 20mM, NaH ₂ PO ₄ 8mM, D Wash using -glucose 6mM, KCl 5mM, MgSO ₄ 0.8mM, DI water 1L, pH 7.35). Thereafter, rat cardiomyocytes were cultured on a CoCr substrate, and the culture medium was changed once every 72 hours in an incubator maintained at 37°C and 5% CO ₂ . This photo was taken 10 days later using a metal microscope (Keyence, VHX-1000).

Referring to Figure 9-(a), in the case of the CoCr surface 300 after the electron beam pulse is applied, fibrinogen, von Willebrand Factor (vWF), albumin, and fibronectin ( It can be confirmed that the growth of proteins that promote restenosis of stent struts inserted into the body, such as Fibronectin, is difficult, and as a result, the growth of cells such as intracellular membranes is difficult, effectively reducing restenosis of blood vessels.

Although specific embodiments according to the present invention have been described so far, it goes without saying that various modifications are possible without departing from the scope of the present invention. Therefore, the scope of the present invention should not be limited to the described embodiments, but should be determined by the claims described below as well as their equivalents. As described above, although the present invention has been described with reference to limited embodiments and drawings, the present invention is not limited to the above embodiments, and those skilled in the art can make various modifications and modifications from these descriptions. Transformation is possible. Accordingly, the spirit of the present invention should be understood only by the claims set forth below, and all equivalent or equivalent modifications thereof shall fall within the scope of the spirit of the present invention.

T1: pulse application time
T2: Rest time
110: cathode
120: anode
130: solenoid
200: stent body
210: Oxide layer
220: Inside the stent
300: CoCr surface after application of electron beam pulse
310: CoCr surface before electron beam pulse application
320: Cardiac muscle cells

Claims (11)

A water-repellent stent manufacturing method for manufacturing a stent for implantation in the body, comprising:
(a) preparing a metal stent containing CoCr; and
(b) converting Cr(OH) ₃ formed on the surface of the stent into Cr ₂ O ₃ by electron beam treatment of repeatedly applying electron beam pulses to the stent multiple times, thereby modifying the surface of the stent to be water-repellent. do,
Step (b) above is:
(b1) applying an electron beam pulse to the stent by an electron beam pulse application device for a set pulse application time; and
(b2) after the electron beam pulse is applied, resting for a set pause time to cool the surface of the stent;
Step (b1) and step (b2) are sequentially repeated multiple times to modify the surface of the stent,
The pulse application time is set within 1 μsec to 3 μsec, and the pause time is set within 3 seconds to 7 seconds.
delete According to claim 1,
The step (b) is a water-repellent stent manufacturing method in which the surface of the stent is modified by repeating the electron beam pulse 3 to 5 times.
delete According to claim 1,
The water-repellent stent manufacturing method wherein the pause time is set to 1*10 ⁶ times to 7*10 ⁶ times the pulse application time.
According to claim 1,
The step (b) is a water-repellent stent manufacturing method in which the electron beam pulse is applied by plasma in an oxygen atmosphere.
According to claim 1,
In step (b), the cathode voltage is set to 20 kV to 30 kV, the anode voltage is set to 3 kV to 5 kV, the solenoid voltage is set to 1 kV to 1.5 kV, and the electron beam pulse gun and the stent are used. A method of manufacturing a water-repellent stent in which the electron beam pulse is applied by setting the distance between the teeth to 20 mm to 40 mm.
According to claim 1,
Step (b) above is:
polishing the stent to reduce surface roughness of the stent; and
A method of manufacturing a water-repellent stent comprising: modifying the surface of the stent to be water-repellent by repeatedly applying the electron beam pulse to the stent with reduced surface roughness a plurality of times.
delete A water-repellent stent manufactured by the water-repellent stent manufacturing method of any one of claims 1, 3, and 5 to 8,
stent body for implantation in the body; and
It includes; an oxidation layer formed on the surface of the stent body by a plurality of electron beam pulses,
A water-repellent stent having a contact angle with water of 120° to 150°.
According to claim 10,
The stent body is a metal stent containing CoCr, the oxidation layer contains Cr ₂ O ₃ , and the oxidation layer serves as a protective layer to prevent the interior of the stent body from oxidation.