JP7041902B2 - Surface treatment method for bioabsorbable medical equipment - Google Patents

Description

The present invention is a surface treatment method for a bioabsorbable medical device, in particular, while maintaining an open state for a sufficient time for indwelling in a stenosis or occlusion formed in a lumen in a living body to ensure vascular remodeling. It relates to a surface treatment method for a bioabsorbable medical device that gradually disappears in a living body.

Examples of the medical device of the present invention include various devices such as a stent, a cannula, a catheter, an artificial blood vessel, a stent graft, and a drug-loaded cancer treatment device. In the following, the stent will be described as an example.

In vivo stents are used to dilate and secure the stenosis or occlusion site in order to treat various diseases caused by the stenosis or occlusion of blood vessels or other in vivo lumens. It is generally a tubular medical device that is placed in the stenosis.
Since the stent is inserted into the body from outside the body, the diameter is small at that time, and the stent is expanded at the target stenosis or occlusion site to increase the diameter, and the lumen is retained as it is.

The stent is generally a metal wire such as stainless steel or CoCr alloy, or a cylindrical one obtained by processing a metal tube. On the other hand, a catheter or the like is attached in a thin state, inserted into a living body, expanded by some method at a target site, and adheres to and fixed to the inner wall of the lumen to maintain the shape of the lumen.

At present, non-absorbable metal-based stents have become the medical standard with many successes. However, there has been the problem that permanently implanted stents pose a risk of endothelial cell dysfunction and subsequent thrombosis due to permanent interaction with surrounding tissue.

Recently, as a stent that solves the above-mentioned problems, a stent has been allowed to exist in the body for a period until it finishes performing functions such as maintaining the opening of blood vessels and / or delivering a drug. Bioabsorbable stents that are absorbed into the body have been proposed.

Such stents include stents based on bioabsorbable polymers such as polylactic acid and polyglycolic acid (Patent Document 1) and stents based on bioabsorbable metals such as magnesium and magnesium alloys (Patent). Document 2, Patent Document 3, Patent Document 4).

Stents using bioabsorbable polymers as a substrate may not provide the mechanical properties necessary to perform functions such as maintaining vascular opening and / or delivering drugs, resulting in sufficient mechanical properties. Stents based on bioabsorbable metals such as magnesium and magnesium alloys are desired.

However, because magnesium alloys have an extremely high rate of decomposition in the body, the mechanical strength of the stent is sufficient for sufficient time to ensure vascular remodeling while ensuring sufficient vascular support (radial force) after placement. It was difficult to hold.

Patent No. 455584 Special table 2001-511049 JP 2006-167078 JP-A-2004-160236

Therefore, an object of the present invention is sufficient for about 6 months to regulate the in vivo decomposition rate of an in vivo indwelling stent made of a bioabsorbable metal such as magnesium or a magnesium alloy to ensure vascular remodeling. It is to provide a surface treatment method for a bioabsorbable medical device such as a bioabsorbable stent so that it can be indwelled in the body for a certain period of time while ensuring a sufficient vascular bearing capacity (radial force).

The present inventors polished the surface of a bioabsorbable metal tube made of magnesium or a magnesium alloy for stents with diamond paper having a particle size of 3 μm, and then observed the surface. As a result, the surface was surprisingly about 2 μm. It was discovered that the convex body is covered with a convex body, and the surface roughness of the convex body can be adjusted by bombing under specific conditions, and the present invention has been reached.
That is, the first configuration of the present invention is a surface treatment method for a bioabsorbable medical device using a magnesium alloy as a base material, in which the surface of the bioabsorbable medical device is polished with an abrasive paper and then pressure is adjusted. Bomberd gas is introduced into the vacuum container, and the polished surface of the bioabsorbable medical device is bombarded to adjust the surface roughness, and then the surface of the bioabsorbable medical device has a film thickness of 10 nm or more. It is a surface treatment method for a bioabsorbable medical device, which comprises coating a diamond-like carbon thin film of 2 μm.

The second configuration of the present invention is a surface treatment method for a bioabsorbable medical device in which the bombard gas is an argon bombard gas .

The third configuration of the present invention is a surface treatment method for a bioabsorbable medical device in which the bioabsorbable medical device is a stent .

In the fourth configuration of the present invention, a bombard gas is introduced into a pressure -controlled vacuum container, and a high frequency with an output of 10 to 70 W is applied for 30 to 60 minutes to bombard the surface of the bioabsorbable medical device. It is a surface treatment method for a bioabsorbable medical device, which comprises coating the surface of the base material with a diamond-like carbon thin film after adjusting the surface roughness.

The fifth configuration of the present invention is a surface treatment method characterized in that the arithmetic mean roughness of the surface roughness is 20 nm to 2 μm.

In the surface treatment method of the bioabsorbable medical device of the present invention, the surface roughness of the base material can be adjusted by Ar bomber, and then the diamond-like thin film can be locally coated. The disassembly speed can be adjusted. Further, an extremely thin amorphous film can be formed by adopting a local coating method for the diamond-like thin film, and further, the coating area and the thickness of the film can be easily controlled by changing the film forming conditions of the diamond-like thin film. Bioabsorbable medical devices whose degradation rate has been adjusted by the above method are at risk of endothelial cell dysfunction and subsequent thrombosis due to the permanent interaction of the medical device indwelling in the living body with the living body, which is currently a problem. Can be solved. Further, since the required decomposition rate of the stent may differ depending on the state of the stenosis site, it is possible to provide a corresponding stent.

It is schematic cross-sectional view of the surface treatment apparatus which performs the surface treatment of the bioabsorbable medical instrument. It is a figure which shows the relationship between the surface roughness and the high frequency output of the Mg alloy wire which performed the Ar bombing process. It is a graph which shows the corrosion test result. It is a graph which shows the mass change rate. It is a schematic diagram explaining the cause which the mass of the DLC process decreased.

Hereinafter, embodiments of the present invention will be described with reference to the drawings.

FIG. 1 is a schematic cross-sectional view showing a surface treatment apparatus according to an embodiment of the present invention. In the present embodiment, a plasma CVD apparatus whose discharge power supply is a high frequency power supply is used as the surface treatment apparatus. The surface treatment apparatus (plasma CVD apparatus) 1 according to the present embodiment has a vacuum vessel 3 in which an electrode plate 2 also serving as a substrate holder is installed at the bottom, and the Mg alloy substrate 4 is mounted on the electrode plate 2. Placed. A high frequency (RF) power supply 5 and a blocking capacitor 6 are connected to the electrode plate 2.

The vacuum vessel 3 contains a gas introduction line 7 into which a hydrocarbon gas (acetylene, methane, etc.) as a raw material gas and a bomberd treatment gas (an inert gas such as Ar) are introduced, and an exhaust system (not shown). The connected exhaust port 8 is provided. A raw material gas supply device 9 and a bombard gas supply device 10 are connected to the gas introduction line 7 via mass flow controllers 11 and 12, respectively. The vacuum container 3 is grounded.

Next, the surface treatment method of the Mg alloy substrate 4 by the surface treatment device 1 described above will be described.

After placing the Mg alloy substrate 4 on the electrode plate 2 and exhausting the inside of the vacuum vessel 3 from the exhaust port 8 by an exhaust system (not shown) to adjust the pressure to a predetermined pressure, first, the bombard gas supply device 10 A gas for bombard treatment, for example, argon (Ar) gas is supplied from the gas flow controller 12, the flow rate is adjusted by the mass flow controller 12, and the gas is introduced into the vacuum vessel 3. At this time, high frequency (RF) is applied from the high frequency power source 5 to the electrode plate 2 to cause Ar ions, which are ionized argon (Ar) gas introduced into the vacuum vessel 3, to collide with the surface of the Mg alloy substrate 4.

At this time, self-bias is applied to the surface side of the electrode plate 2 on which the Mg alloy substrate 4 is placed, so that Ar ions collide with the surface of the Mg alloy substrate 4, and the surface of the Mg alloy substrate 4 is subjected to Ar bombard treatment. Will be done. In the Ar bombard treatment, the surface roughness of the alloy substrate surface can be adjusted by controlling the high frequency (RF) output and the Ar bombard treatment time. After the Ar bombard processing, the high frequency power supply 5 is turned off.

Then, after the bombarding process is completed, the inside of the vacuum vessel 3 is exhausted from the exhaust port 8 by an exhaust system (not shown) to adjust the pressure to a predetermined pressure, and the raw material gas supply device 9 is used to control the hydrocarbon system which is the raw material gas. Gas (for example, CH ₄ ) is supplied, the flow rate is adjusted by the mass flow controller 11, and the gas is introduced into the vacuum vessel 3. At this time, a high frequency (RF) is applied from the high frequency power source 5 to the electrode plate 2 to turn the hydrocarbon gas (CH ₄ ) introduced into the vacuum vessel 3 into plasma.

At this time, by applying self-bias to the electrode plate 2 on which the Mg alloy substrate 4 is placed, positive ions (C +, CH ₄ +, etc.) in the plasma are attracted to the Mg alloy substrate 4, and the Mg alloy substrate 4 is mounted. A locally dense diamond-like thin film (hereinafter referred to as DLC film) is formed on the Ar bombarded surface of the above.

In this way, after the surface of the Mg alloy substrate 4 is Ar-bombered, the hydrocarbon gas (for example, CH ₄ ) is ionized by the plasma CVD method to locally form a DLC film on the surface of the Mg alloy substrate 4. By doing so, it was possible to obtain the Mg alloy substrate 4 in which the decomposition rate of the Mg alloy substrate 4 was adjusted.

Further, the decomposition rate of the Mg alloy substrate 4 can be adjusted with high productivity and at low cost by a simple process of Ar bombarding treatment and forming a DLC film on the surface of the Mg alloy substrate 4 in the same apparatus.

Then, the Ar bombard treatment obtained as described above and the film formation of the DLC film were carried out under the conditions of Examples 1 to 4 below, and the state of corrosion was observed by weight change. The corrosion test conditions at this time were as follows: using a phosphate buffered saline (concentration 10 times) at 37 ° C. as the corrosive liquid and immersing it in this corrosive liquid. For comparison, the same corrosion test was performed for the untreated, Ar bomber treated, and DLC treated.

In this embodiment, AZ31 (diameter 1.45 × 20 mm) was used as the Mg alloy wire, and the bombard treatment was performed under four conditions in which the RF output was changed.

Mg alloy wire: Polished with diamond paper with a particle size of 3 μm and 9 μm Bomberd treatment conditions:
Vacuum reach: 8.0 x 0 ^-3
Raw material gas: Ar
Pressure: 80 (Pa)
RF output: 10, 30, 50, 70 (W)
Processing time: 60 (min)
The surface roughness of the Mg alloy wire under the bombard treatment conditions is shown in FIG. As is clear from FIG. 2, the surface roughness of the Mg alloy wire subjected to the Ar bombing process depends on the RF power.

In this example, an AZ31 Mg alloy stent (diameter 1.8 mm × 0.2 mm × length 18 mm) was used, and three samples subjected to the following treatment were prepared.
Ar bombard processing only, DLC processing only, DLC processing after Ar bombard processing Bomberd processing conditions:
Vacuum reach: 8.0 x 0 ^-3
Raw material gas: Ar
Pressure: 80 (Pa)
RF output: 70 (W)
Processing time: 60 (min)
DLC film formation conditions:
Vacuum reach: 8.0 x 0 ^-3
Raw material gas: CH ₄
Pressure: 4 (Pa)
RF power: 500 (W)
Film formation time: 5 (min)
A sample obtained by bombarding and / or forming a DLC film under the above conditions was immersed in a corrosive solution for 148 hours, and the corrosion test results are shown in FIG. After 148 hours from the figure, changes were observed in the sample with only DLC film treatment. After 312 hours, all samples were finely divided.

The mass change rate of each sample after 148 hours from the test result of Example 2 is shown in FIG. From the figure, it is clear that the sample treated with DLC after the Ar bomber treatment has a mass of about 8% more than that of the untreated sample, suggesting that it is effective in suppressing corrosion. As shown in Fig. 5, the cause of the decrease in the mass of the DLC-treated sample is that the anode-cathode reaction occurred at the interface between the Mg alloy wire and the DLC film, causing rapid corrosion, and as a result, it is presumed that the mass decreased. Will be done.

In the above-described embodiment, the DLC film is formed by a high-frequency plasma CVD method, but in addition to this, a sputtering method, a DC magnetron sputtering method, an RF magnetron sputtering method, and a chemical vapor deposition method (CVD method) are used. ), Plasma CVD method, plasma ion implantation method, superimposed RF plasma ion implantation method, ion plating method, arc ion plating method, ion beam deposition method, laser ablation method, etc. Can be formed into.

Further, although the DLC film can be formed directly on the surface of the medical device main body, an intermediate layer is provided between the medical device main body and the DLC film in order to make the medical device main body and the DLC film more firmly adhere to each other. May be good. When the intermediate layer is provided, various ones can be used depending on the material of the medical instrument main body, but known ones such as an amorphous film made of Si and carbon can be used.

Further, in order to make the surface of the DLC film hydrophobic and improve the antithrombotic property, elements such as fluorine and silicon may be added to the DLC film.

Examples of the base material of the bioabsorbable medical device of the present invention include pure magnesium, magnesium alloy, pure iron, and iron alloy. The magnesium alloy contains magnesium as a main component and contains at least one element selected from the biocompatible element group consisting of Zr, Y, Ti, Ta, Nd, Nb, Zn, Ca, Al, Li, and Mn. Is preferable. For example, magnesium is 50-98%, lithium (Li) is 0-40%, iron is 0-5%, and other metals or rare earth elements (cerium, lanthanum, neodymium, praseodymium, etc.) are 0-5%. Can be mentioned. The iron alloy contains iron as a main component, and Mn, Co, Ni, Cr, Cu, Cd, Pb, Sn, Th, Zr, Ag, Au, Pd, Pt, Re, Si, Ca, Li, Al, Zn. , Fe, C, S, preferably containing at least one element selected from the biocompatible element group. Examples include those containing 88-99.8% iron, 0.1-7% chromium and 0-3.5% nickel as well as less than 5% other metals.

The above-mentioned magnesium alloys are produced by various metal material manufacturing processes such as ordinary casting and die casting, casting plastic processing, casting strong processing, chip solidification molding, rapid solidification, and rapid solidification powder metallurgy. In the process, it is known that the rapid coagulation powder metallurgy method is particularly important in order to realize high strength, high ductility and high corrosion resistance.

Further, the stent skeleton may be coated with a biodegradable polymer. Biodegradable polymers include poly-L-lactic acid (PLLA), poly-D, L-lactic acid (PDLLA), poly (lactic acid-glycolic acid) (PLGA), polyglycolic acid (PGA), polycaprolactone (PCL). , Polylactic acid-ε-prolactone (PLCL), poly (glycolic acid-ε-caprolactone) (PGCL), poly-p-dioxanone, poly (glycolic acid-trimethylene carbonate), poly-β-hydroxybutyric acid, etc. Be done. In general, when the molecular weights of these polymers are similar, PCL and PLCL are preferable because they are excellent in flexibility and ductility at 37 ° C. and excellent in hydrophobicity as compared with other polymers.

In addition, the biodegradable polymer may contain a therapeutic agent that does not inhibit the proliferation of endothelial cells. Therapeutic agents include antiproliferative agents such as sirolimus, biolimus, everolimus, anti-inflammatory agents such as steroidal anti-inflammatory agents, anti-neoplastic agents such as taxol and dosekitaxel and / or anti-division agents, heparin sodium, hirudin, argatroban. , Ximeragatran, Melagatran, Davigatlan, Davigatlan etechel and other anti-platelet drugs, anti-coagulants, anti-fibrin drugs, and anti-thrombin drugs, angiopeptin, captopril and other anti-proliferative or anti-proliferative drugs, antibiotics, permilo Antiallergic agents such as Last Potassium, Antioxidants, HMG-CoA Reductase Inhibitors such as Atrubastatin, Seribastatin, Fluvastatin, Pitabastatin, Pravastatin, Symvasstatin, Plasma DNA, Genes, Decoys, siRNA, Oligonucleotides, Antisense oligonucleotides , Ribozyme, nucleic acid drugs such as aptamer, and drugs for suppressing re-stenosis of blood vessels such as tamivarotene.

The stent, which is one of the bioabsorbable medical instruments of the present invention, has a characteristic shape, and such a shape can be integrally manufactured by laser processing. In the manufacturing process by laser machining, first, a tool path in laser machining is created using CAM based on the shape data of the designed stent. The tool path is set taking into consideration that the stent shape can be maintained after laser cutting and that chips do not remain. Next, laser processing is performed on the biodegradable metal tube. In order to prevent the thermal effect on the biodegradable metal, a method disclosed in Japanese Patent Application Laid-Open No. 2013-215487, for example, a rod-shaped core metal is inserted into a hollow portion of a tube-shaped stent material to form a skewer-shaped tube. After maintaining the linearity of the stent material, laser processing is performed on the tubular stent material while suppressing the thermal effect with a laser (water laser) that uses the water column formed up to the stent material as the waveguide for the laser beam. After that, it is preferable to form a stent shape by removing the core metal from the tube.

After the mesh shape is formed by laser cutting, the surface is finished to be glossy by electrolytic polishing, and the edge part is finished to a smooth shape. In the stent processing process, the post-processing process after laser cutting processing is important. In the stent after laser cutting, the oxide on the metal cut surface is first dissolved with an acidic solution, and then electrolytic polishing is performed. In the case of a biodegradable metal, for example, a magnesium alloy, in electrolytic polishing, a metal plate such as a stent and a stentless is immersed in an electrolytic solution, and the two metals are connected via a DC power supply. With the stent side as the anode and the metal plate side as the cathode, a voltage is applied to dissolve the stent on the anode side and obtain a polishing effect. In order to obtain an appropriate polishing effect, it is necessary to study the composition of the electrolytic solution and the current conditions to be applied.

The stent manufactured by the above laser processing method is placed on the electrode plate 2 of the surface treatment apparatus of FIG. 1, and is subjected to Ar bombing treatment and then DLC treatment as described above.

In the surface treatment method of the bioabsorbable medical device of the present invention, the surface of the base material is subjected to Ar bombing treatment to adjust the surface roughness, and then DLC treatment is performed to locally apply a diamond-like thin film on the surface of the base material. By coating the substrate, the rate of decomposition of the substrate in the living body can be adjusted, and the risk of endothelial cell dysfunction and subsequent thrombosis caused by the stent permanently placed in the living body, which is currently a problem, is solved. be able to.

1 Surface treatment equipment (plasma CVD equipment)
2 Electrode plate
3 Vacuum container
4 Mg alloy substrate
5 High frequency power supply
6 Blocking capacitor
7 Gas introduction line
8 exhaust port
9 Raw material gas supply device
10 Bomberd gas supply device
11 Mass flow controller
12 Mass flow controller

Claims (5)

A surface treatment method for bioabsorbable medical devices using magnesium alloy as a base material.
After polishing the surface of the medical device with polishing paper, bombard gas is introduced into a pressure-adjusted vacuum vessel, and the polished surface of the bioabsorbable medical device is bombarded to adjust the surface roughness. A method for surface treating a bioabsorbable medical device, which comprises coating the surface of the bioabsorbable medical device with a diamond-like carbon thin film having a film thickness of 10 nm to 2 μm. The method for surface-treating a bioabsorbable medical device according to claim 1, wherein the bombard gas is argon bombard gas . The surface treatment method for a bioabsorbable medical device according to claim 1 or 2, wherein the bioabsorbable medical device is a stent . The surface treatment method for a bioabsorbable medical device according to any one of claims 1 to 3, wherein a bombard gas is introduced into a pressure-controlled vacuum vessel and a high frequency of 10 to 70 W is applied to 30 to 60. The surface of the bioabsorbable medical device is subjected to a minute application to bombard the surface of the bioabsorbable medical device to adjust the surface roughness, and then the surface of the substrate is coated with a diamond-like carbon thin film. Processing method. The surface treatment method for a bioabsorbable medical device according to claim 4, wherein the arithmetic mean roughness of the surface roughness is 20 nm to 2 μm .

Images