JP2019166014A - Magnesium alloy material used for medical implant, and method for producing magnesium alloy material - Google Patents

Abstract

To provide: a magnesium alloy material used for medical implant, in which, when using an implant made of Mg alloy material, the material has a strength during osteosynthesis, and has a biodegradability of disappearance in vivo after osteosynthesis; and a method for producing magnesium alloy material, in which, in order to satisfy the required biodegradability and strength depending on the use site in the body, both of these qualities can be controlled at the same time.SOLUTION: In a magnesium alloy material used for medical implant, a material in which Mg concentration excluding zinc is 99.99 wt.% or more and the concentration of zinc is 0.003 wt.% or more and less than 1.0 wt.%, is produced. Also, this alloy material is subjected to extrusion molding and/or die forging.SELECTED DRAWING: Figure 5

Description

  The present invention relates to an implant material using a magnesium (Mg) alloy and a method for manufacturing a medical implant. In particular, the present invention relates to a Mg alloy material having biodegradability, a manufacturing method for imparting strength suitable for an implant to the Mg alloy material, and a medical implant using the Mg alloy material.

  Conventionally, a metal material excellent in mechanical properties such as strength and workability has been used as an implant material used for bone fixation, prosthesis, etc. in jointing or reconstruction of a damaged or fractured portion of a bone. I came. In particular, stainless steel, tantalum, titanium, or titanium alloy having high biocompatibility and high strength is used.

  However, the above-mentioned metal bone plates and stents have a risk of being left in the body for a long time or semi-permanently after treatment. Specifically, if left in place over a long period of time, the implant will support the load instead of the bone, resulting in a phenomenon called stress shielding (stress shielding) that reduces bone mass or weakens the bone. is there. In addition, when the implant is used in a growing child, there is a concern that it inhibits bone growth.

  Therefore, after treatment of bone damage or fracture, the bone plate is removed by re-operation. However, since it is a burden on the patient to perform reoperation, it is desired to develop a bone plate that does not require reoperation.

  In the case of a stent, it has been pointed out that chronic inflammation may occur due to the risk of stent thrombosis and mechanical stress generated on the blood vessel wall by the stent body. In addition, there is a problem that it becomes an obstacle during bypass surgery and CT imaging. Therefore, development of a material that decomposes and disappears after a certain period is desired.

  As such a biodegradable material that does not require reoperation, an implant using polylactic acid or a high-purity Mg material having a concentration exceeding 99.99% by weight has been proposed (Patent Documents 1 to 3, 6). ).

  Patent Document 1 discloses an osteosynthesis material having biodegradability using high-purity Mg. According to the embodiment, a bone plate or the like is manufactured by pressure forming or forging forming an Mg lump having a Mg concentration of 99.998% by weight.

  Patent Document 2 discloses a biological device such as a bone plate having a first portion made of high-purity Mg metal having high corrosion resistance and a second portion made of low-purity Mg metal having low corrosion resistance. ing. By using two types of Mg having different purities, the dissolution rate in vivo is to be controlled.

  Patent Document 3 discloses a vascular stent formed of a thread made of a bioabsorbable polymer having a shape memory function. Polylactic acid (PLLA) and polyglycolic acid (PGA) are disclosed as bioabsorbable polymers.

  Patent Document 6 discloses a method of manufacturing an implant by distillation, extrusion, or die forging using a material containing 99.99% by weight or more of Mg and limiting the amount of other contained elements.

International Publication No. 2013/021913 International Publication No. 2015/098071 International Publication No. 00/13737 JP-A-2005-126802 JP2013-198698A International Publication No. 2016/148172

Development of bioabsorbable bone plate manufacturing technology using ultra-high purity magnesium, 2011 third hour supplementary budget project, Strategic basic technology advancement support project, results report (open version), Tohoku Bureau of Economy, Trade and Industry, 2013.2 Makoto Inoue, Nagaoka University of Technology 1999 Doctoral Dissertation "Research on Purification and Corrosion Resistance of Magnesium Alloys"

  The method disclosed in Patent Document 1 uses high purity magnesium (Mg) of 4N (N represents the number of consecutive 9 digits of concentration) or more (99.99% by weight or more), Although biodegradability was maintained moderately, there was a problem that the strength was not sufficient. Therefore, sufficient strength cannot be ensured particularly in a bone joint that is loaded. Although the biological device disclosed in Patent Document 2 can control the time taken by the living body, it is difficult to obtain sufficient strength in the combined materials because both are combined with members made of Mg metal. There was a problem. Although the polymer described in Patent Document 3 has good biodegradability, it has low strength and does not cause a problem when used as a stent. However, the polymer is not suitable for use as a loaded member such as a bone plate. It was restricted. The bone plate manufactured by the method disclosed in Patent Document 6 has good biodegradability and strength, but has not been sufficiently evaluated in vivo.

  That is, although polylactic acid and high-purity Mg are excellent in biodegradability, they have a problem of low strength. In particular, polylactic acid is good in biodegradability but weak in strength. For this reason, the load cannot be supported when used for medical members that require strength, such as bone plates used for the treatment of fractures, and the expanded blood vessels cannot be supported when used for stents. Will occur.

  The specific gravity of Mg is 1.74, 1/4 that of iron, and 2/3 of aluminum, which is the lightest among practical metals, and is superior in strength and rigidity per weight compared to iron and aluminum. However, it is necessary to make it as light and thin as possible for use in vivo. Although Mg is more rigid than iron and aluminum, it has lower strength than titanium and titanium alloys. For this reason, as a substitute for titanium, which is an implant material such as a bone plate to be placed in a living body, the present situation is that it has not been put into practical use so far, despite the advantage of bioabsorbability.

  In order to improve the strength of the metal, it is generally attempted to refine the metal structure by processing. Examples of processing methods include rolling, extrusion, twisting, forging, etc. It has been put into practical use. Alloying is one of the methods that have been implemented so far to improve the strength of Mg, and it has been partially put into practical use by obtaining a strength improvement effect by forming a solid solution and a compound with Mg and other metals. .

  As disclosed in Patent Document 5, extrusion, cutting, compression, and punching are applied as processing methods for the Mg alloy material, and the order of these steps and the direction of processing are strictly specified. The reason for this is that compressing in the direction parallel to the a-axis, which is the extrusion direction, will apply a compressive load in the direction perpendicular to the c-axis of the metal crystal, resulting in structural defects in the crystal structure, reduced strength, and material damage. It is to prevent connection. Such a strict processing method must be applied because the target material is an Mg alloy.

  In addition, it is shown in Non-Patent Document 1 that by alloying Mg, although the strength can be improved, the biodegradability becomes very fast, and when used as a bone plate, it melts before bone joining. In order to prevent this, it has been attempted to perform resin coating. However, there is a concern that the joint surface between the metal and the resin may be peeled off when placed in the body, and it has not been put into practical use.

  When used as a bone plate, in order to maintain the strength at the time of osteosynthesis and to have biodegradable properties that disappear after biosynthesis by biodegradation in the living body, it is not an alloy of Mg but reverse There is a method that is considered to be highly purified. For high purity, as shown in Patent Documents 4 and 6 and Non-Patent Document 2, commercially available Mg having a concentration of 99.9% by weight is used to sublimate Mg by vacuum distillation, A method of condensing in a temperature zone different from other contained elements is disclosed.

As methods for achieving high purity of Mg, methods disclosed in Patent Documents 4 and 6 are disclosed. However, Mg that has been sublimated and condensed by vacuum distillation, for example, even if a cylindrical ingot is obtained, becomes a very porous ingot because of the condensation process, and the porosity is about 10% by volume. Since it cannot be used as an implant material as it is, it is necessary to apply a processing method for making pores zero and to add strength comparable to existing materials such as titanium. As a processing method for this purpose, Patent Document 6 discloses a method by extrusion and die forging, but strength evaluation in vivo is not sufficient, and an appropriate processing method has not yet been developed.

Furthermore, when used as a bone plate, no method has been found that can control the biodegradability that maintains strength during osteosynthesis and disappears by biodegradation in vivo after osteosynthesis. Furthermore, the required biodegradability and strength differ depending on the site in the body to be used, and no method has been found that can control both of these properties simultaneously.

  The present invention, when used as a bone plate using an Mg alloy material, has a biodegradability that retains strength during osteosynthesis and disappears in vivo after osteosynthesis, and is already widely used. It is an object to provide an implant made of titanium or a titanium alloy and an implant that is inferior in strength. Therefore, it is an object to stably produce an Mg alloy material, and to produce an Mg alloy material having sufficient strength and biodegradability when used as an implant such as a bone plate and a stent. To do.

It is another object of the present invention to find a production method capable of simultaneously controlling both of these properties so as to satisfy the required biodegradability and strength depending on the site in the body to be used.

  In the magnesium alloy material used for the medical implant, the present invention has a Mg concentration excluding zinc of 99.99% by weight or more and a zinc concentration of 0.003% to less than 1.0% by weight. It is characterized by being.

  It is desirable from the viewpoint of biodegradability that the Mg material used as the implant is a Mg having a concentration exceeding 99.99% by weight, that is, a purity of 4N or more. It is already known that high purity Mg of 4N or more is excellent in corrosion resistance. When placed in the living body for the purpose of treatment such as treatment of fractures and dilation of blood vessels, it is necessary to have sufficient strength in the living body for at least 6 months. It has been pointed out that Mg having a purity of about 3N has a low corrosion resistance, and it cannot absorb a sufficient strength after 6 months because of its rapid absorption in the body. Accordingly, Mg having a purity of 4N or more and excellent corrosion resistance is required as a material for implants such as bone plates and stents.

  Furthermore, as a result of intensive studies by the inventor, it has been clarified that the solubility in vivo differs depending on the composition of impurities even if the Mg concentration is the same purity exceeding 99.99%. When used as an implant, it is important that it is dissolved and absorbed in the body, but if the dissolution rate is fast, there is a possibility that the implant will be absorbed before the bone-joined site has sufficient strength . However, if silicon (Si), aluminum (Al), manganese (Mn), iron (Fe), nickel (Ni), and copper (Cu) contained as impurities are extremely low in concentration, up to about 6 months after osteosynthesis It became clear that it remained in the body without dissolving as an implant. Specifically, when the concentration of Si, Al, Mn, Fe, Ni, and Cu is less than 0.001% by weight, the absorption in the body is relatively slow, and even 6 months after in-vivo infusion. The area can maintain 80% or more of the original cross-sectional area.

Even if zinc (Zn) is contained in Mg whose concentration of Mg excluding zinc is 99.99% by weight or more, the in vivo solubility does not increase greatly. The reason for numerically limiting the Zn concentration is as follows. When the Zn concentration is less than 0.003% by weight, the solubility is not changed, but the strength is not improved. Further, when the Zn concentration is 1.0% by weight or more, the strength is improved, but the solubility is increased.

  In order to manufacture the Mg alloy material having the composition described above, the vacuum distillation method shown in Patent Documents 4 and 6 and Non-Patent Document 2 is used. Alternatively, a material having a Mg concentration excluding Zn of 99.99% by weight or more can be manufactured, and then predetermined Zn can be added and redistilled.

  In the magnesium alloy material used for the medical implant, the present invention has a magnesium concentration excluding Zn of 99.99% by weight or more and a Zn concentration of 0.003% by weight to less than 1.0% by weight. A certain material is subjected to extrusion and / or die forging.

  As described above, a material whose Mg concentration excluding Zn is 99.99% by weight or more and whose Zn concentration is 0.003% by weight to less than 1.0% by weight has biodegradability in the body. It is very good and remains in the body without dissolving as an implant until about 6 months after the treatment. By extruding this material, the strength can be improved by work hardening. However, since the increase in the Zn concentration itself contributes to the strength improvement, the strength can be further improved by extrusion.

In order to further improve the strength, die forging is performed. In extrusion molding, there is not much improvement in strength by changing the extrusion ratio (the value obtained by dividing the cross-sectional area of the crucible before extrusion by the cross-sectional area of the extrusion die), but the strength is improved by changing the forging rate in forging. You can adjust the bill.

In the case of use as an implant, a manufacturing method capable of simultaneously controlling both of these properties so as to satisfy the required biodegradability and strength depending on the site in the body to be used was invented as follows.

The biodegradability is controlled as follows. That is, the concentration of Zn contained in Mg having a Mg concentration excluding Zn of 99.99% by weight or more is controlled in a range from 0.003% to 1.0% by weight. The lower the Zn concentration, the lower the biodegradability.

The intensity is controlled as follows. That is, the strength increases as the Zn concentration increases. By performing extrusion molding on this, the strength is further improved. Further, by performing die forging, the strength is improved as compared with extrusion molding. The extrusion ratio at the time of extrusion molding is not a parameter for strength control, but the forging rate of forging (usually changed in the range of 5% to 15%) is a parameter for strength control.

There are three methods for controlling the strength improvement: Zn concentration, extrusion molding, and die forging. Depending on the required strength, these three methods can be used in combination. Although the biodegradability control method was only Zn concentration, extrusion molding and die forging can reduce the grain size of the material structure, release the direction of the structure, and make the structure dense. Affects the biodegradability, so a method satisfying the biodegradability and strength can be selected from these measures.

  The implant of the present invention is characterized by using the magnesium alloy material. The implant may be a bone plate, a stent, or a hemostatic clip.

  The implant manufactured using the Mg alloy material of the present invention has high strength, good biodegradability, and extremely little metal other than Zn in in vivo absorption decomposition, so it is safe for clinical use in humans. Is expensive. Therefore, it has the required strength even when used as a bone plate, stent, or hemostatic clip. Further, since it is absorbed by the living body, it is not necessary to remove it by re-operation, and the burden on the patient is small.

  Since the implant manufactured using the Mg alloy material of the present invention is absorbed in vivo, there is no need for re-operation for removal. Moreover, although it is absorbed in the living body, its absorption speed is relatively slow, so that it is possible to obtain sufficient strength to support a load for a long period of time even when used for the treatment of fractures.

The figure which shows the erosion rate of the commercially available Mg alloy (AM60, AZ91) after the extrusion molding of Mg alloy (Mg-0.005Zn, Mg-0.5Zn) manufactured by vacuum distillation by this invention, and a raw material. The figure which shows the tensile strength (UTS) after the extrusion molding of Mg alloy (Mg-0.005Zn, Mg-0.5Zn) manufactured by vacuum distillation by this invention. The figure which shows the elongation after the extrusion molding of Mg alloy (Mg-0.005Zn, Mg-0.5Zn) manufactured by vacuum distillation by this invention. The figure which shows the Vickers hardness (HV) after the extrusion molding of Mg alloy (Mg-0.005Zn, Mg-0.5Zn) manufactured by vacuum distillation by this invention. The figure which shows the bending strength after extrusion molding of Mg alloy (Mg-0.005Zn, Mg-0.5Zn) manufactured by vacuum distillation by this invention, and after performing forging further.

  The inventor, when producing Mg by a vacuum distillation method, the concentration of Mg excluding Zn is 99.99% by weight or more, and the concentration of Zn is in the range from 0.003% to 1.0% by weight. I found a way to control.

Specifically, as shown in Table 1, using a commercially available Mg alloy (AM60) as a starting material, the concentration of Mg excluding Zn is 99.99% by weight or more, and the concentration of Zn is 0.0051% by weight. Mg alloy (hereinafter referred to as Mg-0.005Zn) and a commercially available Mg alloy (AZ91) are used as starting materials, the Mg concentration excluding Zn is 99.99 wt% or more, and the Zn concentration is A 0.49 wt% Mg alloy (hereinafter referred to as Mg-0.5Zn) was produced.

  What is necessary is just to use the vacuum distillation apparatus generally used for the vacuum distillation apparatus. Here, vacuum distillation was performed using a device basically the same as the self-made device described in Non-Patent Document 2. Specifically, Mg alloy as a starting material is stored in a crucible and sublimated by heating to about 600 ° C. under a reduced pressure of 10 Pa or less.

  Next, the sublimated Mg vapor is condensed in a condenser (cooled to about 350 ° C.) disposed above the crucible. By maintaining the state of heating at about 600 ° C. for about 12 hours under a reduced pressure of 10 Pa or less as described above, 4N or more of Mg excluding Zn can be obtained.

  As the Mg material to be a starting material, in addition to the above-mentioned commercially available Mg alloys (AM60, AZ91), commercially available Mg metal (Mg concentration is 3N grade) can be used. The material having an Mg concentration of 3N class includes Si, Al, Mn, Fe, Ni, Cu and the like as impurities.

  Mg having a concentration of 4N or more is said to be excellent in terms of biodegradability. The inventor also immersed 3M grade low-purity Mg in a simulated body fluid and conducted a test simulating absorption in a living body. As a result, dissolution was fast and the original shape could not be retained in a few hours. Conventionally, it was said that the purity of Mg used as an implant material was important, but the inventors' research has revealed that the composition of impurities as well as the purity of Mg is deeply involved in absorption in the body. In addition to Mg purity, what impurities are contained is important in terms of biodegradability and strength. Fe, Ni, and Cu are said to be involved in the in vivo stability of Mg, and the smaller the content, the more stable. The Mg material of the present invention contains almost no of these elements, and it is possible to produce an implant that is highly stable in vivo.

  The inventor measured the erosion rate of commercially available Mg alloys (AM60, AZ91) shown in Table 1 and Mg-0.005Zn and Mg-0.5Zn produced by the vacuum distillation method. The erosion rate was converted to mm / year using a 5 wt% sodium chloride (NaCl) solution in accordance with JIS H 0541 as the erosion liquid. As shown in FIG. 1, compared with commercially available Mg alloys (AM60, AZ91), Mg-0.005Zn and Mg-0.5Zn produced by the vacuum distillation method are overwhelmingly low in speed, and erosion in the body is reduced. I understand that it is slow. Further, it can be seen that Mg-0.5Zn has an erosion rate higher than that of Mg-0.005Zn, but is much lower than the commercially available Mg alloy (AM60, AZ91).

Next, the inventor has found a method for processing an ingot of Mg alloy vacuum-distilled. Since the Mg alloy ingot adopts a method of sublimation and condensation by vacuum distillation, it is a block containing about 10% by volume of pores. As it is, it does not become a material for manufacturing an implant, so it needs to be densified. Further, even if the pores are completely removed by densification, the ingots are aligned in the direction of sublimation and condensation. If an implant is produced as it is, the directionality will be a cause of lowering the strength.

The inventor performed extrusion molding of an ingot of Mg alloy that was vacuum distilled. For extrusion molding, a generally used extrusion apparatus may be used. Here, extrusion was performed using a device basically the same as the self-made device described in Non-Patent Document 2. The horizontal axis in FIG. 2 shows the extrusion ratio. The extrusion ratio is a value obtained by dividing the cross-sectional area of the crucible before extrusion by the cross-sectional area of the extrusion die. The higher this value, the more the material is densified. Will be. As shown in FIG. 2, Mg-0.005Zn cannot confirm the influence on tensile strength (UTS) even if the extrusion ratio is changed, and is about 120 to 160 MPa. Although the UTS of the titanium alloy currently used is as high as about 1000 MPa, it is higher than about 60 MPa, which is the UTS of resin (polylactic acid), so there is no problem in use as an implant material.

As shown in FIG. 3, Mg-0.005Zn has an elongation of 7% regardless of the extrusion ratio, and can be processed by extrusion. However, it is difficult to control the strength by the extrusion ratio, and it is necessary to consider another measure for improving the strength.

It has also been found that the phenomenon in which the strength changes in each direction of the structure due to the sublimation of the ingot of the Mg alloy vacuum-distilled and the change in the direction of condensation can be almost eliminated by performing extrusion molding.

As shown in FIG. 2, the UTS of Mg-0.5Zn using the material after extrusion is improved by 1.5 times or more compared to the UTS of Mg-0.005Zn, and the Zn concentration itself is You can see the effect on strength improvement. At this time, as shown in FIG. 3, 7% of elongation is secured, and there is no problem in workability.

Furthermore, as shown in FIG. 4, according to the Vickers hardness test based on JIS Z 2244 using the material after extrusion molding, the hardness of Mg-0.5Zn is higher than that of Mg-0.005Zn. It can be seen that the Zn concentration itself contributes to the increase in hardness.

  Next, the inventor has found a method for die forging in order to further improve the strength of the extruded ingot. For die forging, a generally used forging device may be used. The material after extrusion is densified by forging. A thin plate having the same size as the bone plate (4 mm × 13 mm × thickness 1.6 mm) was prepared from the material after forging and the material before forging after extrusion, and 3 in accordance with JIS T 0311 A point bending test was performed. When forging at a forging rate of 5% and 15% was performed on Mg-0.005Zn, the strength was improved three times or more. This is shown in FIG.

  When the forging rate is changed, the degree of densification of the extruded material will be different, so the effect on strength improvement was expected to be proportional, but not necessarily proportional, and there is an optimal forging rate .

When the magnesium alloy material of the present invention is used as an implant, a production method capable of simultaneously controlling both properties so as to satisfy the required biodegradability and strength depending on the site in the body to be used is as follows. become.

The biodegradability is controlled as follows. That is, the concentration of Zn contained in Mg having a Mg concentration excluding Zn of 99.99% by weight or more is controlled in a range from 0.003% to 1.0% by weight. The lower the Zn concentration, the lower the biodegradability.

There are three control methods for strength improvement: Zn concentration, extrusion molding, and die forging. These three methods are used in combination depending on the required strength. Usually, Zn concentration control and extrusion molding, or Zn concentration control and die forging, and further Zn concentration control, extrusion molding and die forging are combined.

  According to the production method of the present invention, it is possible to obtain an implant having sufficient strength as a bone plate and a stent and having an appropriate absorption rate in vivo in clinical use.

Hereinafter, the industrial applicability of the present invention will be described.

Provided is a medical implant material that has the strength and biodegradability proposed in the present invention and does not adversely affect the living body, and a bone plate, a stent, or a hemostatic clip is provided as a medical implant product using the material. In this case, an epoch-making treatment method that is epoch-making for the patient is realized in the treatment by the joint operation or the reconstruction operation for the damaged portion or the fracture portion of the bone.

Claims (4)

In the magnesium alloy material used for medical implants, the magnesium concentration excluding zinc is 99.99% by weight or more, and the zinc concentration is 0.003% by weight to less than 1.0% by weight. Magnesium alloy material. A method for producing a magnesium alloy material, comprising performing extrusion molding and / or die forging of the magnesium alloy material according to claim 1. A medical implant using the magnesium alloy material according to claim 1. 4. The medical implant according to claim 3, wherein the medical implant is a bone plate, a stent, or a hemostatic clip.

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