WO2014027612A1

WO2014027612A1 - Bone repair material and production method therefor

Info

Publication number: WO2014027612A1
Application number: PCT/JP2013/071596
Authority: WO
Inventors: 小久保　正; 松下　富春; シーカーナス; 山口　誠二
Original assignee: 学校法人中部大学
Priority date: 2012-08-16
Filing date: 2013-08-09
Publication date: 2014-02-20
Also published as: JP6206880B2; JP2017144342A; JP6358765B2; JPWO2014027612A1

Abstract

[Problem] To provide a highly safe bone repair material that gradually releases bone-forming ions and that exhibits excellent apatite-forming ability and storability. [Solution] The production method of the present invention is characterized by comprising: a step in which a substrate comprising titanium or a titanium alloy is immersed in an alkaline first aqueous solution that contains cations of sodium ions and/or potassium ions and that does not contain calcium ions or bone-forming ions; a step in which the substrate is immersed in a second solution that contains calcium ions and at least one kind of bone-forming ions selected from among strontium ions, magnesium ions, zinc ions, lithium ions, and gallium ions; a step in which the substrate is heated in a dry atmosphere; and a step in which the substrate is immersed in a third aqueous solution containing at least one of water, an acidic aqueous solution, and/or an aqueous solution containing bone-forming ions.

Description

Bone repair material and manufacturing method thereof

The present invention relates to a bone repair material and a manufacturing method thereof. This bone repair material can be suitably used for bone repair in a portion to which a large load is applied such as a femur, a hip joint, a spine, and a tooth root.

Titanium metal or titanium alloy having an apatite layer on the surface has great fracture toughness and is bonded to living bone through apatite in vivo, so it is expected as a bone repair material in a portion where a large load is applied. Various methods for forming an apatite layer on the surface of a substrate made of a metal or a titanium alloy have been studied. Among these, what is obtained by immersing an alkali-treated base material in an aqueous solution having a saturated concentration of apatite or more to precipitate apatite tends to crack the apatite during drying. Moreover, what is obtained by the method of coat | covering an apatite by a plasma spraying or flame spraying to a base material tends to produce a crack in an apatite layer by the thermal expansion difference with a base material at the time of cooling. For this reason, various chemical treatment methods for titanium metal or titanium alloy have been proposed in which apatite is formed in the body, and a titanate layer having an apatite-forming ability is formed on the surface in order to form apatite through the body and bond with living bone. (Patent Documents 1-3).

On the other hand, ions such as strontium, magnesium, zinc, lithium and gallium are reported to promote the formation of new living bones in the body (Patent Documents 4-5 and Non-Patent Documents 1-6). If a living bone is formed around the bone repair material at an early stage and an apatite layer is formed on the material surface at an early stage, it is expected that a strong bond will be obtained between the bone repair material and the living bone at an early stage. In addition, recovery of bone mass is expected even in patients whose bone mass has decreased due to osteoporosis or the like.

WO95 / 13100 publication WO2009 / 147819 WO2010 / 087427 Special table 2010-533012 Special table 2010-533011

However, the material obtained only by the process described in Patent Document 1 loses the ability to form apatite when the bone repair material is exposed to high temperature and humidity for a long period of time as an accelerated test assuming long-term storage. Therefore, it is not possible to store inventory in preparation for repair surgery.
The materials obtained only by the processes described in Patent Documents 2 and 3 are excellent in apatite forming ability and storage stability, but are poor in ability to promote bone formation.
The materials obtained by the methods described in Patent Document 4-5 and Non-Patent Document 1-2 promote the bone formation by eluting ions of strontium, zinc or lithium, but their apatite forming ability is low.
Therefore, an object of the present invention is to provide a highly safe bone repair material that releases bone-forming ions gradually and is excellent in apatite-forming ability and storage stability.

In order to solve the problem, the bone repair material of the present invention is
It comprises a substrate made of titanium metal or a titanium alloy and a titanate layer containing calcium ions and osteogenic ions on the surface of the substrate, and has a scratch resistance of 10 mN or more. In this specification, the scratch resistance means that a stylus having a spring constant of 200 g / mm is given an amplitude of 100 μm on the titanate layer, and a stylus is moved at a speed of 10 μm / sec while applying a load of 100 mN / min. The critical scratch strength of the titanate layer when it is applied.

According to this bone repair material, since the titanate layer contains both calcium ions and bone forming ions, the bone forming ions contained in the titanate layer gradually elute in vivo to promote the surrounding bone formation. At the same time, calcium ions are eluted in the living body, exhibiting the ability to form apatite, and can bind to bone. The scratch resistance is not only a mechanical property directly shown by itself, but also an index showing apatite forming ability and sustained release of bone forming ions. That is, if the interparticle bond in the titanate layer is so weak that the scratch resistance is less than 10 mN, the bone-forming ions are rapidly eluted, which is not effective in promoting bone formation. Similarly, calcium ions are also eluted rapidly and do not show the effect of promoting apatite nucleation and growth.

The method for producing a bone repair material of the present invention comprises titanium or a titanium alloy in an alkaline first aqueous solution that does not contain calcium ions and bone forming ions but contains at least one cation of sodium ions and potassium ions. A step of immersing the base material, a step of immersing the base material in a second aqueous solution containing calcium ions and osteogenic ions, a step of heating the base material in the air, water, an aqueous acid solution, and an aqueous solution containing bone forming ions It comprises a step of immersing in a third aqueous solution comprising at least one selected from the group consisting of:

By soaking in the first aqueous solution, the titanium in the base material reacts with the aqueous solution to form a sodium hydrogen titanate or potassium hydrogen titanate layer on the surface of the base material. Then, when immersed in the second aqueous solution, sodium or potassium ions in the sodium hydrogen titanate or potassium hydrogen titanate layer are exchanged with calcium ions and bone forming ions in the aqueous solution. The ratio of calcium ions and osteogenic ions to be exchanged can be arbitrarily controlled by changing the concentration ratio of calcium ions and osteogenic ions in the second aqueous solution. The reason that such control is possible is that sodium hydrogen titanate or potassium hydrogen titanate formed by the first aqueous solution treatment has a layered structure. By gradually immersing in two different aqueous solutions in this way, a titanate layer having a gradient composition containing calcium ions and osteogenic ions in a desired ratio and gradually decreasing from the surface toward the inside is obtained. Formed on the material.

By heating this in the air, it becomes dehydrated and becomes a mechanically and chemically stable anhydrous titanate layer, and the scratch resistance of the surface layer is remarkably improved.
Thereafter, when immersed in a third aqueous solution made of water or an acid aqueous solution, calcium ions and bone-forming ions in the titanate layer are partially exchanged for hydronium ions, and the surface exhibits an apatite-forming ability. Activated. When an aqueous solution containing osteogenic ions is used as the third aqueous solution, some of the calcium ions are exchanged for hydronium ions without eluting the osteogenic ions in the titanate layer into the third aqueous solution. Therefore, the substrate surface is activated to such an extent that it exhibits the ability to form apatite without reducing the bone-forming ion concentration in the titanate layer. The apatite-forming ability is as high as 3 days to form apatite on the entire surface, and is maintained even when stored for a long time under high humidity. Bone-forming ions contained in the titanate layer are gradually eluted in vivo to promote bone formation.

As described above, when the bone repair material obtained by the present invention is embedded in a living body, it can promote the formation of surrounding bone, and can quickly bond to a living bone to repair a bone defect, Since it is excellent in preservability, it can be kept for surgery.

The ion distribution near the surface of the sample of Example 1 based on X-ray photoelectron spectroscopy (XPS) is shown. The ion distribution near the surface of the sample of Example 2 based on XPS is shown. The ion distribution near the surface of the sample of Example 4 based on XPS is shown. The ion distribution near the surface of the sample of Example 5 based on XPS is shown. The ion distribution near the surface of the sample of Example 7 based on glow discharge optical emission spectrometry (GD-OES) is shown. The ion distribution near the surface of the sample of Example 8 based on GD-OES is shown. The ion distribution near the surface of the sample of Example 9 based on GD-OES is shown. The thin film X-ray diffraction pattern of the sample of an Example is shown. The inductively coupled plasma emission spectrometry (ICP) analysis result of the osteogenic ion eluted from the sample of Examples 1, 4, 7, 8, and 9 to PBS is shown. The ICP analysis result of the osteogenic ion eluted from the sample of Examples 1 and 2 into PBS is shown. The ICP analysis result of the osteogenic ion eluted from the samples of Examples 4 and 5 into PBS is shown.

The titanate layer usually has a calcium ion concentration of 0.1 to 10 atomic% and an osteogenic ion concentration of 0.1 to 5 atomic% in a depth range of 0.1 to 10 μm from the surface. Preferably it has a calcium ion concentration of -5 atomic% and an osteogenic ion concentration of 0.1-5 atomic%. The calcium ion concentration and osteogenic ion concentration that can be introduced can be increased to about 10 atomic% by raising the pH of the second aqueous solution. When the calcium ion concentration is less than 0.1 atomic%, the calcium component constituting the apatite is too scarce on the surface, and it is difficult to form apatite. If it exceeds 5 atomic%, the ratio of a stable compound such as calcium titanate in the surface layer increases, so that it is difficult to form apatite. The amount of bone-forming ions eluted in the body depends on the bone-forming ion concentration in the titanate layer. Therefore, when the bone-forming ion concentration is less than 0.1 atomic%, the amount of elution in the body is reduced and a sufficient bone-forming effect cannot be obtained. However, if it exceeds 5 atomic%, the surface layer becomes a stable compound, so it is difficult to form apatite.

The concentration of calcium ions in the second aqueous solution is usually in the range of 0.01 to 5000 mM, preferably 0.01 to 100 mM. The concentration of osteogenic ions is usually in the range of 0.01 to 5000 mM, preferably in the range of 0.01 to 100 mM. When both are less than the lower limit, it becomes extremely difficult to introduce calcium ions and osteogenic ions into the titanate layer at the preferable concentration. When the upper limit is exceeded, a stable compound that is disadvantageous for apatite formation is easily formed on the surface.

The temperature and immersion time of the second aqueous solution when dipping the substrate are usually 20 ° C. or more and 0.5 hour or more, respectively, preferably 40 ° C. or more and 24 hours or more, respectively. When both are less than the lower limit, it becomes extremely difficult to introduce calcium ions and osteogenic ions into the titanate layer at the preferable concentration.
The temperature and holding time when heating the substrate in the atmosphere are usually 400 ° C. or more and 0.5 hour or more, respectively, preferably 600 ° C. or more and 1 hour or more. When both are less than the lower limit, the scratch resistance of the titanate layer becomes poor.

When an aqueous solution containing acid and osteogenic ions is used in the third aqueous solution, the acid and osteogenic ion concentrations are usually 0.001 to 100 mM and 1 to 1000 mM, respectively, preferably 0.01 to 100 mM and 1 respectively. ~ 1000 mM. When both are less than the lower limit, only the same effect as when water is used is obtained, and when the upper limit is exceeded, a stable compound that is disadvantageous for apatite formation is easily formed on the surface. The aqueous solution containing osteogenic ions is usually acidic, neutral or weakly alkaline, and those having pH = 10 or more are not preferred.
The temperature and immersion time of the third aqueous solution when dipping the substrate are usually 60 ° C. or more and 3 hours or more, respectively, preferably 80 ° C. or more and 24 hours or more, respectively. When an acid solution is used for the third aqueous solution, activation is performed in a shorter time than when water is used. The preferred acid contained in the acid aqueous solution is one or more selected from hydrochloric acid, nitric acid, acetic acid and sulfuric acid. This is because these acids are easy to handle and do not erode the substrate. When the immersion temperature and the immersion time are less than the lower limit, they are not sufficiently activated.
By changing the concentration of osteogenic ions in the second and third aqueous solutions, the concentration in the titanate layer can be changed.

-Example 1-
A pure titanium metal plate with a size of 10 mm × 10 mm × 1 mm is polished with a # 400 diamond pad, ultrasonically washed with acetone, 2-propanol, and ultrapure water for 30 minutes each, and then 5M aqueous sodium hydroxide solution It was immersed in 5 ml at 60 ° C. for 24 hours (hereinafter referred to as “alkali treatment”) and washed with ultrapure water for 30 seconds. This titanium metal plate was immersed in 10 ml of an aqueous solution mixed so that the concentrations of calcium chloride and strontium chloride were both 50 mM at 40 ° C. for 24 hours. (Hereinafter referred to as “calcium / strontium treatment”.) Next, the titanium metal plate was heated from normal temperature to 600 ° C. at a rate of 5 ° C./min in an electric furnace and held at 600 ° C. for 1 hour in the atmosphere. The inside was allowed to cool (hereinafter referred to as “heat treatment”). Then, it was immersed in warm water at 80 ° C. for 24 hours (hereinafter referred to as “warm water treatment”) and washed with ultrapure water for 30 seconds.

-Example 2-
In Example 1, a sample was produced under the same conditions as in Example 1 except that the sample was immersed in 1M strontium chloride at 80 ° C. for 24 hours instead of hot water treatment (hereinafter referred to as “strontium treatment”).

-Example 3-
In the calcium / strontium treatment of Example 1, the same conditions as in Example 1 except that it was immersed in 10 ml of an aqueous solution mixed so that the concentrations of calcium chloride and strontium chloride were 80 mM and 20 mM, respectively, at 40 ° C. for 24 hours. Samples were manufactured.

-Example 4-
In Example 1, instead of the calcium / strontium treatment, it was immersed in 10 ml of an aqueous solution mixed so that the concentrations of calcium chloride and magnesium chloride were 40 mM and 60 mM, respectively, at 40 ° C. for 24 hours (hereinafter referred to as “calcium / magnesium treatment”). A sample was produced under the same conditions as in Example 1 except that.

-Example 5
In Example 4, a sample was produced under the same conditions as in Example 4 except that it was immersed in a 1 M aqueous magnesium chloride solution at 80 ° C. for 24 hours (hereinafter referred to as “magnesium treatment”) instead of hot water treatment.

-Example 6-
In the calcium / magnesium treatment of Example 4, it was immersed in 10 ml of an aqueous solution mixed so that the concentrations of calcium chloride and magnesium chloride were 2M and 3M, respectively, at 40 ° C. for 24 hours, except that it was treated with magnesium instead of hot water treatment. Other than that, a sample was manufactured under the same conditions as in Example 4.

-Example 7-
In Example 1, instead of the calcium / strontium treatment, the sample was immersed in 10 ml of an aqueous solution mixed so that the concentrations of calcium acetate and zinc acetate were 99.99 mM and 0.01 mM, respectively, at 40 ° C. for 24 hours (hereinafter referred to as “calcium”). The sample was produced under the same conditions as in Example 1 except that it was immersed in 1 mM acetic acid at 80 ° C. for 24 hours (hereinafter referred to as “acetic acid treatment”) instead of hot water treatment. .

-Example 8-
In Example 1, instead of calcium / strontium treatment, the sample was immersed in 10 ml of an aqueous solution mixed so that the concentrations of calcium chloride and lithium chloride were 0.01 mM and 99.99 mM at 40 ° C. for 24 hours (hereinafter referred to as “calcium / strontium”). A sample was prepared under the same conditions as in Example 1 except that it was immersed in a 1M aqueous lithium chloride solution at 80 ° C. for 24 hours (hereinafter referred to as “lithium treatment”) instead of hot water treatment. .

-Example 9-
In Example 1, instead of the calcium / strontium treatment, it was immersed in 40 ml of an aqueous solution mixed so that the concentrations of calcium chloride and gallium chloride were 99.95 mM and 0.05 mM, respectively (hereinafter referred to as “calcium / strontium”). A sample was manufactured under the same conditions as in Example 1 except that it was referred to as “gallium treatment”.

-Comparative Example 1-
In Example 1, a sample was produced under the same conditions as in Example 1 except that the hot water treatment was not performed.
-Comparative Example 2-
In Example 1, a sample was manufactured under the same conditions as in Example 1 except that the holding temperature in the heat treatment was set to 200 ° C. and the hot water treatment was not performed.
-Comparative Example 3-
In Example 1, a sample was produced under the same conditions as in Example 1 except that the heat treatment and the hot water treatment were not performed.

The production conditions of the samples of the above examples and comparative examples are summarized in Table 1.

[Composition analysis]
The composition of the sample surface of the example and the comparative example was analyzed by an energy dispersive X-ray analysis method at an acceleration voltage of 9 kV, or the calcium ion and the lithium ion eluted by being immersed in 1 M hydrochloric acid at 80 ° C. for 24 hours were analyzed by ICP. did. As a result, in each sample, 5.5 atomic% of sodium was detected immediately after the alkali treatment in the course of production, but as shown in Table 2, calcium / strontium, calcium / magnesium, calcium / zinc, calcium / lithium, calcium / In the gallium-treated sample, sodium disappears, and instead 1.5 to 3.3 atomic% calcium and 0.4 to 1.7 atomic% strontium, magnesium, zinc, gallium are detected, or 0. 27 ppm of calcium ions and 0.19 ppm of lithium ions were detected. As shown in Tables 1 and 2, by changing the concentration ratio of calcium ions and osteogenic ions contained in the second aqueous solution, and by changing the concentration of osteogenic ions contained in the third aqueous solution, It was possible to arbitrarily control the ratio of calcium ions and osteogenic ions introduced.

According to the XPS of Examples 1, 2, 4 and 5 and the GD-OES results of Examples 7 to 9, as shown in FIGS. 1 to 7, strontium ions, magnesium ions, zinc together with calcium ions to a depth of 1 μm from the surface. It was observed that ions, lithium ions or gallium ions were introduced and their concentrations decreased in a gradient with depth.
When the crystal structure of the surface sample is examined by thin film X-ray diffraction, as shown in FIG. 8, all of the samples of Examples 1, 4, and 7-9 contain calcium titanate containing bone-forming ions, rutile type, and anatase type titanium oxide. It was found that it was formed.

[Evaluation of scratch resistance]
The scratch resistance of the sample of Example 1-3 and the sample of Comparative Example 1-3 was measured with a scratch tester. As shown in Table 3, the scratch resistance of the sample heat-treated at 200 ° C. or lower was as low as less than 10 mN. However, the scratch resistance of the sample heat-treated at 600 ° C. was as high as 50 mN or more.

[Apatite forming ability evaluation]
When the samples of Examples and Comparative Examples were immersed in a simulated body fluid (SBF) of ISO standard 23317 maintained at 36.5 ° C., as shown in Table 2 and Table 3, in all Examples, within 3 days of SBF immersion Apatite was deposited so as to cover the entire surface, ie 99% or more of the total surface area. Therefore, it was confirmed that these samples showed high apatite-forming ability in vivo. On the other hand, after the heat treatment, the sample of Comparative Example 1 that was not subjected to the third aqueous solution treatment did not form apatite within 3 days of SBF immersion.

[Evaluation of dissolution of bone-forming ions]
The samples of Examples 1-2, 4-5, and 7-9 were immersed in phosphate buffer (PBS) maintained at 36.5 ° C. for various times, and the concentration of osteogenic ions eluted in each PBS was determined. Measured by ICP. As a result, as shown in FIG. 9, it was observed that 0.03 to 0.9 ppm of osteogenic ions were gradually eluted in PBS. Therefore, this sample was found to release bone-forming ions in vivo. In particular, the samples of Examples 2 and 5 using the third aqueous solution containing bone-forming ions are compared to the samples of Examples 1 and 4 using warm water from the beginning of immersion as shown in FIGS. The amount of osteogenic ions eluted was large. Further, since the zinc ion concentration eluted from the sample of Example 7 is approximately twice the concentration reported in Non-Patent Document 5 as having an effect on bone formation, a high bone formation effect is expected. Furthermore, as shown in Table 3, by changing the concentration of strontium ions in the second and third aqueous solutions, the concentration of strontium ions in the surface layer can be changed, and as a result, the concentration of eluted strontium ions can be changed. Was also confirmed.

Claims

A bone repair material comprising: a base material made of titanium metal or a titanium alloy; and a titanate layer containing calcium ions and osteogenic ions on the surface of the base material, and having a scratch resistance of 10 mN or more.
The bone repair material according to claim 1, wherein the bone-forming ions are one or more selected from ions of strontium, magnesium, zinc, lithium and gallium.
The bone repair material according to claim 1, wherein the calcium ion concentration in the titanate layer is in the range of 0.1 to 10 atomic% and the bone forming ion concentration is in the range of 0.1 to 5 atomic%.
The bone repair material according to claim 1, wherein the titanate layer has a thickness of 0.1 to 10 µm.
The bone repair material according to claim 1, wherein a surface of 99% or more of the total surface area is coated with apatite within 3 days after being immersed in a simulated body fluid of ISO standard 23317 maintained at 36.5 ° C.
A step of immersing a base material made of titanium or a titanium alloy in an alkaline first aqueous solution not containing calcium ions and osteogenic ions but containing one or more cations of sodium ions and potassium ions; and calcium ions and bones A step of immersing the substrate in a second aqueous solution containing forming ions, a step of heating the substrate in the atmosphere, and a third aqueous solution comprising at least one selected from water, an aqueous acid solution and an aqueous solution containing bone forming ions The manufacturing method of the bone repair material characterized by including the process to immerse.
The method according to claim 6, wherein the bone forming ions contained in the second and third aqueous solutions are one or more selected from ions of strontium, magnesium, zinc, lithium and gallium.
The production method according to claim 6, wherein the calcium ion concentration in the second aqueous solution is in the range of 0.01 to 5000 mM and the concentration of osteogenic ions is in the range of 0.01 to 5000 mM.
The method according to claim 6, wherein the temperature of the second aqueous solution is 20 ° C or higher, and the time for immersing the substrate in the second aqueous solution is 0.5 hours or longer.
The manufacturing method according to claim 6, wherein the temperature of the heat treatment is 400 ° C or higher and the holding time is 0.5 hours or longer.
The production method according to claim 6, wherein the third aqueous solution is an aqueous solution containing osteogenic ions, and the concentration of the osteogenic ions is in the range of 1 to 1000 mM.
The method according to claim 6, wherein the third aqueous solution is an acid aqueous solution, and the acid contained in the acid aqueous solution is one or more selected from hydrochloric acid, nitric acid, acetic acid, and sulfuric acid.
The method according to claim 12, wherein the acid concentration in the acid aqueous solution is in the range of 0.001 to 100 mM.
The method according to claim 6, wherein the temperature of the third aqueous solution is 60 ° C or higher, and the time for immersing the substrate in the third aqueous solution is 3 hours or longer.