Biocompatible material and method for producing the same

Abstract

To provide a biocompatible material with a membrane that realizes bone formation around the periphery thereof in a relatively short period of time.SOLUTION: Provided is a biocompatible material with a membrane that includes magnesium and optionally calcium, and the membrane includes, setting the total weight of magnesium and calcium as 100 wt.%, calcium by 0 to 40 wt.%, and the arithmetic mean surface height Sa1 of the membrane surface roughness is 2 μm or less, and the biocompatible material solves the problem.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a biocompatible material having a film comprising magnesium and optionally calcium, particularly to a biocompatible material having a film comprising magnesium and optionally calcium, which has a predetermined surface roughness, a predetermined adhesion, and / or a predetermined hardness. The present invention also relates to a method for producing the biocompatible material. [Background technology]

[0002] Dental implant treatment is gaining attention as a type of treatment for tooth loss for people of all ages, from young to old. Materials used for dental root implants are metallic titanium, titanium alloys, or ceramic zirconia, which are relatively harmless to the body.

[0003] There is a need to shorten the time from implantation of a dental root implant until the tooth root becomes functional and the patient can chew, i.e., the time until secondary fixation, in which bone cells are formed around the dental root implant. The dental root implant materials such as titanium alone cannot meet the demand for shortening the time until secondary fixation, and improvements are needed.

[0004] For example, Non-Patent Documents 1 and 2 show that forming apatite on the surface of a dental root implant is effective for the formation of surrounding bone, and disclose that apatite is formed by thermal spraying or sputtering on the surface of a dental root implant before implantation.

[0005] Patent Documents 1 and 2 also form apatite on titanium implants, but they disclose that adhesion can be improved by chemically forming a calcium-containing film on the implant, or by forming apatite on top of an intermediate layer containing calcium.

[0006] Non-Patent Document 3 discloses that generating an appropriate pressure between the dental root implant and the alveolar bone is effective in promoting secondary fixation. Non-Patent Document 3 also discloses that the dental root implant must be tightened with an appropriate torque when tightening for initial fixation. However, the apatite films formed before implantation described in Non-Patent Document 1, Non-Patent Document 2, Patent Document 1, and Patent Document 2 above are low in hardness and / or have insufficient adhesion, so they easily peel off during tightening and implantation, and are unable to fully fulfill their functions.

[0007] Patent Document 3 discloses that in order to simultaneously maintain the strength of the implant and improve its bonding function with bone, a metal is used for the core (substrate) of the implant, and a film of bioactive glass containing oxides of silicon, sodium, magnesium, calcium, and potassium is formed on the surface instead of apatite. However, because this film is made of inorganic glass or inorganic compounds, it has the drawback of being brittle although it is hard.

[0008] Patent Document 4 attempts to promote bone formation by moderately roughening the surface of a dental root implant made of ceramics such as zirconia. However, in this case, although the implant can be tightened regardless of membrane peeling, bone formation is not sufficient. Patent Document 5 discloses that a dental root implant is covered with a protective film to protect the implant and make the most of the active surface of the base material. This protective film is designed to disappear after implantation in order to maintain aesthetics, but the film itself does not contain any components or functions that promote bone formation.

[0009] Patent Document 6, like Patent Document 3, discloses that a protective film is formed on the surface of a dental root implant substrate to protect the active surface, and that the film is composed of salts that generate sodium, potassium, magnesium, and calcium cations. However, salts do not provide sufficient strength and adhesion to the film required for implantation.

[0010] Non-Patent Document 4 discloses an orthopedic implant in which a pure magnesium metal film is formed on the surface by ion plating instead of apatite. Although the effect of magnesium ions on bone formation is demonstrated, the absence of calcium, the main component of apatite, means that the apatite formation ability is insufficient. Furthermore, the arc ion plating used here produces large particles that form the film, resulting in high surface roughness that is difficult to control. Furthermore, even if calcium is further used as an alloying target, this method forms the film as clusters, resulting in the formation of intermetallic compounds such as Cr, which makes the film brittle.

[0011] Non-Patent Document 5 proposes that Mg-Ca-Zn ternary alloys are useful as biodegrading materials for implant cores (substrates). When Mg is considered the main alloy, the solid solubility limit of an alloy made by adding Ca is 1% or less, and any addition of more Ca results in the formation of intermetallic compounds such as MgCa. Therefore, the Ca content of such alloys is at most 5% or less, and there is a possibility that intermetallic compounds may remain in the body in addition to Mg and Ca ions.

[0012] Non-Patent Document 6 discloses that Mg-Ca-Zn containing up to 15% Ca can be produced as amorphous ribbons by high-temperature, high-speed spinning. However, about 7% intermetallic compounds are formed, making it difficult to produce a uniform amorphous material, and the shape and size are limited. Furthermore, Non-Patent Document 7 shows that attempts have been made to produce a Ca-Mg-Zn alloy containing Ca as the primary metal using a similar method in order to enhance the effect of Ca, but have not yet achieved uniform amorphous formation.

[0013] Non-Patent Documents 8 and 9 disclose that an Mg-Ca-Zn ternary system containing 4 to 24% by weight of Ca is produced as an amorphous thin film by sputtering. These thin films contain at least 30% by weight of Zn to facilitate the formation of an amorphous state. Non-Patent Document 9 shows that Zn ions are cytotoxic, and the higher the amount of Zn, the stronger the cytotoxicity.

[0014] To stably produce amorphous metals, multi-component alloys (containing three or more elements) that can lower the liquidus temperature are generally required.Until now, it has been impossible to produce amorphous metals that are essentially composed of the two components Mg and Ca. [Prior art documents] [Non-patent literature]

[0015] [Non-Patent Document 1] Kyocera Corporation POIEX / HACEX catalog. [Non-patent document 2] Kyosuke Ueda, Material, Vol. 51, No. 9 (2012). [Non-patent document 3] Implant Journal 2017 Autumn Issue, p.8. [Non-patent document 4] X. Li et al., Scientific Reports, 7:40755 (2017). [Non-Patent Document 5] J. Hofsteter et al., JOM, Vol. 68, No. 4 (2014), p. 566-572. [Non-patent document 6] S.Paul al.,S25 Materialia (2020). [Non-Patent Document 7] K. Saksl et al., J. Alloys and Compounds 801 (2019) p.651-657. [Non-patent document 8] J. Liu et al., J. Alloys and Compounds 742 (2018) p. 524-535. [Non-Patent Document 9] J. Li et al., Chemical Communications 53 (2017) p.8288-8291 [Patent documents]

[0016] [Patent Document 1] Publication WO2009 / 147819. [Patent Document 2] Publication JP4425198. [Patent Document 3] Special Publication No. 3-2540. [Patent Document 4] WO2016 / 189099A1. [Patent Document 5] WO2020 / 099334A2. [Patent Document 6] EP1847278A1. Summary of the Invention [Problem to be solved by the invention]

[0017] SUMMARY OF THE INVENTION It is therefore an object of the present invention to provide a biocompatible material having a membrane that allows bone formation around the material in a relatively short period of time. Another object of the present invention is to provide a biocompatible material having a film with a relatively smooth surface roughness that is suitable for implantation or tightening with an appropriate implantation torque, in addition to or in addition to the above-mentioned object.

[0018] Furthermore, an object of the present invention is to provide a biocompatible material having a film with sufficient adhesion and / or hardness to withstand implantation or tightening with an appropriate implantation torque, in addition to or in addition to the above-mentioned object. Another object of the present invention is to provide a method for producing the biocompatible material, in addition to or in addition to the above object. [Means for solving the problem]

[0019] The present inventors have discovered the following inventions. <1> A biocompatible material having a film containing magnesium and optionally calcium, wherein the film contains 0 to 40% by weight of calcium when the total weight of magnesium and calcium is 100% by weight, and the arithmetic mean height Sa1 of the surface roughness of the film is 2 μm or less, preferably 1 μm or less.

[0020] <2> A biocompatible material having a film containing magnesium and optionally calcium, wherein the film contains 0 to 40% by weight of calcium when the total weight of magnesium and calcium is 100% by weight, and the difference between the arithmetic mean height Sa1 of the surface roughness of the film and the arithmetic mean height Sa2 of the surface roughness of the surface not having the film is 300 nm or less, preferably 200 nm or less, and more preferably 150 nm or less. <3> the above <2> In the above, the arithmetic mean height Sa1 of the surface roughness of the film is 2 μm or less, preferably 1 μm or less.

[0021] <4> A biocompatible material having a film containing magnesium and optionally calcium, wherein the film contains 0 to 40% by weight of calcium when the total weight of the magnesium and calcium is taken as 100% by weight, and the film has any one, two, or all of the following properties i) to iii): i) The hardness obtained by an indentation test is 0.4 GPa or more, preferably 0.9 GPa or more, and more preferably 1.2 GPa or more. ii) The relationship Wc / t between the critical load Wc (N) and the film thickness t (μm) is 1 N / μm or more, and more preferably 2 N / μm or more. iii) The critical shear stress at the interface between the film and the substrate is 80 MPa or more, preferably 160 MPa or more.

[0022] <5> the above <4> In a) the arithmetic mean height Sa1 of the surface roughness of the film is 2 μm or less, preferably 1 μm or less, and / or b) the difference between the arithmetic mean height Sa1 of the surface roughness of the film and the arithmetic mean height Sa2 of the surface roughness of the surface not having the film is 300 nm or less, preferably 200 nm or less, and more preferably 150 nm or less; It is better to do so. <6> the above <1> ~ <5> In any of the above, the average thickness of the film is preferably 0.10 to 30 μm. In particular, the average thickness of the film corresponding to the contact area with the bone and its vicinity is preferably 0.10 to 30 μm, more preferably 0.20 to 20 μm, and even more preferably 0.40 to 15 μm.

[0023] <7> the above <1> ~ <6> In the above, the film may consist essentially of magnesium. <8> the above <1> ~ <6> In the above, the film preferably consists of magnesium only.

[0024] <9> the above <1> ~ <6> In the above, the membrane contains magnesium and calcium, and when the total weight of magnesium and calcium is taken as 100% by weight, the membrane contains calcium in an amount of more than 0% by weight but not more than 40% by weight, preferably 0.8 to 35% by weight, more preferably 5 to 30% by weight, and most preferably 15 to 25% by weight. <10> the above <9> In the above, the film preferably consists essentially of magnesium and calcium. <11> the above <9> In the above, the film preferably consists of only magnesium and calcium.

[0025] <12> the above <9> ~ <11> In any of the above, the film is preferably Mg2Ca-free. <13> the above <9> ~ <12> In any of the above, the film may have an amorphous portion. <14> the above <9> ~ <12> In any of the above, the film should be essentially made of amorphous material, and preferably made of only amorphous material.

[0026] <15> the above <1> ~ <14> In any one of the above, the biocompatible material has a biocompatible substrate, and the biocompatible substrate is preferably at least one selected from the group consisting of pure titanium, zirconia, cobalt-chromium alloy, stainless steel, and titanium alloy.

[0027] <16> the above <1> ~ <15> In any one of the above, the biocompatible material is preferably one selected from the group consisting of an artificial bone material, an intraosseous fixation device material, a dental implant material, an orthodontic anchor screw material, an intramedullary nail material, and an intervertebral body fusion material, such as an artificial bone, a pin, a wire, a bolt, a screw, a washer, an intramedullary nail, or a vertebral spacer. <17> the above <1> ~ <16> In any of the above, the shape of the biocompatible material is preferably one selected from the group consisting of a cylindrical shape, a truncated conical shape, a conical shape, a shape having a screw-like thread portion in a part of the shape, a rectangular parallelepiped and a cube, a block shape such as a rectangular parallelepiped and a cube having a part of an inclined surface, and a wedge shape.

[0028] <18> (A) providing a biocompatible substrate; (B) providing a sputter target comprising magnesium and optionally calcium; (C) cleaning the surface of the biocompatible substrate in a vacuum; and (D) forming a film containing magnesium and optionally calcium on the biocompatible substrate by sputtering using the sputtering target while adjusting the temperature of the biocompatible substrate obtained in step (C) to 130°C or less, preferably 90°C or less, more preferably 60°C or less; A method for producing a biocompatible material, which has a film containing magnesium and optionally calcium, and in which the film contains 0 to 40% by weight of calcium when the total weight of magnesium and calcium is 100% by weight.

[0029] <19> the above <18> In a) the arithmetic mean height Sa1 of the surface roughness of the film is 2 μm or less, preferably 1 μm or less, and / or b) The difference between the arithmetic mean height Sa1 of the surface roughness of the film and the arithmetic mean height Sa2 of the surface roughness of the surface not having the film is 300 nm or less, preferably 200 nm or less, and more preferably 150 nm or less. <20> the above <18> or <19> In the above, the film may have one, two, or all of the following characteristics i) to iii): i) The hardness obtained by an indentation test is 0.4 GPa or more, preferably 0.9 GPa or more, and more preferably 1.2 GPa or more. ii) The relationship Wc / t between the critical load Wc (N) and the film thickness t (μm) is 1 N / μm or more, and more preferably 2 N / μm or more. iii) The critical shear stress at the interface between the film and the substrate is 80 MPa or more, preferably 160 MPa or more.

[0030] <21> the above <18> In any of the above ranges, the average thickness of the film is 0.10 to 30 μm, preferably 0.20 to 20 μm, and more preferably 0.40 to 15 μm. [Effects of the Invention]

[0031] According to the present invention, it is possible to provide a biocompatible material having a membrane that allows bone formation around it in a relatively short period of time. Furthermore, in addition to or in addition to the above-mentioned effects, the present invention can provide a biocompatible material having a film with a relatively smooth surface roughness that is suitable for implantation or tightening with an appropriate implantation torque.

[0032] Furthermore, the present invention can provide a biocompatible material having a film that has adhesion and / or hardness that can withstand implantation or tightening with an appropriate implantation torque, in addition to or in addition to the above-mentioned effects. Furthermore, the present invention can provide a method for producing the biocompatible material in addition to or in addition to the above-mentioned effects. [Brief explanation of the drawings]

[0033] [Figure 1] FIG. 1 shows the measurement results of the arithmetic mean surface roughness for Al-C0, Al-C10, Al-C20, and Al-C30 films formed using a titanium plate-shaped substrate (the values ​​with diagonal lines are Sa1 values, and the values ​​without diagonal lines are Sa2 values). [Figure 2] FIG. 1 shows the measurement results of the arithmetic mean surface roughness for A2-C0, A2-C10, A2-C20, and A2-C30, which were formed using a plate-shaped substrate made of zirconia (the values ​​with diagonal lines are Sa1 values, and the values ​​without diagonal lines are Sa2 values). [Figure 3] 1 shows scanning electron microscope (SEM) images of the cross-section of films of AC1-C0, AC1-C10, AC1-C20, and AC1-C30 formed using glass substrates. [Figure 4] 1 shows scanning electron microscope images of the film-bearing surfaces of Al-C0, Al-C10, Al-C20, and Al-C30, which were formed using titanium plate-shaped substrates. [Figure 5] 1 shows scanning electron microscope images of the film-bearing surfaces of A2-C0, A2-C10, A2-C20, and A2-C30, which were formed using plate-shaped substrates made of zirconia. [Figure 6] FIG. 1 shows the results of X-ray diffraction analysis of films AC1-C0, AC1-C10, AC1-C20, and AC1-C30 formed using glass substrates. [Figure 7] FIG. 1 shows the results of X-ray diffraction analysis of films A1-C0, A1-C10, A1-C20, and A1-C30 formed using a plate-shaped substrate made of titanium. [Figure 8] FIG. 1 shows the results of X-ray diffraction analysis of A2-C0, A2-C10, A2-C20, and A2-C30, which were formed using a plate-shaped substrate made of zirconia. [Figure 9]FIG. 1 shows the results of a hardness test by nanoindentation using an apparatus (Elionix ultra-microindentation hardness tester "ENT-1100A") under the following conditions: indenter: Berkovich indenter; indentation load: 20 mN; holding time: 0 seconds. [Figure 10] FIG. 10 shows SEM images of the appearance near the critical load after a scratch test in a direction parallel to the grinding marks for A1-C0, A1-C10, A1-C20, and A1-C30, which were formed using a plate-shaped substrate made of titanium. [Figure 11] FIG. 10 shows SEM images of the appearance near the critical load after a scratch test in a direction parallel to the grinding marks for A2-C0, A2-C10, A2-C20, and A2-C30, which were formed using a plate-shaped substrate made of zirconia. [Figure 12] This figure shows the results of measurements to find the load when the indenter nearly reaches the substrate, i.e., the critical load of the film, in scratch tests in parallel or perpendicular to the grinding marks for A1-C0, A1-C10, A1-C20, and A1-C30, which were formed using titanium plate-shaped substrates. [Figure 13] These are the results of measurements to find the load when the indenter almost reaches the substrate, i.e., the critical load of the film, in scratch tests parallel or perpendicular to the grinding marks for A2-C0, A2-C10, A2-C20, and A2-C30, which were formed using a plate-shaped substrate made of zirconia. [Figure 14] FIG. 14 is a diagram showing the yield shear stresses of A1-C0 to C30 and A2-C0 to C30 converted from the hardness of the films of A1-C0 to C30 and A2-C0 to C30. [Figure 15] FIG. 1 shows a schematic diagram of a method for determining the critical load in a scratch test when the substrate has a cylindrical shape. [Figure 16] This figure shows SEM images of films newly formed on the substrates A1-C0, A1-C10, A1-C20, and A1-C30, which were formed using titanium plate-shaped substrates, and immersed in HBSS for one week. [Figure 17]This figure shows SEM images of films newly formed on the substrates A2-C0, A2-C10, A2-C20, and A2-C30, which were formed using plate-shaped substrates made of zirconia, and immersed in HBSS for one week. [Figure 18] FIG. 1 shows the results of X-ray diffraction (XRD) analysis by a thin film method for a plate-shaped substrate A1 using titanium and films A1-C0, A1-C10, A1-C20, and A1-C30 formed using the substrate. [Figure 19] FIG. 1 shows the results of X-ray diffraction (XRD) analysis by a thin film method for a plate-shaped substrate A2 using zirconia and films A2-C0, A2-C10, A2-C20, and A2-C30 formed using the substrate. [Figure 20] FIG. 10 is a diagram showing a comparison of the arithmetic mean height Ra1 of line roughness between sample AIPC1-C0, in which a pure magnesium film is formed by arc ion plating using a glass substrate, and sample AC1-C0, AC1-C10, AC1-C20, and AC1-C30, in which a film is formed by sputtering using a glass substrate. [Figure 21] FIG. 10 is a diagram showing a comparison of the results of XRD and scratch tests of A2-C20, which was formed using a plate-shaped substrate made of zirconia, and A2-C20-H, which was obtained by subjecting A2-C20 to heat treatment. DETAILED DESCRIPTION OF THE INVENTION

[0034] The invention described in this application (hereinafter sometimes abbreviated as "the present invention") will be described below. The present application provides a biocompatible material having a film containing magnesium and optionally calcium, wherein the film contains 0 to 40% by weight of calcium, and when calcium is present, the amount of calcium is greater than 0% by weight and not more than 40% by weight, preferably 0.8 to 35% by weight, more preferably 5 to 30% by weight, and most preferably 15 to 25% by weight, assuming the total weight of magnesium and calcium to be 100% by weight.

[0035] In one aspect, the present invention provides a biocompatible material, wherein a) the arithmetic mean height Sa1 of the surface roughness of the film is 2 μm or less, preferably 1 μm or less. In another aspect, the present invention provides a biocompatible material in which the difference between the arithmetic mean height Sa1 of the surface roughness of the film and the arithmetic mean height Sa2 of the surface roughness of a surface not having the film is 300 nm or less, preferably 200 nm or less, and more preferably 150 nm or less.

[0036] In a further aspect of the present invention, the membrane may have any one, two, or all of the following characteristics i) to iii): i) The hardness obtained by an indentation test is 0.4 GPa or more, preferably 0.9 GPa or more, and more preferably 1.2 GPa or more. ii) The relationship Wc / t between the critical load Wc (N) and the film thickness t (μm) is 1 N / μm or more, and more preferably 2 N / μm or more. iii) The critical shear stress at the interface between the film and the substrate is 80 MPa or more, preferably 160 MPa or more.

[0037] The term "biocompatibility" in the "biocompatible material" of the present invention refers to a property that is considered to be present in the body without causing any problems in terms of safety for the body. <Membrane> The biocompatible material of the present invention preferably has the above-mentioned properties, specifically, a predetermined arithmetic mean height Sa1 of the surface roughness, a predetermined difference between the arithmetic mean heights Sa1 and Sa2 of the surface roughness, a predetermined critical load which is an index of adhesion, a predetermined hardness, and / or a predetermined critical shear stress at the interface between the film and the substrate.

[0038] <<Arithmetic mean surface roughness Sa1 of the surface with the coating>> The arithmetic mean height Sa1 of the surface roughness of the film of the biocompatible material of the present invention is 2 μm or less, preferably 1 μm or less. Here, the arithmetic mean height Sa1 of the surface roughness of the film-bearing surface, that is, the film, can be measured in accordance with ISO25178. When measuring surface roughness with a laser beam, it is possible to obtain more than 10,000 measurement points over a measurement range of 100 μm x 100 μm. The arithmetic mean height can be calculated by removing the shape using a quadratic polynomial on a calibration surface that has been leveled using the least squares method, without using a filter to separate the wavelength components of the profile curve. It is also recommended to measure the total measurement distance in one direction more than the number of times that equals the evaluation length in accordance with JIS0633 / ISO4288, and then calculate the average value.

[0039] The surface of the biocompatible substrate in the biocompatible material of the present application may be ground in a certain direction or polished entirely. When the surface is polished entirely, the surface roughness becomes nearly uniform. However, when the surface is ground in a certain direction, scanning the probe light along the directional roughness can easily result in measurement errors, and the arithmetic mean surface roughness along that direction may differ from the arithmetic mean height of the surface roughness perpendicular to that direction. In the present application, the arithmetic mean height of the surface roughness of the film refers to the value measured in the direction with the lowest roughness by scanning the probe light in three directions (parallel, perpendicular, and at an angle of approximately 45°) relative to the center line of the shape of the biocompatible material.

[0040] <<Arithmetic mean height Sa2 of surface roughness on the surface without a coating>> In the present application, the "surface having no film" in the "arithmetic mean height Sa2 of surface roughness of the surface having no film" refers to the surface of the substrate before a film is formed, or the surface of the substrate when the film is removed after film formation. As described above, the film of the present application contains magnesium and optionally calcium. The film can generally be almost completely removed by immersion in a weakly acidic aqueous solution or water. Note that the biocompatible substrate in the biocompatible material of the present application is not corroded by the weakly acidic aqueous solution used to remove the film. Therefore, the arithmetic mean height Sa2 of the surface roughness of the substrate surface before the film is formed and the arithmetic mean height Sa2' of the substrate surface when the film is removed after the film is formed are substantially the same. Like Sa1, Sa2' can also be measured in accordance with ISO25178.

[0041] In one aspect, the present invention is such that the difference between the arithmetic mean height Sa1 of the surface roughness of the film and the arithmetic mean height Sa2 of the surface roughness of the surface not having the film is 300 nm or less, preferably 200 nm or less, and more preferably 150 nm or less.

[0042] In one aspect of the present invention, the film preferably has one, two, or all of the following properties i) to iii): i) The hardness obtained by an indentation test is 0.4 GPa or more, preferably 0.9 GPa or more, and more preferably 1.2 GPa or more. ii) The relationship Wc / t between the critical load Wc (N) and the film thickness t (μm) is 1 N / μm or more, and more preferably 2 N / μm or more. iii) The critical shear stress at the interface between the film and the substrate is 80 MPa or more, preferably 160 MPa or more.

[0043] <<Hardness obtained by indentation test>> In one aspect of the present invention, the hardness of the film obtained by an indentation test is 0.4 GPa or more, preferably 0.9 GPa or more, and more preferably 1.2 GPa or more. Here, in the hardness test using the nanoindentation method, the indentation load should be set so that the indentation depth is no more than one-fifth, preferably no more than one-tenth, of the film thickness. Measurements should be made 20 times or more, preferably 30 times or more, per sample to determine the average value. For example, the test can be performed under the following conditions: indenter: Berkovich indenter; indentation load: 20 mN; holding time: 0 seconds.

[0044] <<Critical load obtained by scratch test>> In this application, the critical load Wc refers to the load at which a brittle crack occurs without the film exhibiting ductility, or the load at which the film partially peels off, or the load at which the film is scraped off and the substrate is exposed. In one aspect, the film preferably has a Wc / t (Wc is the critical load (N) and t is the film thickness (μm)) of 1 N / μm or more, more preferably 2 N / μm or more. For example, when the film thickness is 5 μm, the film preferably has a critical load of 5 N or more, preferably 10 N or more.

[0045] Here, the scratch test can be performed using a device commonly used for scratch tests, using a Rockwell indenter with a diameter of 0.8 mm, by applying a load in the range of, for example, 0 to 8 kgf, up to a maximum of twice the load at which the substrate is exposed, or up to a maximum of twice the load at which the film is partially peeled off, or up to a maximum of twice the load at which brittle cracks occur without the film exhibiting ductility. In this case, the sample after the scratch test is observed using SEM / EDX, and the critical load can be determined by measuring the shorter distance from the initial position of the scratch test to the position where brittle cracks occur without the film showing ductility, to the position where the film is partially peeled off, or to the position where the substrate is exposed. The critical load corresponds to the adhesiveness between the film and the substrate, and the film of the biocompatible material of the present invention should have a critical load within the above range.

[0046] <<Appearance of the film after scratch test>> When observing the sample after the scratch test with SEM / EDX, it is desirable that the film does not exhibit ductility, no brittle cracks occur, the film does not peel off in parts, and the film appears to have been ductilely scraped off until the substrate is exposed.

[0047] <<Critical shear stress at the interface>> From the torque required when embedding the implant screw, the shear stress generated on the screw surface can be calculated as follows: Shear force τ generated on the screw surface i can be calculated as in Equation 1. That is, the radius of the implant screw (half the diameter of the periphery) is r, and the area where the screw contacts the alveolar bone is A. i , where T is the torque when embedding, and this can be roughly expressed as in Equation 1.

[0048]

number

[0049] The pressure and shear stress generated on the screw surface during implantation are concentrated near the tip of the screw thread. Furthermore, when a screw is implanted, high pressure and shear force are generated mainly in the area of ​​the hard cortical bone. The average thickness of cortical bone is about 1.0 to 1.5 mm, and the screw pitch is 1 to 2 mm, so the screw is screwed in with shear force concentrated on almost one circumference of the thread. If the width of the tip of the thread is h, then the area A of the tip of the thread where shear stress is highest is i is expressed as Equation 2.

[0050]

number

[0051] When the minimum embedding torque T for promoting bone formation is 40 Ncm (Non-Patent Document 3), the radius r of the implant screw is 2 mm, and the width of the tip of the screw thread is 0.2 mm, the shear stress τ generated on the surface can be calculated by substituting these values ​​into Equation 1 and Equation 2. i When the tip of the screw thread is sharper and the thread width is 0.1 mm, the shear stress τ generated on the surface is i The shear force is approximately 160 MPa. As such, depending on the shape of the tip of the thread, the shear force ranges from 80 to 160 MPa, and the sharper the tip of the thread, the greater the shear force. In order for the film to not peel off, the adhesive force at the interface between the film and the substrate (interface shear stress τ c ) is the shear force τ on this surface i Bigger is better. Interfacial shear stress τ between membrane and substrate to satisfy embedding torque c It is preferable that the elastic modulus is 80 MPa or more, and more preferably 160 MPa or more.

[0052]

number

[0053] <<Film Thickness>> The thickness of the film of the biocompatible material of the present application is not particularly limited as long as it has one, two, or all of the above characteristics i) to iii), or the above surface roughness or the difference therebetween, but for example, the average thickness is preferably 0.10 to 30 μm.In particular, the average thickness of the film corresponding to the contact area with bone and its vicinity is preferably 0.10 to 30 μm, preferably 0.20 to 20 μm, and more preferably 0.40 to 15 μm.

[0054] In one aspect, the biocompatible material of the present invention may be such that the film essentially consists of magnesium. In one aspect, the film preferably consists of only magnesium.

[0055] Furthermore, in one aspect of the present application, the film contains magnesium and calcium, and when the total weight of magnesium and calcium is taken as 100% by weight, the film contains calcium in an amount of more than 0% by weight but not more than 40% by weight, preferably 0.8 to 35% by weight, more preferably 5 to 30% by weight, and most preferably 15 to 25% by weight. In this case, the membrane may contain biocompatible materials in addition to magnesium and calcium, such as, but not limited to, zinc, phosphorus, and the like. In addition, when the material contains zinc and is composed only of a ternary system with magnesium and calcium, the amount of zinc should be 10% by weight or less, assuming that the total weight of magnesium, calcium, and zinc is 100% by weight, in order to cause the film to disappear after implantation.

[0056] In one aspect of the present invention, when the film contains magnesium and calcium, it is preferable that the film be Mg2Ca-free. Here, "Mg2Ca-free" means that no peaks due to Mg2Ca are observed in X-ray diffraction analysis, and preferably no peaks due to Mg2Ca are observed at diffraction angles where the diffraction peaks arising from the substrate and Mg2Ca crystals do not overlap (i.e., the respective diffraction peaks are separated by 1° or more in X-ray analysis using a cobalt (Co) tube), for example, no peaks are observed in the range of 36 to 37° in X-ray analysis using a Co tube.

[0057] In one aspect of the present invention, the film preferably has an amorphous portion. In one aspect of the present invention, the film is preferably essentially made of amorphous material, and more preferably made of only amorphous material. Here, "amorphous" means that no sharp peaks are observed in X-ray diffraction analysis.

[0058] In one aspect of the present invention, the film may consist essentially of magnesium and calcium. Furthermore, in one aspect of the present invention, the film may consist of only magnesium and calcium.

[0059] <Biocompatible materials> The biocompatible material of the present invention preferably has a biocompatible substrate in addition to the film having the above properties. The biocompatible substrate is not particularly limited as long as it has the above-mentioned "biocompatibility," and examples thereof include, but are not limited to, pure titanium, titanium alloys, cobalt-chromium alloys, stainless steel, zirconia, etc.

[0060] The biocompatible material of the present invention may have other layers in addition to the biocompatible substrate and the membrane. For example, it may have one or more layers between the biocompatible substrate and the membrane. It may also have one or more layers on top of the membrane, i.e., on the side opposite the substrate.

[0061] The shape of the biocompatible material of the present invention is not particularly limited, but it is preferably one selected from the group consisting of, for example, a cylindrical shape, a cylindrical, a truncated conical shape, a conical shape, a shape with a screw-like thread portion in part of the shape, a rectangular parallelepiped and a cube, a block shape such as a rectangular parallelepiped and a cube with a partial inclined surface, and a wedge shape.

[0062] The biocompatible material of the present invention is not particularly limited in its field of application, and may be, for example, one selected from the group consisting of artificial bone materials, intraosseous fixation device materials, dental implant materials, orthodontic anchor screw materials, intramedullary nail materials, and intervertebral body fixation materials, including, but not limited to, artificial bones, pins, wires, bolts, screws, washers, intramedullary nails, and vertebral spacers.

[0063] <Method for manufacturing biocompatible materials> The biocompatible material of the present invention can be produced, for example, by the following method. That is, (A) providing a biocompatible substrate; (B) providing a sputter target comprising magnesium and optionally calcium; (C) cleaning the surface of the biocompatible substrate in a vacuum; (D) forming a film containing magnesium and optionally calcium on the surface of the biocompatible substrate by sputtering using the sputtering target, while adjusting the temperature of the biocompatible substrate obtained in step (C) to 130°C or less, preferably 90°C or less, more preferably 60°C or less; By having the above, the biocompatible material can be obtained.

[0064] Here, the "biocompatible substrate" can be the same as that described above. Also, the "membrane" is the same as that described above. Step (A) is a step of preparing a biocompatible substrate. The above-mentioned "biocompatible substrate" may be purchased commercially, or a commercially purchased product may be shaped into the desired shape. The method may also include a step of grinding and / or polishing the surface of the purchased product or the resulting shape. Conventional grinding and polishing methods can be used here.

[0065] Step (B) is a step of preparing a sputtering target containing magnesium and optionally calcium. A sputtering target may be prepared according to the desired composition of the film, for example, by melting predetermined metals in a predetermined ratio.

[0066] In step (C), prior to sputtering, the substrate surface is bombarded with argon ions or the like in a vacuum, specifically in a vacuum chamber, with an appropriately adjusted bias, to remove impurities at the atomic level and clean the surface. By performing this step appropriately, the adhesion of the film can be stabilized and the substrate surface can be activated.

[0067] Step (D) is a step of forming a film containing magnesium and optionally calcium on the surface of the biocompatible substrate by sputtering using a sputtering target, while setting the temperature of the biocompatible substrate to 130°C or less, preferably 90°C or less, more preferably 60°C or less.

[0068] The sputtering device is preferably a magnetron sputtering device. A magnetron sputtering device places a powerful magnet (magnetron) behind the target, and uses a magnetic field to efficiently deposit sputter particles (metal particles) generated by colliding argon ions with the target. By adjusting the sputtering voltage, substrate bias, pressure inside the device, and temperature of the substrate material, the desired film can be formed at a constant deposition rate.

[0069] Since magnesium-based metal films have a linear expansion coefficient three times greater than that of the substrates zirconium, titanium, and titanium alloys, if the sputtering temperature is high, the temperature difference with the room temperature where the implant is used will be large, and tensile stress (thermal stress) will be generated at the interface on the film side, making the film more likely to peel off. Therefore, in order to prevent the film from peeling off after deposition and to prevent harmful stress from remaining when the implant is inserted, the temperature of the substrate during sputtering is controlled to a certain temperature or below, i.e., 130°C or below, preferably 90°C or below, and more preferably 60°C or below, so that a highly adhesive film can be formed.

[0070] The above temperatures can be estimated by calculating the thermal stress as follows: That is, the interfacial stress (thermal stress) that occurs when the temperature is lowered from the sputtering temperature to room temperature can be approximately expressed as in Equation 4. In Equation 4, ΔT is the temperature difference between the substrate temperature Td during sputtering and room temperature Tr, α1 is the average linear expansion coefficient of the substrate between temperatures Tr and Td, α2 is the average linear expansion coefficient of the coating film between temperatures Tr and Td, E1 is the average elastic modulus of the substrate between temperatures Tr and Td, and E2 is the average elastic modulus of the film between temperatures Tr and Td.

[0071]

number

[0072] For example, if the substrate is zirconia and the coating film is pure magnesium, and the linear expansion coefficient is 8 × 10 -6 and 25 × 10 -6 , and the elastic modulus is calculated by giving 210 GPa and 40 GPa, respectively. The yield strength of pure magnesium is generally said to be approximately 90 to 100 MPa, which translates to a shear yield strength of approximately 50 MPa. To keep the thermal stress at at least this value, it is best to keep the temperature difference below 100°C. For example, if the operating temperature is 36°C, which is the same as body temperature, the film deposition temperature should be 130°C or below. Considering a two-fold safety factor of 90°C or below, and a safety factor of approximately three-fold, it is preferable to deposit the film at 60°C or below.

[0073] The manufacturing method of the present invention may include steps other than the above steps (A) to (D). For example, as described above, after step (A) and before step (B), it may include a step of forming the "biocompatible substrate" into a desired shape, or a step of grinding and / or polishing the surface of the shape. For example, when a layer is provided between the substrate and the film, the step of providing the layer is preferably carried out after step (A) and before step (D). The present invention will be specifically described below using examples, but the present invention is not limited to these examples. [Example]

[0074] <Base material> As substrate materials intended for implants, we used plates of pure titanium (A1) and zirconia (A2), which were cut into 10 x 10 mm pieces with a thickness of 3 mm and ground in a specific direction on one plane. To investigate the properties of the formed film in detail, we also used a 26 x 76 mm glass substrate (AC1) with a thickness of 1.2 mm.

[0075] In addition, pure titanium B1 and zirconia B2 were used, each of which was cylindrical (φ4 mm, length 10 mm) similar to the shape of an actual dental root implant. In addition, for each substrate, a part of the surface was masked in order to measure the thickness of the film formed.

[0076] <Sputtering Apparatus and Sputtering Method> A magnetron sputtering device was used as the sputtering device. The sputtering targets used were four types of ingots made by melting pure magnesium and pure magnesium and pure calcium in a specified ratio, which were then machined into disk shapes with a diameter of approximately 120 mm. The four types of ingots had calcium contents of 0%, 10%, 20%, or 30%, with the remainder being magnesium. Here, the percentage of calcium refers to the percentage of calcium weight when the total weight of calcium and magnesium is 100% by weight, and is expressed as follows: Calcium weight % = calcium weight / (magnesium weight + calcium weight) x 100

[0077] The substrates were placed on the stage of the sputtering apparatus so as to face the sputtering target. The cylindrical substrates were placed with the bottom surfaces of the cylinders facing up and down, and the plate-like substrates were placed with the ground surface facing up.

[0078] In the film formation process, the pressure was first reduced to a predetermined value, harmful gases were removed from the chamber, and then argon gas was sealed in. By appropriately adjusting the voltage and substrate bias required for discharge, the surfaces of the sputtering target and substrate are ion-cleaned, removing oxides and harmful compound layers from the surface, eliminating impurities that reduce adhesion at the interface between the substrate and the film, and forming an active surface that is favorable for bone formation. The temperature of the substrate was kept at room temperature, the argon pressure was set to 1 to 10 mTorr, and the sputtering voltage and bias of the substrate were adjusted to carry out a film formation process (deposition) for 12 hours.

[0079] The thickness of the obtained film was measured as follows: The difference in level between the film-formed portion on the substrate and the masked portion on which no film was to be formed was measured by a stylus method. The components of each film were also measured using an energy dispersive X-ray analyzer (EDX). The calcium weight percentage of the target, the type of substrate, the Ca content (weight%) obtained from the EDX results, and the film thickness (μm) obtained by the stylus method are shown in Table 1. The Ca content (weight%) obtained from the EDX results for the cylindrical sample was not measured because it was considered to be equivalent to that for the plate-shaped sample.

[0080] [Table 1]

[0081] From Table 1, it can be seen that the calcium weight percentage in the target and the calcium content (weight percentage) of the formed film are almost identical. This indicates that there were no problems with the target or sputtering. Although not shown, it was confirmed that the film thickness increases in proportion to the time of the film formation process (deposition), demonstrating that the film thickness can be controlled by the film formation time. Furthermore, although the film thicknesses of "B1" and "B2" for "10% Ca" in Table 1 were not measured precisely, it was confirmed that they were approximately the same as the film thicknesses of the other "B1" and "B2" films.

[0082] <Arithmetic mean surface height of surface roughness> The arithmetic mean height Sa1 of the surface roughness of the surfaces of A1-C0, A1-C10, A1-C20, and A1-C30, which were formed using a plate-shaped substrate made of titanium, and A2-C0, A2-C10, A2-C20, and A2-C30, which were formed using a plate-shaped substrate made of zirconia, were measured. In addition, the arithmetic mean height Sa2 of the surface roughness of the surface before deposition was measured for A1-C0, A1-C10, A1-C20, and A1-C30, and for A2-C0, A2-C10, A2-C20, and A2-C30, which were deposited using plate-shaped substrates made of zirconia. Furthermore, for samples A1-C0, A1-C10, A1-C20, and A1-C30, and for samples A2-C0, A2-C10, A2-C20, and A2-C30, which were formed using zirconia plate-shaped substrates, the films were removed by immersion in a 5% hydrochloric acid solution for approximately 10 seconds. The arithmetic mean height Sa2' of the surface roughness of the resulting samples from which the films had been removed was measured. As described below, it was confirmed that Sa2 and Sa2' were nearly identical.

[0083] The arithmetic mean height of the surface roughness was measured by scanning the measurement probe perpendicular to the grinding marks. Measurements were performed in accordance with ISO 25178 using a laser probe-type non-contact 3D measuring device (NH-3SP, Mitaka Kohki Co., Ltd.). A laser with a probe diameter of 1 μm was used to measure an area of ​​100 μm x 100 μm at a measurement pitch of 1 μm. The arithmetic mean height of the surface roughness was measured using analysis software TalyMapGold (Version 7, TaylorHobson). The arithmetic mean height was calculated without using a filter to separate the wavelength components of the profile curve after performing shape removal using a quadratic polynomial on the calibration surface leveled using the least-squares method. For each sample, the arithmetic mean height Sa1 of the surface roughness of the surface with a film and the arithmetic mean height Sa2 (=Sa2') of the surface roughness of the surface without a film are shown in FIGS. The arithmetic mean roughness of the surface without the film was measured using a) the measured value Sa2 before the film was formed and b) the measured value Sa2' of the surface removed after the film was formed. Although not shown, the results were confirmed to be nearly identical. From these results, it was confirmed that the method of removing the film after the film was formed was appropriate.

[0084] Figure 1 shows the results of measuring the arithmetic mean surface roughness for Al-C0, Al-C10, Al-C20, and Al-C30 films formed using titanium plate-shaped substrates. In the figure, the shaded areas represent the Sa1 values, and the unshaded areas represent the Sa2 values. Moreover, Figure 2 shows the results of a sample formed using a plate-shaped substrate that uses "zirconia" instead of "titanium" in Figure 1. As in Figure 1, the values ​​with diagonal lines are the values ​​of Sa1, and the values ​​without diagonal lines are the values ​​of Sa2.

[0085] Furthermore, Table 2 summarizes the Sa1 values ​​(the values ​​with diagonal lines in FIGS. 1 and 2) for each sample. Table 3 also shows the difference between the Sa1 value (the value with diagonal lines in FIGS. 1 and 2) and the Sa2 value (the value without diagonal lines in FIGS. 1 and 2) for each sample.

[0086] [Table 2]

[0087] The following can be seen from Figures 1 and 2 and Tables 2 and 3. For example, when implanting dental implant materials, a relatively smooth surface roughness is important for reducing patient discomfort and ensuring proper implantation and tightening. However, this depends on the maximum arithmetic mean surface height of the sample's surface roughness. As shown in Table 2 above, in this example, the maximum arithmetic mean surface height of the surface roughness was 1 μm or less, allowing for smooth implantation of the sample. While a substrate subjected to conventional grinding was used in this example, an even smoother surface roughness can be achieved by using a smoother substrate, as described in the comparative example. Such a substrate shortens the time required for secondary fixation after implantation for screws intended for removal (bone screws and anchor screws) and allows for smoother removal by reducing physical engagement due to the unevenness of the substrate surface. Furthermore, by forming the films of the examples using sputtering, the difference (Sa1-Sa2) (nm) between Sa1 and Sa2 of each sample can be made relatively small. That is, as will be described later in the comparative example, the maximum surface roughness of the film itself is 30 nm or less, so forming the film hardly increases the surface roughness. Furthermore, making the difference small indicates that the film is not formed locally but is formed to cover the surface of the substrate evenly, and it can be expected that the effect of the film will be exerted stably throughout the entire substrate.

[0088] <Scanning electron microscope image> The cross-sectional direction of the film and the surface having the film were examined using a scanning electron microscope (SEM). FIG. 3 shows scanning electron microscope (SEM) images of the cross-section of the films AC1-C0, AC1-C10, AC1-C20, and AC1-C30 formed using glass substrates. Figure 4 shows scanning electron microscope images of the surfaces with films of A1-C0, A1-C10, A1-C20, and A1-C30 formed using a plate-shaped substrate made of titanium. Figure 5 shows scanning electron microscope images of the surfaces with films of A2-C0, A2-C10, A2-C20, and A2-C30 formed using a plate-shaped substrate made of zirconia.

[0089] From Figure 3, it can be seen that in the case of 0% calcium (AC1-C0), magnesium columnar crystals are densely arranged with orientation in the vertical direction from the interface of the substrate. In contrast, for the film with 10% calcium (AC1-C10), no columnar orientation is observed, and it can be seen that fine grains are dispersed in disordered directions. Also, in the cases of 20% calcium (AC1-C20) and 30% calcium (AC1-C30), no fine grains can be confirmed, and it can be seen that the surface has become very smooth. Also, from the appearance of the upper surfaces in Figures 4 and 5, those with only magnesium (A1-C0 and A2-C0) have a relatively smooth surface, but hexagonal columnar cross-sections can be seen in part. This corresponds to the (0001) plane of the hexagonal close-packed structure (HCP) of the magnesium crystal lattice, and it was found that the crystals are oriented in this direction. For 10% calcium (A1-C10 and A2-C10), it can be seen that fine grains without directionality are dispersed. Also, in both cases of 20% calcium (A1-C20 and A2-C20) and 30% calcium (A1-C30 and A2-C30), it can be seen that smooth surfaces are presented similar to the cross-sections.

[0090] <X-ray Diffraction Analysis> X-ray diffraction analysis was performed on the obtained samples, the films of AC1-C0, AC1-C10, AC1-C20, and AC1-C30 formed using a glass substrate, A1-C0, A1-C10, A1-C20, and A1-C30 formed using a plate-shaped substrate made of titanium, and A2-C0, A2-C10, A2-C20, and A2-C30 formed using a plate-shaped substrate made of zirconia. Specifically, X-ray diffraction analysis was performed using an X-ray diffractometer (D8ADVANCE, manufactured by BRUKER) under the following conditions: detector: 2D detector, tube: Co, tube voltage: 30 kV, tube current: 40 mA, slit: Φ1.0 mm, collimator: Φ1.0 mm. The results are shown in Figures 6, 7, and 8. As shown in Figure 6, a peak is observed near 2θ = 40 degrees for all films. In the case of 0% calcium (AC1-C0), the diffraction intensity is very high and sharp. As the calcium content in the magnesium increases, the peak becomes smaller, and at 30% (AC1-C30), the peak broadens and becomes unclear. Furthermore, although a low peak is observed in the case of 20% calcium (AC1-C20), the peak position shifts to the lower angle side and becomes broader, indicating that the lattice spacing has widened and become distorted. Figures 7 and 8 show that similar results are obtained when films are formed on plate-shaped substrates made of titanium and zirconia.

[0091] These results show that the sample is crystalline up to 10% calcium, but becomes almost amorphous above 20% calcium, as can be seen from the X-ray diffraction results (Figs. 6, 7, and 8) and SEM images (Figs. 3, 4, and 5). In addition, the significantly high intensity of the (00-2) peak near 40 degrees in the 0% calcium film is thought to be due to the crystal orientation that was also observed in the appearance of the SEM images (Figs. 3, 4, and 5). In the 10% calcium films on the titanium and zirconia plate-shaped substrates, not only the (00-2) peak but also the (-10-1) peak was observed, which suggests that they are fine crystals with random orientation.

[0092] It was found that as the calcium content (%) increased, the structure changed from a dense columnar structure to fine crystals and then to an amorphous structure, and this is also reflected in the crystallite size shown in Table 4, which shows that as the calcium content increased, the crystallite size became smaller and closer to an amorphous structure. Here, the crystallite size was calculated using the Scherrer method from the integral width of the peak around 2θ = 40 degrees (00-2) for the film formed on the glass substrate. This change in structure is also reflected in the characteristics of the arithmetic mean surface roughness mentioned above: the surface roughness is small and smooth for all samples.

[0093] [Table 3]

[0094] <Hardness test> Hardness tests were performed by nanoindentation on A1-C0, A1-C10, A1-C20, and A1-C30, which were formed using a titanium plate-shaped substrate, and on A2-C0, A2-C10, A2-C20, and A2-C30, which were formed using a zirconia plate-shaped substrate. A nanoindentation hardness test was performed using an apparatus (Elionix ultra-microindentation hardness tester "ENT-1100A") under the following conditions: indenter: Berkovich indenter; indentation load: 20 mN; holding time: 0 seconds. The results of the hardness test are shown in Figure 9. From FIG. 9, it was found that all of the films exceeded the bone hardness of 0.4 to 0.9 GPa, and had sufficient "wear resistance" against bone.

[0095] <Film adhesion by scratch test> Scratch tests were carried out on A1-C0, A1-C10, A1-C20 and A1-C30, which were formed using a titanium plate-shaped substrate, and on A2-C0, A2-C10, A2-C20 and A2-C30, which were formed using a zirconia plate-shaped substrate. The scratch tester used was a Scratch Tester CSR1000 (manufactured by Rhesca Corporation), and a load ranging from 0 to 8 kg was applied using a Rockwell indenter with a diameter of 0.8 mm. The sample after the scratch test was observed using SEM / EDX, and the critical load was determined by measuring the distance from the initial position of the scratch test to the position where the substrate was exposed.

[0096] Figure 10 shows SEM images of the appearance near the critical load after a scratch test parallel to the grinding marks for A1-C0, A1-C10, A1-C20, and A1-C30, which were formed using titanium plate-shaped substrates. Figure 11 shows SEM images of the appearance near the critical load after a scratch test parallel to the grinding marks for A2-C0, A2-C10, A2-C20, and A2-C30, which were formed using zirconia plate-shaped substrates. 10 and 11 show that all films showed good adhesion with no partial peeling observed, which indicates that the films exhibit sufficient abrasion resistance when force is applied to the surface.

[0097] Furthermore, the results shown in Figures 10 and 11 indicate that no flaking or cracks during deformation were observed in any of the films tested, indicating that the films exhibited sufficient "ductility" and were not brittle.

[0098] Figure 12 shows the results of measurements to determine the load when the indenter nearly reaches the substrate, i.e., the critical load of the film, in scratch tests performed parallel or perpendicular to the grinding marks on films A1-C0, A1-C10, A1-C20, and A1-C30 formed using titanium plate-shaped substrates. Figure 13 shows the results of scratch tests performed on A2-C0, A2-C10, A2-C20, and A2-C30 films formed on zirconia plate substrates in parallel or perpendicular directions to the grinding marks. The load at which the indenter nearly reaches the substrate, i.e., the critical load of the film, is measured. The critical load also indicates the degree of film adhesion.

[0099] The following can be seen from Figures 12 and 13. Of the films A1-C0, A1-C10, A1-C20, and A1-C30 formed using a titanium plate-shaped substrate, and the films A2-C0, A2-C10, A2-C20, and A2-C30 formed using a zirconia plate-shaped substrate, A1-C10 in the scratch test parallel to the grinding marks, and A1-C10, A1-C20, and A1-C30 in the scratch test perpendicular to the grinding marks, have a critical load of 78.4 N or more, demonstrating their superiority. Even A2-C0, which has the smallest critical load, is approximately 10 N, satisfying the requirement of a critical load of 10 N or more. A critical load of approximately 10 N corresponds to an implant screw with a screw radius of 2 mm and a thread tip width of 0.2 mm, requiring an implant to be inserted with an insertion torque of 150 Ncm without the membrane peeling. This 150 Ncm strength provides a safety factor of approximately four times the insertion torque of 35 to 45 Ncm required for implants, demonstrating that the membrane of this example has the desired adhesiveness.

[0100] <Critical shear stress at the interface> The critical shear stress at the interface can be determined using the results of a scratch test. In a scratch test, a load W is applied to the surface of the film through an indenter, and the tip of the indenter is dragged (skid) parallel to the film, measuring the length until the film is peeled off and the substrate surface is exposed. The load of the indenter is set so that it is proportional to the drag length, so the critical load Wc at which the film is peeled off can be determined from this length. At this time, by observing the appearance of the film's destruction or deformation, the film's brittleness and ductility can also be determined. Here, the commonly used Benjamin-Weaver equation is used to determine this. That is, the load when the film breaks is the critical load Wc, the radius of the tip of the diamond indenter is R, and the Brinell hardness of the substrate is H. B Then, the shear stress τ at the interface is c (Critical shear stress) is expressed as in Equation 5.

[0101]

number

[0102] The tip R of the diamond indenter was set to 0.8 mm, and the Brinell hardnesses of the titanium substrate and zirconia substrate were set to 2.3 GPa and 12.0 GPa, respectively. The critical load was calculated using the scratch test values ​​in Figures 12 and 13. Note that Brinell hardness above 10 GPa is not shown in the conversion table, so for zirconia, the Vickers hardness value, which shows almost the same value as Brinell, using a diamond as the indenter, was used. The critical load was calculated using the result of the scratch test in the direction giving the smallest value (parallel to the grinding marks).

[0103] As shown in Figure 14, for all film-substrate combinations A1-C0 to C3 and A2-C0 to C3, the interfacial shear stress τ c The shear stress at the interface of the film made by the present invention was found to be significantly higher than 80 MPa and even higher than 160 MPa. This indicates that the shear stress at the interface of the film made by the present invention satisfies Equation 3, and that the adhesion is sufficiently stronger than the shear stress generated at the periphery when the film is embedded, and that the film will not peel off when embedded.

[0104] 14 shows the yield shear stress of A1-C0 to C30 and A2-C0 to C30 converted from the hardness of the films of A1-C0 to C30 and A2-C0 to C30. The method for calculating the yield shear stress can be found, for example, in GE Dieter: Mechanical metallurgy, McGraw-Hill, 1988. The yield stress of the film is smaller than the shear stress at the film interface, and when a shear force is applied to the surface, the film undergoes ductile deformation before the interface, preventing peeling from the film interface. This is evident from the appearance of the scratch test results in Figures 10 and 11.

[0105] In scratch tests, when the substrate is cylindrical, such as a screw, the indenter is set on the surface perpendicular to the axis of the cylinder, and a load W is applied in the radial direction of the cylinder, and the cylinder is rotated around its axis to drag the indenter along the circumferential direction, as shown in Figure 15. This allows measurements similar to those for flat surfaces, and the critical load can be determined. However, since the substrate is cylindrical in this measurement, W is calculated according to Hertz's theoretical formula (see KL Johnson: Contact mechanics, Cambridge University Press, 1985). c For example, for a Φ4mm cylinder, W c For a 5mm diameter cylinder, multiply by approximately 1.96, and for a 5mm diameter cylinder, multiply by approximately 1.74.

[0106] The results of the hardness test and scratch test showed that the film of the present invention formed on the implant screw has sufficient wear resistance, adhesion, and ductility, and has unprecedentedly excellent film properties as a film for an implant screw.

[0107] <In vitro biological reaction testing using simulated body fluids> In vitro biological reaction tests using simulated body fluid were conducted on A1-C0, A1-C10, A1-C20, and A1-C30, which were formed using a titanium plate-shaped substrate, and on A2-C0, A2-C10, A2-C20, and A2-C30, which were formed using a zirconia plate-shaped substrate.

[0108] Hanks' balanced salt solution (HBSS(+) solution) containing calcium and magnesium was used as the simulated body fluid. In the simulated body fluid immersion test, each sample was immersed in 400 ml of simulated body fluid and kept in a thermostatic bath at 37°C for one week, after which the sample was removed from the solution. In order to bring the equilibrium pH of the solution closer to the in vivo environment, the amount of HBSS(+) solution was adjusted so that the equilibrium pH after dissolution of the sputtered film would be 8.0 or less. For comparison, tests were also conducted on each substrate without a film.

[0109] Observation of the state of the deposited surface over time revealed that almost all of the deposited film dissolved into the liquid, and then a new film formed on the surface. Although not shown, no new film was formed in HBSS on titanium and zirconia substrates that had not been sputtered, but new film formation was observed on substrates with sputtering ranging from 0% calcium (pure magnesium) to 30% calcium. Furthermore, it was observed that the amount of new film deposited was large on films containing 10% or more calcium.

[0110] FIG. 16 shows SEM images of films newly formed on the titanium plate-shaped substrates A1-C0, A1-C10, A1-C20, and A1-C30 after immersion in HBSS for one week. FIG. 17 shows SEM images of films newly formed on the substrates A2-C0, A2-C10, A2-C20, and A2-C30, which were formed using plate-shaped substrates made of zirconia and immersed in HBSS for one week. Table 5 also shows the results of a component analysis performed using fluorescent X-rays at approximately the center of the SEM image (specifically, the position of the "+" in the SEM image).

[0111] [Table 4]

[0112] In Table 5, the calcium to phosphorus ratio, which is an indicator of the presence of apatite, showed values ​​of 1.5 to 2.0 in all sputtered films, indicating that apatite was likely to have formed in terms of its composition. In order to analyze the structure of the above film, X-ray diffraction (XRD) analysis was performed using a thin film method in which the X-ray incident angle was fixed and only the detector was scanned. The results are shown in Figures 18 and 19. Peaks at diffraction angles characteristic of apatite appeared on most sputtered substrates, both on titanium and zirconia substrates. No apatite peaks were observed on A2-C0, but apatite was present on the surface, as shown in Figure 17 and Table 5. This indicates that the amount of apatite formed on A2-C0 was smaller than on the other samples with sputtered films. From these component and structural analyses, it was confirmed that apatite was formed on all substrates with sputtered films. It was also confirmed that the amount of apatite formed increased when the sputtered film contained calcium.

[0113] (Comparative Example) Figure 20 shows a comparison of the arithmetic mean height Ra1 of the line roughness for sample AIPC1-C0, in which a pure magnesium film was deposited by arc ion plating on a smooth glass substrate to evaluate the surface roughness of the film alone, and sample AC1-C0, AC1-C10, AC1-C20, and AC1-C30, in which films were deposited by sputtering on glass substrates. Comparing the surface roughness of samples with pure magnesium films deposited by arc ion plating and those deposited by sputtering reveals that depositing a pure magnesium film on a glass substrate by arc ion plating increases Ra by more than 2.5 μm. On the other hand, when pure magnesium is deposited by sputtering, Ra increases by only 0.03 μm or less. Furthermore, it can be seen that the addition of calcium further suppresses the increase in roughness during film deposition.

[0114] Figure 21 shows a comparison of the XRD and scratch test results for A2-C20, which was formed using a zirconia plate substrate, and A2-C20-H, which was heat-treated. The heat treatment was performed at 200°C in a vacuum for 1 hour, followed by furnace cooling. The XRD results indicate that A2-C20 is amorphous and MgCa-free, while A2-C20-H has a structure containing a mixture of magnesium crystals and MgCa. The critical load for A2-C20, which has an amorphous, MgCa-free structure, was approximately 30 N, while the critical load for A2-C20-H, which has a mixture of magnesium crystals and MgCa, was approximately 2.7 N. Furthermore, photographs of A2-C20 after the scratch test show no cracks or partial delamination. On the other hand, photographs of A2-C20-H after the scratch test show numerous cracks and partial delamination. These results indicate that the amorphous, Mg2Ca-free structure provides non-brittle properties and a high critical load, whereas the presence of Mg2Ca results in a significantly lower critical load.

[0115] Table 6 shows a comparison of the adhesion strength between the prior art film and the film of the present invention. The adhesion strength of the calcium titanate film in Patent Document 2 is 4.9 MPa, and the adhesion strength of the calcium phosphate coating film in Non-Patent Document 2 is 80 MPa. These are tensile strengths obtained in a pin tensile test using an adhesive material. The tensile strength of the membrane of the present invention was measured using a similar pin tensile test, but the tensile strength was so strong that the adhesive broke first, making it impossible to measure. For samples for which adhesion strength cannot be measured using a pin tensile test, it is common to use a scratch test or other method that can measure stronger adhesion strength. According to the 2008 Guidelines for Development of Implantable Materials issued by the Ministry of Economy, Trade and Industry, it is desirable for the tensile strength and shear strength of a membrane to be 20 MPa or greater. Therefore, the shear stress calculated in this example and the tensile strength of prior art can be compared as adhesion strengths at the same level. Therefore, even the lowest adhesion strength calculated in this example, A2-C20, at 170 MPa, is still significantly higher than the prior art.

[0116] Table 5

Claims

1. A biocompatible material having a membrane consisting of only magnesium and calcium, The film has calcium in an amount of more than 0 wt % and not more than 40 wt % when the total weight of magnesium and calcium is 100 wt %; The above biocompatible material, wherein the membrane is Mg 2 Ca-free.

2. The biocompatible material according to claim 1 , wherein the film has an amorphous portion.

3. The biocompatible material according to claim 1 or 2, wherein the membrane has any one, two, or all of the following properties i) to iii): i) the hardness obtained by indentation testing is 0.4 GPa or more; ii) The relationship Wc / t between the critical load Wc (N) and the film thickness t (μm) is 1 N / μm or more; iii) The critical shear stress at the interface between the film and the substrate is 80 MPa or more.

4. The biocompatible material according to any one of claims 1 to 3, having the following properties a), b), or a) and b): a) the arithmetic mean surface height Sa1 of the surface roughness of the film is 2 μm or less; b) The difference between the arithmetic mean surface height Sa1 of the surface roughness of the film and the arithmetic mean surface height Sa2 of the surface roughness of the surface not having the film is 300 nm or less.

5. 5. The biocompatible material according to claim 1, wherein the average thickness of the film is 0.10 to 30 μm.

6. The biocompatible material according to any one of claims 1 to 5, which has a biocompatible substrate, and the biocompatible substrate is at least one selected from the group consisting of pure titanium, zirconia, a cobalt-chromium alloy, stainless steel, and a titanium alloy.

7. The biocompatible material according to any one of claims 1 to 6, which is one selected from the group consisting of an artificial bone material, an intraosseous fixation device material, a dental implant material, an orthodontic anchor screw material, an intramedullary nail material, and an interbody fusion material.

8. The biocompatible material according to any one of claims 1 to 7, wherein the shape of the biocompatible material is one selected from the group consisting of a cylindrical shape, a truncated conical shape, a conical shape, a shape having a screw-like thread portion in a part of the shape, a rectangular parallelepiped shape, a cube, a block shape having a part of an inclined surface, and a wedge shape.

9. (A) providing a biocompatible substrate; (B) preparing a sputtering target consisting solely of magnesium and calcium; (C) cleaning the surface of the biocompatible substrate in a vacuum; and (D) using the sputtering target, a step of forming a film consisting only of magnesium and calcium on the biocompatible substrate obtained in step (C) by sputtering while setting the temperature of the biocompatible substrate to 130°C or less; By having A method for producing a biocompatible material, which has a film consisting only of magnesium and calcium, wherein the film contains more than 0 wt% and not more than 40 wt% of calcium, when the total weight of magnesium and calcium is 100 wt%, and the film is Mg2Ca-free.

10. The method of claim 9, wherein the membrane has any one, two, or all of the following properties: i) to iii): i) the hardness obtained by indentation testing is 0.4 GPa or more; ii) The relationship Wc / t between the critical load Wc (N) and the film thickness t (μm) is 1 N / μm or more; iii) The critical shear stress at the interface between the film and the substrate is 80 MPa or more.

11. The method according to claim 9 or 10, having the following characteristics a), b), or a) and b): a) the arithmetic mean surface height Sa1 of the surface roughness of the film is 2 μm or less; b) The difference between the arithmetic mean surface height Sa1 of the surface roughness of the film and the arithmetic mean surface height Sa2 of the surface roughness of the surface not having the film is 300 nm or less.

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