Patent Application
20240050624
The present invention relates to a biocompatible material comprising a film comprised of magnesium and optional calcium. In particular, the present invention relates to a biocompatible material comprising a film comprised of magnesium and optional calcium, having a predetermined surface roughness, a predetermined adhesion and/or a predetermined hardness.
The present invention also relates to a method of manufacturing the biocompatible material.
The treatment of teeth by implants has attracted attention as a type of treatment method for tooth loss for young people to elderly people.
Metallic titanium, a titanium alloy, or ceramic zirconia, that does not relatively adversely affect a living body, is used as a material of a dental root implant,
It is required to shorten a period between the placement of the root implant and the functioning of the root for the patient to be able to bite, that is, a time until secondary fixation in which bone cells are formed around the dental root implant. The above-mentioned implant materials for dental roots such as titanium alone have not been able to meet the demand for shortening the time to secondary fixation, and improvement thereof is required.
For example, Non-Patent Documents 1 and 2 show that the formation of apatite on the surface of a dental root implant is effective for the formation of surrounding bone, and disclose that apatite is applied on the surface of a dental root implant before implantation, to form a film, or that apatite is sputtered to form a film.
Patent Documents 1 and 2 disclose that apatite is similarly formed on a titanium implant. The documents also disclose that a calcium-containing film was chemically formed on the implant adhesion, or that apatite is formed on the calcium-containing film as an intermediate layer, to enhance the adhesiveness.
Non-Patent Document 3 discloses that it is effective to generate an appropriate pressure between a dental root implant and the alveolar bone in order to promote secondary fixation. Therefore, Non-Patent Document 3 discloses that it is necessary to clamp the dental root implant with an appropriate torque at the time of clamping upon initial fixing. However, since the above-described apatite films formed before implantation described in Non-Patent Documents 1 and 2, Patent Documents 1 and 2 have low hardness and/or insufficient adhesiveness, the films are easily peeled off at the time of clamping and embedding so that functions thereof cannot be sufficiently fulfilled.
Patent Document 3 discloses that metal is used for a core body (substrate) of an implant, and that a bioactive glass film including oxides of silicon, sodium, magnesium, calcium, and potassium is formed on a surface thereof instead of apatite, in order to simultaneously realize maintenance of strength of the implant and improvement of a bonding function with a bone. However, since the film is made of inorganic glass or an inorganic compound, the film has hardness but a drawback of being brittle.
Patent Document 4 attempts to promote bone formation by appropriately roughening the surface of a dental root implant made of ceramics such as zirconia. However, in this case, it is possible to perform clamping regardless of the peeling of the film, but the bone formation is not sufficient.
Patent Document 5 discloses that a dental root implant is covered with a protective film in order to take advantage of an active surface of a base material to protect the implant. The protective film is designed to disappear after implantation for the purpose of maintaining aesthetics, but the film has no component or function for promoting bone formation.
As with the case of Patent Document 3, Patent Document 6 discloses that a protective film is formed on the surface for the purpose of protecting the active surface of a base material for a dental root implant, and that a component of the film is formed of a salt that generates cations of sodium, potassium, magnesium, and calcium. However, in salts, the strength and adhesiveness of the film required at the time of implantation are not sufficient.
Non-Patent Document 4 discloses an orthopedic implant in which a metallic pure magnesium film is formed on the surface by an ion plating method instead of apatite. Although the effect of magnesium ions on bone formation has been shown, the ability to form apatite is not sufficient because calcium, which is a main component of apatite, does not exist, Further, in the arc ion plating used in the Non-Patent Document 4, since the particles which is to be the film are large, the surface roughness is large, and thus, it is difficult to control the roughness. More, even if calcium is further used as a target to form an alloy in this method, an intermetallic compound is formed in the film or the like, and thus the film becomes brittle, since the film is made of the cluster of the alloy.
Non-Patent Document 5 proposes that a ternary alloy of Mg—Ca—Zn is useful as a core body (substrate) of an implant as a biodegrading material. When Mg is considered as a main component, if Ca is added to form an alloy, the solid solution limit is 1% or less, and, if Ca is added more than 1%, an intermetallic compound such as Mg2Ca is formed. Therefore, the content of Ca in such an alloy is at most 5%, and there is a possibility that an intermetallic compound may remain in the body in addition to Mg ions and Ca ions.
Non-Patent Document 6 discloses that Mg—Ca—Zn to which Ca is added up to 15% is manufactured as an amorphous ribbon at a high temperature by high-speed rotary quenching method (spinning method). However, since about 7% of the intermetallic compound is formed, it is not easy to produce uniform amorphous, and thus, the shape and the size are limited. Further, Non-Patent Document 7 discloses that a Ca—Mg—Zn alloy including Ca as main metal is attempted to be manufactured by a similar method in order to enhance the effect of Ca. However, the method cannot achieve uniform amorphous formation.
Non-Patent Documents 8 and 9 disclose that a Mg—Ca—Zn ternary system in which Ca is added from 4% by weight to 24% by weight is manufactured as a thin film in an amorphous state by sputtering. Non-Patent Document 9 discloses that these thin films contain at least 30% by weight of Zn in order to easily form an amorphous state. However, the document also disclose that Zn ions exhibit cytotoxicity, and thus that the higher amount of Zn exhibits the stronger cytotoxicity.
In order to stably manufacture an amorphous metal, a multi component alloy (having components of three or more elements) capable of lowering the liquid phase temperature is generally required. However, conventional method cannot manufacture amorphous metal consisting essentially of two components, Mg—Ca.
An object of the present invention is to provide a biocompatible material comprising a film that realizes bone formation around the biocompatible material in a relatively short period of time.
Further, other than or in addition to the above object, an object of the present invention is to provide a biocompatible material comprising a film with a relatively smooth surface roughness, suitable for implantation or clamping at an appropriate implanting torque.
More, other than or in addition to the above objects, an object of the present invention is to provide a biocompatible material comprising a film with adhesiveness and/or hardness that can withstand implantation or clamping at an appropriate implanting torque. Further, other than or in addition to the above objects, an object of the present invention is to provide a method of manufacturing the biocompatible material.
The present inventors have found the following inventions:
The present invention can provide a biocompatible material comprising a film that realizes bone formation around the biocompatible material in a relatively short period of time.
Further, other than or in addition to the above effect, the present invention can provide a biocompatible material comprising a film with a relatively smooth surface roughness, suitable for implantation or clamping at an appropriate implanting torque.
More, other than or in addition to the above effects, the present invention can provide a biocompatible material comprising a film with adhesiveness and/or hardness that can withstand implantation or clamping at an appropriate implanting torque.
Further, other than or in addition to the above effects, the present invention can provide a method of manufacturing the biocompatible material.
The invention described in the present application (hereinafter, may be abbreviated as the “present invention”) is explained hereinafter.
The present application provides a biocompatible material comprising a film comprised of magnesium and optional calcium, in which the film comprises 0 to 40% by weight of calcium, when a total weight of magnesium and calcium is 100% by weight, and an amount of calcium is more 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, when calcium is comprised.
Further, the amount of calcium may be more preferably 5 to 35% by weight, more preferably 15 to 35% by weight, most preferably 25 to 35% by weight.
In one aspect, the present invention provides a biocompatible material in which a) an arithmetic mean height Ra1 of line roughness of the film is 2 μm or less, preferably 1 μm or less.
Further, in another aspect, the present invention provides a biocompatible material in which b) a difference between the arithmetic spmean height Ra1 of the line roughness of the film and an arithmetic mean height Ra2 of line roughness of a surface which does have the film is 300 nm or less, preferably 200 nm or less, more preferably 150 nm or less.
More, in one aspect, the present invention provides a biocompatible material in which c) an arithmetic mean height Sa1 of surface roughness of the film is 2 μm or less, preferably 1 μm or less.
Further, in another aspect, the present invention provides a biocompatible material in which d) a difference between the arithmetic mean height Sa1 of the surface roughness of the film and an arithmetic mean height Sa2 of surface roughness of a surface which does not have the film is 300 nm or less, preferably 200 nm or less, more preferably 150 nm or less.
The biocompatible material may have the characteristics of the above a) and/or b) and the characteristics of the above c) and/or d).
More, in the present invention, on still another aspect, the film may have the characteristics of any one or two, or all of the following i) to iii):
The “biocompatibility” in the “biocompatible material” of the present invention refers to a characteristic of being maintained in a living body and not causing a biological safety problem.
The biocompatible material of the present invention may have the above-mentioned characteristics a) and/or b), specifically, the arithmetic mean height Ra1 of predetermined line roughness, a predetermined difference between the arithmetic mean heights Rai and Ra2 of the line roughness, a predetermined critical load that is an index of predetermined adhesiveness, predetermined hardness, and/or a predetermined critical shear stress at the interface between the film and the substrate.
Further, the biocompatible material of the present invention may have the above-mentioned characteristics c) and/or d), specifically, the arithmetic mean height Sa1 of predetermined surface roughness, a predetermined difference between the arithmetic mean heights Sa1 and Sa2 of the surface roughness, a predetermined critical load that is an index of predetermined adhesiveness, predetermined hardness, and/or a predetermined critical shear stress at the interface between the film and the substrate.
More, the biocompatible material of the present invention may have any one, any two, any three, or all of the characteristics a) to d) described above.
<<Arithmetic Mean Surface Height Ra1 of Line Roughness of Surface having Film>>
The arithmetic mean height Ra1 of the line roughness of the film of the biocompatible material of the present invention may be 2 μm or less, preferably 1 μm or less.
The surface of the film, i.e., the arithmetic mean height Ra1 of the line roughness of the film, can be measured in accordance with JIS B 0601: 2013. In the standard, a reference length and an evaluation length are determined according to the classification of the Ra value. For example, in a case of 0.1<Ra(μm)≤2, the reference length and the evaluation length are 0.8 mm and 2.0 mm, respectively. If the reference length cannot be continuously measured due to an interference between a stylus and a measurement object, a reference length of a section lower than an Ra value of the measurement object is used, the number of times of the evaluation length or more in total is measured, and the average value thereof can be set as Ra.
Furthermore, the surface of the biocompatible substrate in the biocompatible material of the present application may be ground in a certain direction or polished all over the surfaces. In the case of polishing all over the surfaces, the roughness of the surface becomes substantially uniform. However, in the case of grinding the surface in a certain direction, when the probe light is deflected along the directional roughness, a measurement error is likely to occur, and the arithmetic mean surface of the line roughness along the direction and the arithmetic mean height of the line roughness in the direction perpendicular to the direction may have different values. When the biocompatible substrate has a cylindrical shape or a threaded shape, the arithmetic mean height of the line roughness of the film in the present application refers to a value measured by moving a probe in a circumferential direction. In the case of other shapes, the biocompatible substrate may be measured in all directions, but for example, the arithmetic mean height refers to a value obtained by measuring the biocompatible substrate in four directions at intervals of 45° and averaging measured values.
In the present application, the “surface which does not have a film” of the “arithmetic mean height Ra2 of the line roughness of the surface which does not have a film” refers to the surface of the substrate before film formation or the surface of the substrate when the film is removed after the film formation,
The film of the present application is comprised of magnesium and optional calcium as described above. The film can generally be substantially completely removed by immersion in a weakly acidic aqueous solution or water. Furthermore, the biocompatible substrate in the biocompatible material of the present application is not eroded by the weakly acidic aqueous solution used for removing the film.
Therefore, the arithmetic mean height Ra2 of the line roughness of the surface of the substrate before film formation is substantially the same as an arithmetic mean height Ra2′ of the surface of the substrate when the film is removed after the film formation.
Ra2′ can also be measured in a manner similar to that of Ra1, in accordance with JIS B 0601: 2013.
In one aspect of the present application, a difference between the arithmetic mean height Ra1 of the line roughness of the film and an arithmetic mean height Ra2 of line roughness of a surface which does not have the film may be 300 nm or less, preferably 200 nm or less, more preferably 150 nm or less.
A method of measuring the arithmetic mean height of the line roughness of a threaded portion of a material which has a generally cylindrical shape or truncated cone shape and having a threaded portion of a screw, such as a dental implant material will be described.
The screw is attached to a device having a rotation mechanism by using a chuck or the like such that a thread shaft WA of a threaded portion W serves as a rotation shaft. The measurement can be performed in a manner similar to the measurement on the flat surface: a tip SP of a probe of a stylus S of a roughness measurement device is seated perpendicularly to a valley portion WG of the thread, and a measurement object W is rotated at a constant speed in a rotation direction WR, with keeping the stylus fixed. Furthermore, since there is a lead angle in the thread, it is preferable to perform measurement by skewing the shaft WA by an angle A1 corresponding to the lead angle, in order to prevent the tip SP of the probe from interfering with a thread flank portion WF. As a result, a measurement length ST1 can be measured along the valley WG of the thread.
It is friction on the flank surface of the thread that most influences on an implanting torque upon implanting the screw. Therefore, the roughness of the thread flank surface WF is important. In order to measure this surface, as illustrated in
When the measurement length ST1 or ST2 is large, it is preferable to provide a mechanism for sliding the shaft WA in the traveling direction of the thread (the left direction in
As described above, even if the measurement object has a substantially cylindrical shape or a truncated cone shape and has the threaded portion of the screw, the line roughness of the threaded portion can be measured.
<<Arithmetic Mean Surface Height Sa1 of Surface Roughness of Surface having Film>>
The arithmetic mean height Sa1 of the surface roughness of the film of the biocompatible material of the present invention may be 2 μm or less, preferably 1 μm or less.
The surface having film, i.e., the arithmetic mean height Sa1 of the surface roughness of the film, can be measured in accordance with ISO 25178.
When the surface roughness is measured by laser light, 10,000 or more measurement points can be acquired in a measurement range of 100 μm×100 μm. The arithmetic mean height can be calculated without using a filter for subjecting a calibration surface leveled by a least squares method to shape removal by a quadratic polynomial and separating wavelength components of a contour curve. Further, an average value may be obtained by totaling measurement distances in one direction and performing the measurement by equal to or more than the number of times to be the evaluation length in accordance with JIS 0633/ISO 4288.
Furthermore, the surface of the biocompatible substrate in the biocompatible material of the present application may be ground in a certain direction or polished all over the surface. In the case of polishing all over the surface, the roughness of the surface becomes substantially uniform. However, in the case of grinding the surface in a certain direction, when the probe light is deflected along the directional roughness, a measurement error is likely to occur, and the arithmetic mean surface along the direction and the arithmetic mean height of the surface roughness in the direction perpendicular to the direction may have different values. In the present application, the arithmetic mean height of the surface roughness of the film refers to a value when the arithmetic mean surface roughness of the surface roughness is measured by deflecting probe light in three directions of parallel, perpendicular, and oblique about 45° with respect to the center line of the shape of the biocompatible material, and the direction in which the roughness is the lowest is measured.
In the present application, the “surface which does not have a film” of the “arithmetic mean height Sa2 of the surface roughness of the surface which does not have a film” refers to the surface of the substrate before the film formation or the surface of the substrate when the film is removed after the film formation.
The film of the present application is comprised of magnesium and optional calcium as described above. The film can generally be substantially completely removed by immersion in a weakly acidic aqueous solution or water. Furthermore, the biocompatible substrate in the biocompatible material of the present application is not eroded by the weakly acidic aqueous solution used for removing the film.
Therefore, the arithmetic mean height Sa2 of the surface roughness of the surface of the substrate before the film formation is substantially the same as an arithmetic mean height Sa2′ of the surface of the substrate when the film is removed after the film formation.
Sa2′ can also be measured in a manner similar to Sa1, in accordance with ISO 25178.
In one aspect of the present application, a difference between the arithmetic mean height Sa1 of the surface roughness of the film and an arithmetic mean height Sa2 of surface roughness of a surface which does not have the film may be 300 nm or less, preferably 200 nm or less, more preferably 150 nm or less.
In one aspect of the present application, the film may have the characteristics of any one or two, or all of the following i) to iii):
In one aspect of the present application, the hardness obtained by an indentation test of the film may be 0.4 GPa or more, preferably 0.9 GPa or more, more preferably 1.2 GPa or more.
In the hardness test of the nanoindentation method, the indentation load may be set so that the indentation depth is ⅕ or less, preferably 1/10 or less of the film thickness. The average value may be obtained by performing measurement 20 times or more, preferably 30 times or more per one sample. For example, the measurement can be performed under the following conditions: an indenter: Berkovich indenter; an indentation load: 20 mN; and retention time: 0 second.
In the present application, the critical load Wc refers to a load when a brittle crack occurs without causing the film to exhibit ductility, a load when the film is partially peeled off, or a load when the film is scraped and the substrate is exposed.
In one aspect of the present application, Wc/t wherein Wc is the critical load (N) and t is the filth thickness (μm)) of the film may be 1 N/μm or more, preferably 2 N/μm or more. For example, when the film thickness is 5 μm, the film may have a critical load of 5 N or more, preferably 10 N or more.
The scratch test can be performed using a device usually used for the scratch test, by using a Rockwell indenter having a diameter of 0.8 mm, for example, in a range in which the load is 0 to 8 kg by weight, to a range in which twice the load at which the substrate is exposed is maximum, a range in which twice the load at which the film is partially peeled is maximum, or a range in which twice the load at which brittle cracks occur without exhibiting ductility in the film is maximum.
At this time, the sample after the scratch test is observed by SEM/EDX, and the critical load can be obtained by measuring any short distance from the initial position of the scratch test to a position where brittle cracks occur without causing the film to exhibit ductility, a position where the film is partially peeled off, and a position where the substrate is exposed.
The critical load corresponds to adhesiveness between the film and the substrate, and the film of the biocompatible material of the present invention may have a critical load in the above range.
<<Appearance of Film after Scratch Test>>
Upon observing the sample after the scratch test by SEM/EDX, it is preferable that the film does not exhibit softness, that brittle cracks do not occur, that the film is not partially peeled off, and that the substrate is scraped in a ductile manner until being exposed.
From the torque required upon implantation of the implant screw, the shear stress generated on the screw surface can be calculated as follows:
Shear force τi generated on the surface of the screw can be calculated as in Equation 1. When the radius (½ of the diameter of the outer periphery) of the implant screw is r, the area where the screw is in contact with the alveolar bone is Ai, and the torque at the time of implantation is T, Equation 1 can be generally expressed.
Pressure and shear stress generated on the surface of the screw during implantation are concentrated near the tip of the ridge of the thread of the screw. Further, when the screw is implanted, high pressure and shear force are generated mainly in the area of the hard cortical bone. Since the average thickness of the cortical bone is about 1.0 to 1.5 mm, and since the pitch of the thread is 1 to 2 mm, the screw is screwed in a state where the shear force is concentrated on almost one round of the ridge of the thread. When the width of the tip of the ridge of the thread is h., the area. Ai of the tip of the ridge of the thread having the highest shear stress is expressed by Equation 2.
Ai=2πrh (Equation 2)
Assuming that minimum implanting 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 ridge of the thread of the screw is 0.2 mm, calculation is performed by substituting these values into Equations 1 and 2 to obtain about 80 MPa as the shear stress τi generated on the surface. When the tip of the ridge of the screw is sharper, and the width of the ridge of the thread is 0.1 mm, the shear stress τi generated on the surface similarly is about 160 MPa. As described above, the shear stress becomes 80 to 160 MPa due to the shape of the tip of the ridge of thread, and the shear force increases as the tip of the ridge of the thread becomes sharper.
In order to prevent the film from peeling off, as seen in Equation 3, the adhesiveness at the interface between the film and the substrate (the shear stress τc at the interface) may be larger than the shear stress τi at the surface.
The shear stress τc at the interface between the film and the substrate for satisfying the implanting torque is preferably 80 MPa or more, preferably 160 MPa or more.
τc>τi (Equation 3)
The thickness of the film of the biocompatible material of the present application is not particularly limited as long as the thickness has any one or two, or all of the characteristics i) to iii), the surface roughness, or a difference thereof, but for example, the average thickness may be 0.10 to 30 μm. In particular, the average thickness of the film corresponding to a contact portion with the bone and the vicinity thereof may be 0.10 to 30 μm, preferably 0.20 to 20 μm, more preferably 0.40 to 15 μm.
In one aspect of the biocompatible material according to the present invention, the film may consist essentially of magnesium.
Further, in one aspect of the present invention, the film may consist of magnesium.
Furthermore, in one aspect of the present application, when the film is comprised of magnesium and calcium, and the total weight of magnesium and calcium is 100% by weight, the content of calcium of the film may be more 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, most preferably 15 to 25% by weight.
In this case, the film may comprise a biocompatible material in addition to magnesium and calcium. Examples of the biocompatible materials may include, but are not limited to, zinc, phosphorus and the like.
In the case of consisting of a ternary system of zinc, magnesium and calcium, the amount of zinc may be 10% by weight or less in order to dissolve the film after implantation when the total weight of magnesium, calcium, and zinc is 100% by weight.
In one aspect of the present application, when the film is comprised of magnesium and calcium, the film may be free from Mg2Ca. The term “be free from Mg2Ca” means that a peak based on Mg2Ca is not observed in X-ray diffraction analysis, and preferably that a peak based on Mg2Ca is not observed at a diffraction angle at which diffraction peaks generated from crystals of the substrate and Mg2Ca do not overlap each other (the respective diffraction peaks are separated by 1° or more in X-ray analysis by using a cobalt (Co) tube lamp), for example, a peak is not observed in a range of 36 to 37° in X-ray analysis using a Co tube lamp.
In one aspect of the present application, the film may have an amorphous portion.
Further, in one aspect of the present application, the film may be formed essentially of an amorphous material and preferably consists of an amorphous material.
The term “amorphous” means that no sharp peak is observed in X-ray diffraction analysis.
Further, in one aspect of the present application, the film may consist essentially of magnesium and calcium.
More, in one aspect of the present application, the film may consist of magnesium and calcium.
The biocompatible material of the present invention may have a biocompatible substrate in addition to the film having the above characteristics.
The biocompatible substrate is not particularly limited as long as the biocompatible substrate has the “biocompatibility”. Examples thereof may include, but are not limited thereto, pure titanium, a titanium alloy, a cobalt-chromium alloy, stainless steel, zirconia, and the like.
Examples of the biocompatible substrate may include, but are not limited thereto, alumina, calcium phosphate, magnesia, and the like.
The biocompatible substrate may preferably be pure titanium, a titanium alloy, or zirconia, more preferably ceramics, still more preferably zirconia,
Further, the biocompatible material of the present invention may have other layers in addition to the biocompatible substrate and the film described above. For example, one or more layers may be provided between the biocompatible substrate and the film. More, one or more layers may be provided on the upper portion of the above-mentioned film, that is, on the side opposite to the substrate.
The shape of the biocompatible material of the present invention is not particularly limited, but for example, the biocompatible material may be one selected from the group consisting of a columnar shape, a cylindrical shape, a truncated cone shape, a conical shape, a shape having a screw-shaped threaded 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 partially inclined surface, and a wedge shape.
The application field of the biocompatible material of the present invention is not particularly limited, but for example, the biocompatible material may be one selected from the group consisting of an artificial bone material, an intraosseous fixture material, a dental implant material, an orthodontic anchor screw material, a medullary nail material, and an interbody fixation material. Examples thereof may include, but are not limited to, an artificial bone, a pin, wire, a bolt, a screw, a washer, a medullary nail, and a vertebral body spacer.
The biocompatible material of the present invention can be manufactured, for example, by the following method.
The biocompatible material can be obtained by the method comprising the steps of:
Furthermore, as the “biocompatible substrate”, those described above can be used.
The “film” is the same as that described above.
Step (A) is a step of preparing a biocompatible substrate. The above-described “biocompatible substrate” may be commercially purchased, or the commercially purchased substrate may be formed into a desired shape. The method may comprise a step of grinding and/or polishing the surface of the purchased product or the obtained shape. Furthermore, as the grinding method and the polishing method, conventional methods may be used.
Step (B) is a step of preparing a sputtering target comprised of magnesium and optional calcium.
A sputtering target may be prepared according to a film having a desired composition. For example, it may be manufactured by dissolving predetermined metal in a predetermined ratio.
Step (C) is a step of, appropriately adjusting a bias in vacuum, specifically in a vacuum chamber and causing argon ions or the like to collide with the surface of the substrate to remove impurities on the surface at an atomic level for cleaning before sputtering. Appropriate execution of the step (C) can lead stabilized adhesiveness of the film, and the activated surface of the substrate.
Step (D) is a step of using the sputtering target and setting a temperature of the biocompatible substrate at 130° C. or lower, preferably 90° C. or lower, more preferably 60° C. or lower and sputtering, to form the film comprised of magnesium and optional calcium on the surface of the biocompatible substrate.
A magnetron sputtering device may be used as the sputtering device.
In the magnetron sputtering device, a strong magnet (magnetron) is disposed behind a target, and sputtered particles (metal particles) generated by causing argon ions to collide with the target can be efficiently deposited on a substrate using a magnetic field. Upon sputtering, the sputtering voltage, the bias of the substrate, the pressure in the device, and the temperature of a substrate material can be adjusted, to form a film at a constant film formation rate.
The metal film based on magnesium has a linear expansion coefficient three times larger or more than that of zirconium, titanium, or a titanium alloy as the substrate. Thus, when the sputtering temperature is high, the temperature difference from around room temperature at which the implant is used and the sputtering temperature becomes large, and thus, tensile stress (thermal stress) is generated at the interface on the film side, and the film is easily peeled off. Therefore, in order to prevent the film from being peeled off after the film formation and to prevent harmful stress from remaining at the time of implanting the implant, the temperature of the substrate in sputtering is controlled to a certain temperature or less, that is, 130° C. or less, preferably 90° C. or less, more preferably 60° C. or less, so that a film having high adhesiveness can be formed.
The above temperature can be estimated by calculating thermal stress as follows: When the temperature is lowered from the sputtering temperature to room temperature, the stress (thermal stress) at the interface generated can be approximately expressed by Equation 4, wherein ΔT: a temperature difference between a substrate temperature during sputtering Td and room temperature Tr, α1: an average linear expansion coefficient of the substrate between the temperatures Tr and Td, α2: an average linear expansion coefficient of the coating film between the temperatures Tr and Td, E1: an average elastic modulus of the substrate between the temperatures Tr and Id, and E2: an average elastic modulus of the film between the temperatures Tr and Td.
For example, assuming that the substrate is zirconia, and the coating film is pure magnesium, calculation is performed by applying the linear expansion coefficients as 8×10−6 and 25×10−6 and the elastic moduli as 210 GPa and 40 GPa, respectively.
Since the yield strength of pure magnesium is generally said to be about 90 to 100 MPa, the shear yield strength is about 50 MPa. In order to suppress the thermal stress to at least this value or less, the temperature difference may be 100 degrees or less. For example, when the operating temperature is 36° C. as a body temperature, the film formation temperature may be 130° C. or lower, and is preferably 90° C. or lower, which is twice the safety factor or 60° C. or lower in consideration of about three times the safety factor.
The manufacturing method of the present invention may comprise steps other than the steps (A) to (D) above. For example, as described above, after step (A) and before step (B), the method may comprise the step of forming the “biocompatible substrate” into a. desired shape and the 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 may be provided after step (A) and before step (D).
Hereinafter, the present invention is specifically described with reference to, but is not limited only to, examples.
As a substrate material assumed to be an implant, plate-shaped pure titanium A1 and zirconia A2 cut into 10×10 mm with a thickness of 3 mm and subjected to general grinding processing in a predetermined direction on one plane were used. Furthermore, in order to examine details of the characteristics of the film formed, a glass substrate AC1 having a thickness of 1.2 mm and 26×76 mm was also used.
Further, pure titanium B1 and zirconia B2 having a columnar shape (φ4 mm and the length of 10 mm) close to the shape of an actual dental root implant were used.
Furthermore, for any substrate, a part of the surface was masked in order to measure the thickness of the film formed.
As the sputtering device, a magnetron sputtering device was used.
As a sputtering target, pure magnesium, and four kinds of ingots manufactured by dissolving pure magnesium and pure calcium at a predetermined ratio were machined into a disk shape having a diameter of about 120 mm and used. The four kinds of ingots were those in which the amount of calcium was 0%. 10%, 20%, or 30%, and the remaining amount was magnesium. The % of the calcium amount is a ratio of the calcium weight when the total of the calcium weight and the magnesium weight is 100% by weight and is represented by wt % as below.
Calcium wt %=Calcium Weight(Magnesium Weight+Calcium Weight)×100
The substrate was disposed on the stage of the sputtering device so as to face the sputtering target. Furthermore, the columnar substrate was disposed such that the columnar bottom surface was up and down, and the plate-shaped substrate was disposed such that the ground surface was the upper surface.
In the film formation process, first, the pressure was reduced to a predetermined value, the harmful gas in the chamber was removed, and then an argon gas was sealed.
By appropriately adjusting the voltage and the substrate bias required for discharge, the surfaces of the sputtering target and the substrate were subjected to ion cleaning to remove oxides and harmful compound layers on the surfaces, so that impurities that reduce adhesiveness at the interface between the substrate and the film are removed, and an active surface advantageous for bone formation is formed.
The temperature of the substrate was kept at room temperature, the pressure of argon was 1 to 10 mTorr, the sputtering voltage and the bias of the substrate were adjusted, and a film formation process (deposition) was performed for 12 hours.
The thickness of the obtained film was measured as follows: The thickness of the film was measured by actually measuring a gap distance by a stylus method, the gap distance being between a portion on the substrate where the film was formed and another portion where the film was not formed by performing the above-described masking.
The components of each film were measured with an energy dispersive X-ray analyzer (EDX).
The calcium wt % of the target, the kind of the substrate, the amount of Ca (wt %) according to the EDX results, and the film thickness (μm) obtained by the stylus method are shown in Table 1. Furthermore, the Ca amount (wt %) as a result of EDX for the columnar shape sample was considered to be equivalent to that of the plate-shaped sample, and thus the Ca amount (wt %) for the columnar shape was not measured.
Table 1 shows that the calcium wt % in the target and the calcium amount (wt %) of the formed film are almost the same. From this, it is found that there was no problem in the target and the sputtering. Although not illustrated, it has been confirmed that the film thickness increases in proportion to the time of the film formation process (deposition), and it has been found that the film thickness can be controlled by the film forming time. Also, the film thicknesses of “B1” and “B2” of “10% Ca” in Table 1 were not accurately measured but have been confirmed to be comparable to the film thicknesses of other “B1” and “B2”.
For A1-C0, A1-C 10, A1-C20, and A1-C30 formed as films by using titanium as a plate-shaped substrate, and for A2-CO, A2-C 10, A2-C20, and A2-C30 formed as films by using zirconia as a plate-shaped substrate, the arithmetic mean heights Ra1 of the line roughness of the surfaces were measured.
Further, for A1-C0, A1-C10, A1-C20, and A1-C30 and for A2-C0, A2-C10, A2-C20, and A2-C30 formed as films by using zirconia as a plate-shaped substrate, the arithmetic mean heights Ra2 of the line roughness of the surfaces before film formation were measured.
More, for A1-C0, A1-C10, A1-C20, and A1-C30 and for A2-C0, A2-C10, A2-C20, and A2-C30 formed as films by using zirconia as a plate-shaped substrate, the films after film formation were immersed in a 5% aqueous hydrochloric acid solution for about 10 seconds to remove the film. The arithmetic mean heights Ra2′ of the line roughness of the surfaces of the sample from which the films of the obtained samples were removed were measured. Furthermore, it was confirmed that Ra2 and Ra2′ were substantially the same as described below.
The arithmetic mean heights of the line roughness were measured by moving the stylus in directions parallel and perpendicular to the grinding marks. The measurement was performed with a contact type surface roughness measurement device (SV-3000, manufactured by Mitutoyo Corporation) in accordance with JIS B0601: 2013. By using a stylus with a tip radius of 2 μm, the measurement was performed by contacting the sample with a static measurement force of 0.75 mN. Since the preliminary measurement resulted in 0.02<Ra(μm)≤0.1, the present measurement was performed with a reference length of 0.8 μm, an evaluation length of 4 mm, a cutoff λc of 0.8 mm, and a λs of 2.5 μm. Each sample was measured 10 times, and the average value thereof was taken as Ra.
For each sample, the results of the arithmetic mean heights Ra1 of the line roughness of the surfaces having the films and the arithmetic mean heights Ra2 (=Ra2′) of the line roughness of the surfaces without the films are illustrated in
The arithmetic mean roughness of the surfaces without the films was measured for a) the measured values Ra2 before film formation and b) the measured values Ra2′ of the surfaces removed after film formation. As a result, although not illustrated, it was confirmed that almost the same results were obtained, This result confirmed that b) the removal method after film formation was appropriate.
Further, Table 2 is obtained by summarizing the values of Ra1 (hatched bars in
In addition, Table 3 is obtained by summarizing the difference between the values of Ra1 (hatched bars in
For films A1-C0, A1-C10, A1-C20, and A1-C30 formed by using titanium as a plate-shaped substrate, and for films A2-C0, A2-C10, A2-C20, and A2-C30 formed by using zirconia as a plate-shaped substrate, the arithmetic mean heights Sa1 of the surface roughness of the surfaces were measured.
Further, for films A1-C0, A1-C10, A1-C20, and A1-C30 and for films A2-C0, A2-C10, A2-C20, and A2-C30 formed by zirconia using as a plate-shaped substrate, the arithmetic mean heights Sa2 of the surface roughness of the surfaces before film formation were measured.
More, for films A1-C0, A1-C10, A1-C20, and A1-C30 and for films A2-C0, A2-C10, A2-C20, and A2-C30 formed by using zirconia as a plate-shaped substrate, the films after film formation were immersed in a 5% aqueous hydrochloric acid solution for about 10 seconds, and the films were removed. The arithmetic mean heights Sa2′ of the surface roughness of the surfaces of the sample, from which the films of the obtained samples were removed, were measured. Furthermore, it was confirmed that Sa2 and Sa2′ were substantially the same as described below.
The arithmetic mean heights of the surface roughness were measured by deflecting the measurement probe in directions perpendicular to the grinding marks. The measurement was performed with a laser probe type non-contact three-dimensional measuring device (NH-3 SP, manufactured by Kohki Co., Ltd.) in accordance with ISO 25178. A laser having a probe diameter of 1 μm was used to measure a range of 100 μm×100 μm at a measurement pitch of 1 μm. The measurement of the arithmetic mean height of the surface roughness was carried out by using analysis software TalyMapGold (Version 7, manufactured by AMETEK Taylor Hobson). The arithmetic mean height was calculated without using a filter after subjecting a calibration surface leveled by a least squares method to shape removal by a quadratic polynomial and separating wavelength components of a contour curve.
For each sample, the results of the arithmetic mean heights Sa1 of the surface roughness of the surfaces having the films and the arithmetic mean heights Sa2 (=Sa2′) of the surface roughness of the surfaces without the films are illustrated in
The arithmetic mean roughness of the surfaces without the films was measured for a) the measured values Sa2 before film formation and b) the measured values Sa2′ of the surfaces removed after film formation. As a result, although not illustrated, it was confirmed that almost the same results were obtained. From this result, it was confirmed that b) the removal method after film formation was appropriate.
Further,
More, Table 4 is obtained by summarizing the values of Sa1 (hatched bars in
Further, Table 5 is Obtained by summarizing the difference between the values of Sa1 (hatched bars in
In the implantation of, for example, dental root implant materials, it is important to have a relatively smooth surface roughness in reducing the burden on the patient and in appropriate implantation and clamping, but this depends on the maximum value of the arithmetic mean surface height of the line roughness of the sample and on the maximum value of the arithmetic mean surface height of the surface roughness. Since the present examples from Tables 2 and 4 show that the maximum value of the arithmetic mean surface heights of the line roughness or the surface roughness is 1 μm or less, the sample obtained in the present example can be smoothly implanted. In the present example, a substrate subjected to a general grinding process is used, but as described below in a comparative example, application of a smoother substrate can provide smoother the surface roughness. Such a substrate makes it possible to shorten a period until secondary fixation after implantation in a screw (bone screw or anchor screw), which is used on the premise of removal thereof, to suppress physical engagement due to unevenness of the surface of the substrate at the time of removal, and to smoothly perform removal.
Further, the formation of the film by the example using spattering can relatively minimize the difference value (Ra1−Ra2) (nm) between Ra1 and Ra2 and the difference value (Sa1−Sa2) (nm) between Sa1 and Sa2 of each sample. Since the maximum value of the surface roughness of the film is 30 nm or less as described below in the comparative example, the surface roughness is hardly increased by forming the film.
More, reduction of the difference indicates that the film is not locally formed but is uniformly formed all over the surface of the substrate. It can be expected that the effect of the film is stably exhibited throughout the substrate.
For the sample obtained, the cross-sectional direction of the film and the surface having the film were confirmed with a scanning electron microscope (SEM).
Further, from the appearance of the upper surfaces of
X-ray diffraction analysis was carried out for the samples obtained, films AC1-C0, AC1-C10, AC1-C20, and AC1-C30 formed by using a glass substrate, films A1-C0, A1-C10, A1-C20, and A1-C30 formed by using titanium as a plate-shaped substrate, and films A2-C0, A2-C10, A2-C20, and A2-C30 formed by using zirconia as a plate-shaped substrate.
Specifically, X-ray diffraction analysis was carried out by using an X-ray diffractometer (D8 ADVANCE, manufactured by Bruker Corporation) under the conditions of a detector: a two-dimensional detector, tube lamp: Co, tube lamp voltage: 30 kV, tube lamp current: 40 mA, Φ1.0 mm, and collimator: Φ1.0 mm. Results are shown in
Peaks are observed near 2θ=40 degrees in any film in
These results show that calcium up to 10% has crystallinity, but the film becomes substantially amorphous when calcium exceeds 20%, from the results of X-ray diffraction (
The reason why the intensity of the (00-2) peak near 40 degrees is remarkably high in the film of 0% calcium is considered to be due to the orientation of crystals also observed in the appearance of the SEM image (
It has been found that, as the proportion (%) of calcium increases, the dense columnar structure changes into fine crystals and amorphous, and this also appears in the crystallite size illustrated in Table 6. It is found that, as the proportion of calcium increases, the crystallite size decreases, and that the structure becomes more amorphous. The crystallite size was calculated using the Scherrer method from the integral width of the peak near 2θ=40 degrees (00-2) where a film is formed on the glass substrate.
This structural change is also shown in the characteristics of the arithmetic mean surface roughness described above. That is, the surface roughness is small and smooth in any sample.
For films A1-C0, A1-C10, A1-C20, and A1-C30 formed by using titanium as a plate-shaped substrate, and for films A2-C0, A2-C10, A2-C20, and A2-C30 formed by using zirconia as a plate-shaped substrate, a hardness test was carried out by a nanoindentation method.
A hardness test by a nanoindentation method was carried out by using an apparatus (an ultra-micro indentation hardness tester “ENT-1100A” of ELIONIX INC.) under conditions: Berkovich indenter as an indenter; an indentation load of 20 mN; and retention time of 0 second.
The results of the hardness test are shown in
For films A1-C0, A1-C10, A1-C20, and A1-C30 formed by using titanium as a plate-shaped substrate, and for films A2-C0, A2-C10, A2-C20, and A2-C30 formed by using zirconia as a plate-shaped substrate, a scratch test was carried out.
A scratch tester CSR 1000 (manufactured by RHESCA CO., LTD.) was used as a scratch tester, and a load was applied in a range of 0 to 8 kg by weight by using a Rockwell indenter having a diameter of 0.8 mm. The sample after the scratch test was observed with SEM/EDX, and the critical load was obtained by measuring the distance from the initial position of the scratch test to the position where the substrate was exposed.
Further, the results of
Among films A1-C0, A1-C10, A1-C20, and A1-C30 formed by using titanium as the plate-shaped substrate and films A2-C0, A2-C10, A2-C20, and A2-C30 formed by using zirconia as the plate-shaped substrate, A1-C10 in the scratch test in the direction parallel to the grinding mark and A1-C10, A1-C20, and A1-C30 in the scratch test in the direction perpendicular to the grinding mark have critical loads of 78.4 N or more, indicating that A1-C10, A1-C20, and A1-C30 are excellent in adhesiveness.
Even in case of A2-C0 having the smallest critical load, the critical load is about 10 N and satisfies 10 N or more. The critical load of about 10 N corresponds to an implanting torque of 150 Ncm that can be implanted without peeling the film in an implant screw having a screw radius of 2 mm and the width of the tip of the ridge of the thread of 0.2 mm. The 150 Ncm has a strength of a safety factor of about 4 times the implanting torque of 35 to 45 Ncm required for the implant, indicating that the films according to the present examples have desired adhesiveness.
The critical shear stress of the interface can be obtained by using the result of the scratch test.
In the scratch test, the load W is applied to the surface of the film through an indenter, and the tip of the indenter is dragged (squeezed) in parallel with the film, so that the length is measured until the film is peeled off, and the surface of the substrate is exposed. Since the load of the indenter is set to be proportional to the dragging length, the critical load Wc when the film is peeled off can be known from this length. At this time, the brittleness and ductility of the film are also found by observing the appearance of breakage or deformation of the film. These values are obtained using the commonly used Benjamine-Weaver's equation.
The load when the film is broken is defined as the critical load Wc, the radius of the tip of the diamond indenter is defined as R, and the hardness of the Brinel of the substrate is defined as HB, and thus the shear stress τc (critical shear stress) at the interface at this time is expressed by the following Equation 5.
A tip R of the diamond indenter was set to 0.8 mm, the Brinell hardness of the titanium substrate and the zirconia substrate was set to 2.3 GPa, and 12.0 GPa, respectively, and the critical load was calculated using the values of the scratch test in
As shown in
The yield stress of the film is smaller than the shear stress at the interface of the film, and it is found that, when a shear force is applied to the surface, the film is deformed in a ductile manner prior to the fracture at interface and then does not peel off from the interface of the film. This was apparent in the appearance of the scratch test in
In the scratch test, when the substrate has a cylindrical shape like a screw, as illustrated in
The results of <Hardness Test> and <Scratch Test> show that the films according to the present invention formed on the implant screw have sufficient abrasion resistance, adhesiveness, and ductility, which means the films have excellent characteristics that have not been seen before as a film of the implant screw.
For films A1-C0, A1-C10, A1-C20, and A1-C30 formed as by using titanium as a. plate-shaped substrate, and for films A2-C0, A2-C10, A2-C20, and A2-C30 formed by using zirconia as a plate-shaped substrate, an in vitro biological reaction test using a pseudo body fluid was carried out.
As the pseudo body fluid, a Hank's balanced salt solution (HBSS (+) solution) containing calcium and magnesium was used.
As the pseudo body fluid immersion test, each sample was immersed in 400 ml of the pseudo body fluid, and held in a thermostatic, bath at 37° C. for one week, and then the sample was taken out from the solution.
Further, in order to bring the equilibrium pH in the solution close to the in vivo environment, the solution amount of HBSS (+) was adjusted so that the equilibrium pH after elution of the sputtering film was 8.0 or less. For comparison, each substrate without a film was also tested.
The result of observing the state of the surface on which the film was formed with time showed that almost all of the formed films were eluted into the liquid, and then new films were formed on the surface.
Although not illustrated, in the substrates of titanium and zirconia on which sputtering films were not formed, a new film was not formed in HBSS, but in the substrates of 0% calcium (pure magnesium) to 30% calcium formed by sputtering, the formation of new films was recognized. In addition, it was observed that the film including 10% or more of calcium had a large adhesion amount of a new film.
Further, the results of component analysis performed by fluorescent X-rays around the center (specifically, the position of “+” in the SEM image are shown in Table 7.
In Table 7, the ratio of calcium to phosphorus, which is an index of the presence of apatite, showed a value of 1.5 to 2.0 in all the sputtering films, suggesting that there was a high possibility that apatite was formed as a component.
Further, in order to analyze the structure of the film, X-ray diffraction (XRD) analysis was carried out by a thin film method in which only a detector was scanned while an X-ray incident angle was fixed. Results are shown in
On most substrates sputtered, peaks appeared at diffraction angles representing the characteristics of apatite on both the titanium substrate and the zirconia substrate. In A2-C0, the peak of apatite was not confirmed, but apatite was present on the surface as shown in
As described above, from component analysis and structural analysis, it was able to be confirmed that apatite was formed on all the substrates having the sputtering film. Further, it was able to be confirmed that the amount of apatite to be formed was increased by containing calcium the sputtering film.
These show that the amorphous which is a structure free from Mg2Ca has non-brittle characteristics and exhibits a high critical load Meanwhile, it is found that when Mg2Ca is present and brittle, the critical load is significantly low.
Table 8 shows a comparison of the adhesion strength between the film in the related art and the film of the present application.
The adhesion strength of the calcium titanate film disclosed in Patent Document 2 is 4.9 MPa, and the adhesion strength of the calcium phosphate coating film disclosed in Non-Patent Document 2 is 80 MPa. These are tensile strengths obtained in pin tensile tests using adhesives.
The tensile strength of the film of the present application was measured by a similar pin tensile test, but the tensile strength of the adhesive was too strong to be measured as the adhesive was broken earlier. For a sample of which the adhesion strength cannot be measured by a pin tensile test, a scratch test or the like capable of measuring stronger adhesion strength is generally used. According to the in-vivo implantable material field development guidelines 2008 issued by the Ministry of Economy, Trade and Industry, it is desirable that both the tensile strength and the shear strength of the film be 20 MPa or more. Therefore, the shear stress calculated in the present example and the tensile strength in the prior art can be compared as adhesion strength at the same level. Therefore, it is found that, even when the adhesion strength of A2-C20 is 170 MPa, which is the lowest among those calculated in the present example, the adhesion strength is an extremely high value as compared with the related art.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2020-184954 | Nov 2020 | JP | national |
| 2020-217810 | Dec 2020 | JP | national |
The present application is a national stage entry of International Application No. PCT/JP2021/040544 filed Nov. 4, 2021, which claims the benefit of Japanese Application No. 2020-184954 filed Nov. 5, 2020 and also Japanese Application No. 2020-217810 filed Dec. 25, 2020, the disclosures of which are incorporated by reference in their entireties.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/JP2021/040544 | 11/4/2021 | WO |
