WO2017073591A1

WO2017073591A1 - Chromium-modified implant and method for manufacturing same

Info

Publication number: WO2017073591A1
Application number: PCT/JP2016/081676
Authority: WO
Inventors: 山本　修; 勉小口
Original assignee: 山本　修
Priority date: 2015-10-27
Filing date: 2016-10-26
Publication date: 2017-05-04
Also published as: JP6185679B1; JPWO2017073591A1

Abstract

The purpose of the present invention is to develop an implant that acts on a living body through an unconventional mechanism and can strongly bond to a living tissue. Provided is an implant (1) to be embedded in a living body for a medical purpose, said implant (1) being characterized in that a base material (2) of the implant comprises a metal, a metal alloy, a metal oxide or a ceramic, and a surface (3) of the base material is modified with a chromium group (4) having a hydroxy group. The implant (1) according to the present invention can easily release chromium ion (8). The chromium ion (8) thus released acts on a living body and promotes tissue formation between the implant (1) and a living tissue (5) by, for example, promoting the crosslinking of collagen (9) secreted by a cell (7). As a result, the bond between the implant (1) and the living tissue (5) can be strengthened.

Description

Chromium-modified implant and method for producing the same

The present invention relates to an implant that is embedded in a living body for medical purposes, and whose surface is modified with a chromium group having a hydroxyl group. In the implant of the present invention, chromium is gradually released as ions from the surface, thereby acting on the living body and promoting the binding of the implant to the living tissue. The present invention also relates to an implant production method, an implant surface treatment method, and an implant surface treatment agent using a reaction solution containing chromium hydroxide ions.

】 Implant is a general term for instruments or biomaterials that are implanted in a living body for medical purposes. Implants include dental implants (artificial roots) that are implanted in the jawbone of patients with lost roots, artificial joints that replace damaged knees and hips, bolts that fix broken bones, cardiac pacemakers, cochlear implants, etc. To do. Implants are intended to recover lost function by replacing or assisting in-vivo organs that have lost function.

In recent years, treatment techniques using dental implants (artificial dental roots) have greatly advanced and are widely used for dental treatment, and it is common to simply abbreviate dental implants as “implants”.
A general treatment method using a dental implant is to cut the jaw bone, implant the implant into the jaw bone, and take 2-6 months to fully bond the implant and the bone. It is a method of forming artificial teeth.

One important factor for successful treatment with an implant (intraosseous implant) that is implanted in the bone, such as a dental implant, is to sufficiently bond the implant and the bone. Sweden's professor Brunemark discovered a phenomenon called “Osseointegration” in which titanium and bone tissue combine without causing a rejection reaction. Based on this phenomenon, titanium is used as the material for implants. This has greatly improved implant technology.
In addition, the fact that it was easy to bond to bone by applying a process that roughened the surface of the implant also greatly contributed to the advancement of implant technology.

However, in order to connect titanium and bone by “Osseointegration”, it is necessary to keep titanium and bone adjacent to each other with as little gap as possible. Technology is required.
For this reason, implants utilizing “Bio-integration” have been developed in which bone formation is induced at the joint between the implant and bone, and the two are combined. For example, an implant coated with hydroxyapatite on the surface can deposit calcium between the implant and the bone, so that even if there is a gap between the bone, the implant can be firmly bonded to the bone. It can increase the success rate of treatment by and is widely used in clinical settings.

Thus, in order to improve the biocompatibility of an implant, many techniques for coating, modifying, or roughening the surface of the implant have been developed.
The present inventors have previously developed an implant having a zinc functional group on the surface produced by immersing the base material of an implant made of titanium or an alloy thereof in an alkaline solution containing a zinc hydroxide complex (patent) Document 1, Non-Patent Document 1). This implant having a zinc functional group on the surface can be bonded to bone with high strength comparable to that of an implant coated with hydroxyapatite when implanted in bone.

On the other hand, chromium (Cr) is a metal used as a base material for implants as a cobalt-chromium alloy, and forms a chromium oxide (Cr ₂ O ₃ ) coating on the surface to prevent rust of the implant. Are known.
As another implant containing chromium, Patent Document 2 discloses a strong and wear-resistant implant in which chromium nitride is formed on the surface by plasma treatment of a cobalt chromium alloy in a gas containing nitrogen gas. ing.

In Patent Document 3, an oxide or mixed oxide layer is formed on a metal substrate by subjecting a metal substrate that is titanium or an alloy thereof to an electrolytic treatment in an electrolytic solution containing sulfuric acid, sulfate, carbonate, or the like. Further, there is disclosed an implant in which a coating layer containing hydroxyapatite is formed on the surface thereof. Here, as the oxide layer, in addition to the titanium oxide layer, a mixed oxide layer of titanium oxide impregnated with chromium is also exemplified. It is described that the oxide layer has a relatively good affinity in vivo and has sufficiently high corrosion resistance, so that it can be an implant that is stable and has almost no possibility of elution.
Thus, chromium used in conventional implants has been used to impart or enhance the corrosion resistance of implants.

By the way, chromium is also used as a chemical in the treatment of “skin tanning” for maintaining the flexibility of leather for a long time, and it is shown in Non-Patent Document 2 that chromium crosslinks collagen.

International Publication WO2010 / 150788 International Publication No. WO2005 / 070344 JP-A-63-99868

As described above, many techniques for coating, modifying, or roughening the surface of an implant have been developed to improve biocompatibility. However, even if these techniques are used, failure cases in implant treatment cannot be eradicated, and since there are many cases in which implant treatment is not possible in the first place, further technological development is necessary. In addition, implants that induce bone formation by promoting calcium deposition, such as implants using hydroxyapatite, are limited in the treatment sites and cases that can be applied. Was desired.
In view of the above-described conventional situation, an object of the present invention is to develop an implant that acts on a living body by an unprecedented mechanism and can be firmly bonded to a living tissue.

In order to solve the above problems, the present inventors have conducted intensive research. As a result, in implants to be implanted in a living body for medical purposes, chromium ions are gradually released from the implant by modifying the surface with a chromium group having a hydroxyl group. Thus, the present inventors have found that this chromium ion acts on living tissue by promoting the cross-linking formation of collagen and the like, thereby promoting the strong bond between the implant and the living tissue, and completed the present invention.

That is, the present invention relates to the following first invention relating to an implant, the following second invention relating to a method for producing an implant, the following third invention relating to a surface treatment method for an implant, and the following relating to a surface treatment agent for an implant. The fourth invention is provided.
In a first aspect of the present invention, in an implant that is embedded in a living body for medical purposes, the base material of the implant is a metal, metal alloy, metal oxide, or ceramic, and the surface of the base material is modified with a chromium group having a hydroxyl group. It is related with the implant characterized by being.
In the implant of the first invention, the surface is preferably modified with a group represented by the following general formula (1) as a chromium group having a hydroxyl group.
-O-Cr (OH) R (1)
In the general formula (1), R represents —OH or —O—.
In the implant of the first invention, the chromium group is preferably a chromium group having a trivalent oxidation number.
In the above-described implant invention, the implant is preferably a dental implant.
2nd invention immerses the base material selected from the group which consists of a metal, a metal alloy, a metal oxide, and a ceramic in the reaction solution containing a chromium hydroxide ion, and takes out a base material from a reaction solution. The present invention relates to a method for manufacturing an implant.
In the method for producing an implant of the second invention, it is preferable that the chromium hydroxide is a chromium hydroxide ion in which the ion valence of the chromium atom is trivalent.
3rd invention is related with the surface treatment method of the implant for improving biocompatibility including making the reaction solution containing a chromium hydroxide ion contact an implant.
In the implant surface treatment method according to the third aspect of the invention, the chromium hydroxide is preferably a chromium hydroxide ion in which the ionic value of the chromium atom is trivalent.
A fourth invention relates to a surface treatment agent for an implant, which is a solution containing chromium hydroxide ions.
In the implant surface treatment agent according to the fourth aspect of the invention, the chromium hydroxide is preferably a chromium hydroxide ion in which the ionic value of the chromium atom is trivalent.

Since the surface of the implant of the first invention is modified with a chromium group having a hydroxyl group, chromium ions are gradually released, and the released chromium ions act on the living body by promoting collagen cross-linking. Thus, there is an effect that the tissue formation between the implant and the living tissue is promoted, and the strong bond between the implant and the living tissue is promoted.
In the method for producing an implant of the second invention, a substrate selected from the group consisting of metals, metal alloys, metal oxides, and ceramics is immersed in a reaction solution having chromium hydroxide ions. As a result, the implant is improved in biocompatibility by the surface being modified with a chromium group having a hydroxyl group.
In the surface treatment method for an implant of the third invention, a reaction solution having chromium hydroxide ions is brought into contact with the surface of the implant, so that biocompatibility can be improved by simple treatment even for an already manufactured implant. There is an effect that can be done.
The implant surface treatment agent according to the fourth aspect of the present invention has an effect that biocompatibility can be enhanced by simple treatment even for an already manufactured implant.

It is a schematic cross section which shows one embodiment of the implant of this invention. FIG. 1 (A) shows a state immediately after implanting an implant in a living body, and FIG. 1 (B) shows a state after time has elapsed after implanting the implant in the living body. It is a schematic cross section which shows one mechanism in which the implant of this invention is combined firmly with a biological tissue. FIG. 2 (A) shows the state immediately after implanting the implant in the living body, FIG. 2 (B) shows the state after time has passed after implanting the implant in the living body, and FIG. Furthermore, the state which the implant and the biological tissue couple | bonded with time passes is shown. It is a schematic cross section which shows the implant by which the surface was modified by the group shown by General formula (1). 3A shows a state in which the surface of the implant is modified with a group in which R is —OH in the general formula (1), and FIG. 3B shows a state in which R is —O— in the general formula (1). FIG. 3 (C) shows a state in which the surface of the implant is modified with both groups shown in FIGS. 3 (A) and 3 (B). . It is a photograph replaced with drawing which shows the result of having observed the surface shape of the base material made from titanium, and the surface shape of the implant manufactured in Example 1 with the scanning electron microscope (SEM). The photograph on the left is a photograph of the surface shape of the titanium base material, and the photograph on the right is a photograph of the surface shape of the implant manufactured in Example 1. It is a chart which shows the result of having analyzed the crystal phase of the base material made from titanium, and the crystal phase of the implant manufactured in Example 1 using the X-ray diffraction apparatus. The upper chart in FIG. 5 shows the analysis result of the titanium base material, and the lower chart in FIG. 5 shows the analysis result of the implant manufactured in Example 1. It is the photograph replaced with drawing which shows the result of having conducted the elemental analysis of the surface of the implant manufactured in Example 1 using SEM-EDS. The upper photograph in FIG. 6 is a photograph of the shape of the implant surface taken with a scanning electron microscope (SEM), and the two lower photographs in FIG. 6 show EDS (energy dispersive type) for the same implant surface. It is a photograph which shows the result of having conducted elemental analysis by X-ray analysis. The lower left photograph in FIG. 6 is a photograph showing the detection results of titanium atoms, and the lower right photograph in FIG. 6 is a photograph showing the detection results of chromium atoms. It is a chart which shows the result of having performed the wide scan analysis with respect to the implant manufactured in Example 1 by XPS (X-ray photoelectron spectroscopy). It is a chart which shows the result of having performed narrow scan analysis (high resolution analysis) by XPS (X-ray photoelectron spectroscopy) with respect to the implant manufactured in Example 1. FIG. The chart on the upper left of FIG. 8 is a chart showing the analysis result in the binding energy region (526 to 538 eV) in the vicinity where the O1s spectrum is detected in the wide scan analysis of FIG. The upper right chart in FIG. 8 is a chart showing the analysis results in the vicinity of the binding energy region (452 to 474 eV) where the spectra of Ti2p ^3/2 and Ti2p ^1/2 were detected by the wide scan analysis of FIG. The chart on the lower left of FIG. 8 is a chart showing the analysis results in the vicinity of the binding energy region (570 to 595 eV) where the Cr2p ^3/2 and Cr2p ^1/2 spectra were detected in the wide scan analysis of FIG. The lower right diagram of FIG. 8 is a schematic diagram showing the chemical bonding state of the surface of the implant predicted from the XPS analysis result. It is a graph which shows the result of having conducted the test which immersed the implant manufactured in Example 1 in the physiological saline, and measured the chromium ion discharge | released in the physiological saline. It is the photograph replaced with drawing which shows the mode of the operation which embeds an implant and a titanium rod in a laboratory animal. It is a figure which shows the evaluation item of the coupling | bonding state of the implant embedded in the femur of a rabbit, and a bone. It is a graph which shows the joint force (shear strength) of the implant (CrTi) manufactured in Example 1, and a bone, and the rod made from titanium (Ti) and the bone as a comparative example (shear strength). It is a chart which shows the time change at the time of applying a load to the implant (CrTi) manufactured in Example 1, and the rod (Ti) made from titanium. The upper chart is after 4 weeks of embedding, and the lower chart is after 8 weeks of embedding. It is the photograph replaced with drawing which shows the result of having observed the surface state and the state of the interface of an implant and a bone with the SEM (scanning electron microscope) about the implant embedded in the femur of a rabbit. The lower left photograph in FIG. 14 is a photograph of the interface between the implant (CrTi) manufactured in Example 1 and the bone taken with an SEM (scanning electron microscope). The lower right photograph in FIG. 14 is a photograph of the surface of the same implant (CrTi) taken with an SEM. The upper left photograph in FIG. 14 is a photograph taken by SEM of an interface between a titanium rod (Ti) and a bone as a comparative example. The upper right photograph in FIG. 14 is a photograph of the surface of the same titanium rod (Ti) taken with an SEM. It is a chart which shows the result of having analyzed the component analysis of the membranous product formed in the surface using the scanning electron microscope and the laser Raman spectrophotometer about the implant embedded in the femur of a rabbit. The upper chart in FIG. 15 is a chart showing the result of component analysis of a small piece formed on the surface of a titanium rod (Ti) as a comparative example, and the lower chart in FIG. It is a chart which shows the result of having performed the component analysis of the film-form product formed in the surface of (CrTi). It is a chart which shows the result of having performed the component analysis by XPS (X-ray photoelectron spectroscopy) about the film-form product formed in the surface of an implant (CrTi). It is the photograph replaced with drawing which shows the result of having observed the bone structure | tissue around an implant with a biological microscope about the implant embedded in the femur of a rabbit. The upper photograph in FIG. 17 shows, as a comparative example, the result of observing a bone tissue around a titanium rod (Ti) embedded in a femur of a rabbit with HE (hematoxylin and eosin) and observing it with a biological microscope. The lower photograph in FIG. 17 is a photograph showing the result of observation of the bone tissue around the implant (CrTi) by HE staining and observation with a biological microscope.

1. Implant of the present invention The implant of the present invention is an implant that is embedded in a living body for medical purposes, and is characterized in that the surface is modified with a chromium group having a hydroxyl group.
In the present invention, “implant” means a device that is implanted in a living body for medical purposes. Here, the “medical purpose” includes not only medical treatment for humans but also medical purposes for animals. Examples of the “implant” of the present invention include, but are not limited to, dental implants (artificial dental roots), artificial joints, artificial bones, and screws, plates and rods for orthopedic surgery, brain surgery, or spinal surgery. Can be mentioned.

One embodiment of the implant of the present invention is shown in FIG.
FIG. 1 is a schematic cross-sectional view showing an interface between an implant and a living tissue when the implant of the present invention is embedded in the living body. FIG. 1 (A) shows a state immediately after implanting an implant in a living body, and FIG. 1 (B) shows a state after time has elapsed after implanting the implant in the living body.

As shown in FIG. 1 (A), the implant (1) of the present invention includes a base material (2), and the surface (3) of the base material is modified with a chromium group (4) having a hydroxyl group. Yes. The implant (1) of the present invention embedded in the living body is adjacent to the living tissue (5), and at least partially a gap (between the implant (1) and the living tissue (5) ( 6) exists. Here, the gap (6) is filled with a fluid such as a body fluid, and cells (7) are present in the living tissue (5).
And since the chromium group (4) which exists in the surface (3) of a base material is easy to ionize, as shown to FIG. 1 (B), chromium ion (8) elutes in the liquid which fills a gap | interval (6). . And this chromium ion (8) acts on a biological body, and promotes that an implant (1) and a biological tissue (5) are couple | bonded firmly.

FIG. 2 shows one mechanism by which the implant of the present invention is firmly bonded to living tissue.
FIG. 2 is a schematic cross-sectional view showing the interface between the implant and the living tissue when the implant of the present invention is embedded in the living body. FIG. 2 (A) shows the state immediately after implanting the implant in the living body, FIG. 2 (B) shows the state after time has passed after implanting the implant in the living body, and FIG. Furthermore, the state which the implant and the biological tissue couple | bonded with time passes is shown.

FIG. 2 (A) is the same view as FIG. 1 (A) described above, and the surface (3) of the base material of the implant (1) of the present invention is modified with a chromium group (4) having a hydroxyl group. Yes.
Next, as shown in FIG. 2 (B), when time passes after the implant (1) is implanted in the living body, the chromium group (4) on the surface (3) of the substrate is ionized, and the implant ( The chromium ions (8) are eluted in the liquid that fills the gap (6) between 1) and the living tissue (5). Further, the cells (7) in the living tissue (5) move while proliferating and adhere to the surface of the implant (1). Cells (7) secrete collagen (9) into the liquid that fills the gap (6).
When further time elapses, as shown in FIG. 2 (C), collagen (9) secreted by cells (7) is cross-linked by chromium ions (8) to form fibers. (1) and the biological tissue (5) are firmly bonded.

Here, when the living tissue (5) is a bone and the cell (7) is an osteoblast, hydroxyapatite secreted by the osteoblast is deposited around the collagen fiber, and calcification proceeds. . Thereby, a bone tissue is formed in the gap (6) between the implant (1) and the bone (5), and the implant (1) and the bone (5) are firmly bonded.
The implant of the present invention is preferably an intraosseous implant that is to be bonded to bone by being embedded in bone or brought into contact with bone.

The implant of the present invention gradually releases chromium ions, whereby collagen is cross-linked by chromium ions to form fibers, and the collagen and the living tissue are tightly bound to each other, so that the hydroxy promotes calcium deposition. Unlike implants modified with apatite, the effect of promoting bonding can be expected even when implanted in tissues other than bone. In addition, when used as a dental implant (artificial tooth root), not only the connection with hard tissues such as alveolar bone but also the connection with soft tissues such as gingiva is promoted, and the effect of preventing gingival retraction can be expected.

The implant of the present invention includes a base material, and the surface of the base material is modified with a chromium group having a hydroxyl group. Since the base material of the implant of the present invention is modified with a chromium group having a hydroxyl group, it is necessary to use a metal, a metal alloy, a metal oxide, or a ceramic.
Here, the metal, the metal alloy, and the metal oxide are not limited to these. For example, titanium, titanium alloy, cobalt alloy, zirconia, stainless steel, alumina, tantalum, tantalum alloy, zirconium alloy, niobium, and the like. An alloy or the like can be used.
Further, here, for example, Ti-6Al-4V can be suitably used as the titanium alloy, and as the cobalt alloy, for example, a cobalt-chromium alloy, a cobalt-chromium-molybdenum alloy, or the like can be used.
When ceramic is used as the base material of the implant of the present invention, it is not limited to these. For example, hydroxyapatite, silicon carbide, silicon nitride, etc. can be used.

The “chromium group having a hydroxyl group” for modifying the surface of the implant of the present invention means a group having one or more hydroxyl groups (hydroxy groups) on the chromium atom. This “chromium group having a hydroxyl group” can be bonded to a base material, but has a hydroxyl group, and thus has an effect of easily releasing chromium ions.
The oxidation number of the chromium atom in the “chromium group having a hydroxyl group” of the present invention can be divalent, trivalent, tetravalent or hexavalent. Since hexavalent chromium has strong oxidizing power, it is preferable to use divalent, trivalent or tetravalent chromium. More preferably, the most stable trivalent chromium is used.

The “chromium group having a hydroxyl group” for modifying the surface of the implant of the present invention can be a group represented by the following general formula (1).
-O-Cr (OH) R (1)
(Wherein R represents —OH or —O—)
In the general formula (1), when R is —OH, the chromium group having a hydroxyl group becomes —O—Cr (OH) _{2 and} becomes a monovalent group.
In the general formula (1), when R is —O—, the chromium group having a hydroxyl group is —O—Cr (OH) —O—, which is a divalent group.
Here, monovalent or divalent is not a valence indicating the oxidation number of chromium but a valence indicating the number of sites where a chromium group having a hydroxyl group can be bonded to another atom.

FIG. 3 is a schematic cross-sectional view showing an implant whose surface is modified with a group represented by the general formula (1). 3A shows a state in which the surface of the implant is modified with a group in which R is —OH in the general formula (1), and FIG. 3B shows a state in which R is —O— in the general formula (1). FIG. 3 (C) shows a state in which the surface of the implant is modified with both groups shown in FIGS. 3 (A) and 3 (B). .

As shown in FIG. 3A, atoms (M) are present on the surface (3) of the base material (2) of the implant (1). FIG. 3A shows the case where R is —OH in the general formula (1), and the chromium group having a hydroxyl group is —O—Cr (OH) ₂ . Since this group is a monovalent group, it can be bonded to atoms (M) on the surface of the implant by a single bond to modify the surface of the implant. Here, the atom (M) on the surface of the implant may be modified with another functional group such as a hydroxyl group (—OH). In addition, when chromium ions are released from a group consisting of —O—Cr (OH) ₂ , a hydroxyl group (—OH) may remain.
FIG. 3B shows the case where R in the general formula (1) is —O—, and the chromium group having a hydroxyl group is —O—Cr (OH) —O—. Since this group is a divalent group, as shown in FIG. 3B, it is possible to bond the two atoms (M) on the surface of the implant so as to cross-link and modify the surface of the implant.
FIG. 3C shows the case where the surface of the implant is modified with both —O—Cr (OH) ₂ and —O—Cr (OH) —O— groups, as shown in FIG. As shown, the modification by both groups is mixed. Under the condition where the state shown in FIG. 3A and the state shown in FIG. 3B transition to each other, it is considered that the state shown in FIG.

The “chromium group having a hydroxyl group” for modifying the surface of the implant of the present invention is not limited to the above-described chromium group, but includes, for example, a —Cr (OH) ₂ group, —Cr An (OH) —O— group, —O—Cr (ONa) ₂ group, and the like may also be used.

In the implant of the present invention, “the surface is modified” means that an atom present on the surface of the implant is bonded to a chromium group having a hydroxyl group. Examples of the bond form include covalent bond, coordination bond, ionic bond, hydrogen bond, etc., but in order to gradually release chromium ions, at least a part of the bond must be firmly bonded by covalent bond. preferable.

The surface of the implant of the present invention is modified with a chromium group having a hydroxyl group, but in order to enhance biocompatibility, other treatments such as roughening and hydroxyapatite coating are further performed. It may be used in combination. In this case, however, the coating is performed so that not all of the chromium groups having a hydroxyl group are removed by roughening, and the release of chromium ions is not completely inhibited.

Since the surface of the implant of the present invention is modified with a chromium group having a hydroxyl group, the effect of gradually releasing chromium ions is achieved. The form of chromium ions released by the implant of the present invention can vary depending on the chromium group covering the surface of the implant. Examples of the released chromium ions include, but are not limited to, ordinary chromium ions, chromium ions coordinated with water molecules, chromium ions coordinated with hydroxide ions (OH ⁻ ), Examples include chromium ions coordinated with Cl ⁻ , NH ₃ , SO ₄ ²⁻ , or CrO ₄ ²⁻ (chromate ions), Cr ₂ O ₇ ²⁻ (dichromate ions), and the like. The released chromium ions can be ions in which the ionic valence of the chromium atom is divalent, trivalent, tetravalent or hexavalent. However, under normal conditions, ions with the valence of chromium atoms of trivalent ions are most easily released, and even when ions other than trivalent are released, they change to trivalent ions under normal conditions. Cheap.

2. The method for producing an implant of the present invention comprises immersing a substrate selected from the group consisting of metals, metal alloys, metal oxides and ceramics in a reaction solution containing chromium hydroxide ions. , A production method including removing the substrate from the reaction solution.

The “chromium hydroxide ion” used in the method for producing an implant of the present invention refers to a chromium ion coordinated with a hydroxide ion (OH ⁻ ), and is not limited thereto. For example, [Cr (OH) ₆ ] ³⁻ , [Cr (OH) ₄ ] ⁻ , [Cr (H ₂ O) ₅ (OH)] ²⁺ , [CrNH ₃ (OH) ₅ ] ²⁻ , [CrO ₄ (OH) ₂ ] ^4- etc. Can be used.
Further, as the “chromium hydroxide ion”, an ion with a chromium atom having a valence of 2, 3, 4, or 6 can be used, and a trivalent ion is stable and preferable.
Examples of the chromium hydroxide ion whose valence of chromium atom is trivalent include, but are not limited to, for example, [Cr (OH) ₆ ] ³⁻ , [Cr (OH) ₄ ] ⁻ , [Cr ( H ₂ O) ₅ (OH)] ^{2+ and the} like.

As the solvent of the “reaction solution containing chromium hydroxide ions” used in the production method of the present invention, water or a mixed solvent containing water and alcohol can be used. In addition to the chromium hydroxide ion, the reaction solution may contain a pH adjuster, a pH buffer, an antioxidant, a stabilizer, and other agents that modify the surface of the implant.

The “base material” used in the production method of the present invention needs to use metal, metal alloy, metal oxide or ceramic. Specific examples of these base materials are as described above.

The “base material” used in the production method of the present invention may be molded into a finished product shape as an implant for implantation in a living body, or may be molded into a semi-finished product shape as a material. It may be of the shape. Moreover, the base material may be a finished product as an implant by being connected to another member.
Further, the “base material” may be subjected to roughening or coating for improving biocompatibility. As a method for roughening the surface of the substrate, blasting, etching, or the like can be used. As the coating, titanium coating, hydroxyapatite coating, or the like can be used.

In the production method of the present invention, the concentration of chromium hydroxide ions in the reaction solution is preferably 0.0001 to 10 mol / L, more preferably 0.001 to 1 mol / L, still more preferably 0.01 to It is good to set it as 0.1 mol / L.
The time for immersing the substrate in the reaction solution is preferably 1 second to 5 days, more preferably 2 minutes to 10 hours, and even more preferably 10 minutes to 2 hours.
The temperature of the reaction solution when immersing the substrate is preferably 0 to 200 ° C., more preferably 40 to 80 ° C.

In the production method of the present invention, a substrate selected from the group consisting of metals, metal alloys, metal oxides, and ceramics is immersed in a reaction solution containing chromium hydroxide ions. An effect of being able to produce an implant with improved biocompatibility is obtained by the reaction with chromium hydroxide ions and the modification of the surface with a chromium group having a hydroxyl group.
In the production method of the present invention, “immersing the substrate” includes not only immersing the entire substrate in the reaction solution, but also immersing a part of the substrate in the reaction solution.

The production method of the present invention includes a step of taking out the substrate in the reaction solution. After removing the substrate from the reaction solution, the reaction solution adhering to the surface of the substrate may be removed by washing or the like, but it is preferable to dry without washing. When the reaction solution adhering to the surface of the substrate is dried without washing, there will also be chromium hydroxide that does not covalently adhere to the substrate, and immediately after the implant is implanted in the living body. There is an effect that the amount of chromium ions released into the can be increased.

After the substrate is taken out from the reaction solution, other treatments such as roughening and hydroxyapatite coating can be further performed in order to improve biocompatibility. In this case, however, the coating is performed so that not all of the chromium groups having a hydroxyl group are removed by roughening, and the release of chromium ions is not completely inhibited.
Moreover, after taking out a base material from a reaction solution, an implant can be further processed and it can sterilize and can be set as a finished product. As a sterilization method, a dry heat sterilization method, a sterilization method by irradiating ultraviolet rays or radiation, and the like can be used.

3. The Implant Surface Treatment Method of the Present Invention The implant surface treatment method of the present invention is a method of improving the biocompatibility of an implant by including a step of bringing a reaction solution containing chromium hydroxide ions into contact with the implant.
The surface treatment method of an implant of the present invention has an effect that biocompatibility can be enhanced by simple treatment even for an already manufactured implant.
The surface treatment method of the present invention can be applied to an implant obtained by the production method of the present invention, that is, an implant whose surface is modified with a chromium group having a hydroxyl group. By performing the treatment, it is possible to further improve the biocompatibility.

The “reaction solution containing chromium hydroxide ions” used in the implant surface treatment method of the present invention includes the above-mentioned 2. What has been described can be used.
In the surface treatment method of the present invention, as a method of “contacting” the reaction solution with the implant, a method of immersing the implant in the reaction solution or a method of applying the reaction solution to the surface of the implant can be used.

In the surface treatment method of the present invention, the concentration of chromium hydroxide ions in the reaction solution is preferably 0.0001 to 10 mol / L, more preferably 0.001 to 1 mol / L, and still more preferably 0.01. It is good to set it to 0.1 mol / L.
The time for contacting the substrate with the reaction solution is preferably 1 second to 5 days, more preferably 2 minutes to 10 hours, and even more preferably 10 minutes to 2 hours.
The temperature of the reaction solution when immersing the substrate is preferably 0 to 200 ° C., more preferably 40 to 80 ° C.

4). Surface Treatment Agent for Implants of the Present Invention The surface treatment agent for implants of the present invention is a solution containing chromium hydroxide ions.
The “chromium hydroxide ion” contained in the surface treatment agent of the implant of the present invention refers to a chromium ion coordinated with a hydroxide ion (OH ⁻ ), and is not limited to these. Cr (OH) ₆ ] ³⁻ , [Cr (OH) ₄ ] ⁻ , [Cr (H ₂ O) ₅ (OH)] ²⁺ , [CrNH ₃ (OH) ₅ ] ²⁻ , [CrO ₄ (OH) ₂ ^4- etc. can be used.
Further, as the “chromium hydroxide ion”, an ion with a chromium atom having a valence of 2, 3, 4, or 6 can be used, and a trivalent ion is stable and preferable.
Examples of the chromium hydroxide ion whose valence of chromium atom is trivalent include, but are not limited to, for example, [Cr (OH) ₆ ] ³⁻ , [Cr (OH) ₄ ] ⁻ , [Cr ( H ₂ O) ₅ (OH)] ^{2+ and the} like.

As a solvent used in the surface treatment agent for an implant of the present invention, water or a mixed solvent containing water and alcohol can be used. In addition to the chromium hydroxide ions, the solution may contain a pH adjuster, a pH buffer, an antioxidant, a stabilizer, and other agents that modify the surface of the implant.
The surface treatment agent for implants of the present invention has an effect that biocompatibility can be enhanced by simple treatment even for implants that have already been produced.
The surface treatment agent of the present invention can be applied to an implant obtained by the production method of the present invention, that is, an implant whose surface is modified with a chromium group having a hydroxyl group. By performing the treatment, it is possible to further improve the biocompatibility.

Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited thereto.

(Manufacture of implants)
As a reaction solution for immersing the base material of the implant, a reaction solution containing 0.05 mol / L of [Cr (OH) ₆ ] ^3- ion was prepared. This reaction solution was prepared by mixing an aqueous solution of 0.05 mol / L chromium (III) sulfate nonahydrate and an aqueous solution of 4 mol / L sodium hydroxide and carrying out the reaction represented by the following formula: did.

As the base material of the implant, titanium molded into a rod shape was used. This titanium substrate was immersed in the reaction solution prepared above. Immersion was performed in a reaction solution at 60 ° C. for 12 hours. As a result, the surface of the titanium substrate was modified with a chromium group having a hydroxyl group.
After immersion, the titanium substrate was taken out from the reaction solution. Thereafter, titanium as a base material was allowed to stand at 70 ° C. for 20 minutes, and dried until the solvent on the surface of the base material was sufficiently evaporated.
Furthermore, the implant was sterilized by dry heat by allowing it to stand at 180 ° C. for 2 hours.
As described above, an implant with a modified surface was produced.

(Evaluation of implant material)
(1) Surface observation and measurement of surface roughness The material evaluation of the implant manufactured in Example 1 was performed. First, the surface shape of the implant (CrTi) manufactured in Example 1 was observed with a scanning electron microscope (SEM). As a comparative example, the surface shape of the titanium base material (Ti) before being immersed in the reaction solution was similarly observed. A photograph showing the results is shown in FIG.
The photograph on the left side of FIG. 4 is a photograph of the surface of the titanium substrate (Ti), and the photograph on the right is a photograph of the surface of the implant (CrTi) manufactured in Example 1. As can be understood from the photograph in FIG. 4, no particular difference was observed between the surface shapes of the two.
Next, the surface roughness was measured using a confocal laser microscope (CLSM). The result is shown under each photograph in FIG.
The surface roughness (Ra) of the titanium substrate (Ti) was 3.123 ± 1.751, whereas the surface roughness (Ra) of the implant (CrTi) manufactured in Example 1 was 3.128 ± 1.504. Thus, there is no significant difference in the surface roughness that can affect biocompatibility between the titanium substrate (Ti) and the implant manufactured in Example 1 (CrTi). It was.

(2) X-ray diffraction (XRD)
Using the X-ray diffraction apparatus, the crystal phase of the implant manufactured in Example 1 and the crystal phase of the titanium base material were analyzed. A chart showing the analysis results is shown in FIG. The upper chart in FIG. 5 shows the analysis result of the titanium base material (Ti) whose surface is not modified, and the lower chart in FIG. 5 is the analysis result of the implant (CrTi) manufactured in Example 1. Indicates.
As shown in FIG. 5, a spectrum indicating the presence of Ti and TiO was detected from the chart of the implant (CrTi) manufactured in Example 1. Thereby, it became clear that the crystal phase of the surface of the implant (CrTi) manufactured in Example 1 was Ti and TiO.

(3) Elemental analysis Elemental analysis of the surface of the implant (CrTi) manufactured in Example 1 was performed using SEM-EDS. A photograph showing the result is shown in FIG. The upper photograph in FIG. 6 is a photograph of the shape of the implant surface taken with a scanning electron microscope (SEM), and the two lower photographs in FIG. 6 show EDS (energy dispersive type) for the same implant surface. It is a photograph which shows the result of having conducted elemental analysis by X-ray analysis. The lower left photograph in FIG. 6 is a photograph showing the detection results of titanium atoms, and the lower right photograph in FIG. 6 is a photograph showing the detection results of chromium atoms. As shown in the results of FIG. 6, chromium atoms were detected on the surface of the implant manufactured in Example 1.

(4) XPS analysis The implant (CrTi) manufactured in Example 1 was analyzed by XPS (X-ray photoelectron spectroscopy). Charts showing the analysis results are shown in FIGS. FIG. 7 is a chart showing a wide scan analysis result in the entire binding energy (0 to 1100 eV). In FIG. 7, spectra of Ti2p ^3/2 , Ti2p ^1/2 , O1s, Cr2p ^3/2 , and Cr2p ^1/2 were detected so as to be displayed within a square frame. This indicated that Cr, O and Ti atoms were present on the surface of the modified implant.
FIG. 8 is a chart showing the results of XPS narrow scan analysis (high resolution analysis). The chart on the upper left of FIG. 8 is a chart showing the analysis result in the binding energy region (526 to 538 eV) in the vicinity where the O1s spectrum is detected in the wide scan analysis of FIG. From this chart, one spectrum indicating the presence of Ti—OH chemical bond was detected. The upper right chart in FIG. 8 is a chart showing the analysis results in the vicinity of the binding energy region (452 to 474 eV) where the spectra of Ti2p ^3/2 and Ti2p ^1/2 were detected by the wide scan analysis of FIG. From this chart, a spectrum indicating the presence of a chemical bond of TiO and a metal bond of Ti was detected in the spectra of Ti2p ^3/2 and Ti2p ^1/2 . The chart on the lower left of FIG. 8 is a chart showing the analysis results in the vicinity of the binding energy region (570 to 595 eV) where the Cr2p ^3/2 and Cr2p ^1/2 spectra were detected in the wide scan analysis of FIG. From this chart, a spectrum indicating the presence of a chemical bond of Cr—OH was detected in the Cr2p ^3/2 and Cr2p ^1/2 spectra. The lower right diagram in FIG. 8 is a schematic diagram showing the state of chemical bonding on the surface of the implant identified from the XPS analysis result. It was revealed that —O—Cr (OH) ₂ group and —OH group were bonded to titanium atoms on the surface of the implant.

(5) Ion release test The implant manufactured in Example 1 was immersed in physiological saline, and a test was performed to measure chromium ions released into the physiological saline. The temperature of the physiological saline was 37 ° C. as in the living body, and the implant was immersed in the physiological saline while the flask containing the physiological saline was placed on a shaker and stirred to release chromium ions from the implant. The detection of released chromium ions was measured by ICP-MS after 6 hours, 12 hours, 24 hours, 36 hours and 72 hours, respectively. The result is shown in FIG. As shown in the graph of FIG. 9, up to 2 hours, chromium ions were rapidly released from the implant, and then chromium ions were gradually released.

(Evaluation of implants by animal experiments)
(1) Animal experiment The implant manufactured in Example 1 was embedded in the body of an experimental animal, and the bonding state with a living tissue was evaluated.
As a laboratory animal, Japanese white rabbit (JW / CSK) was used. The right femur of the rabbit is filled with five rod-shaped implants (CrTi) manufactured in Example 1, and the left femur is a titanium rod whose surface is not modified as a comparative example. Five (Ti) were embedded. Three animal experiments with an implantation period of 4 weeks, 8 weeks and 12 weeks were conducted. FIG. 10 shows the operation of implanting an implant and a titanium rod in the experimental animal. As shown in FIG. 10, the left and right thighs of a rabbit are shaved (1), incised to expose the femur (2), and after drilling a 2 mm hole in the femur, the implant ( A CrTi) or titanium rod (Ti) was inserted into the femur (3). The incision was sutured with a thread and closed (4).
After 4 weeks, 8 weeks, or 12 weeks from the implantation, the wound portion was again incised to cut out the femur, and the joint state of the implant with the femur was evaluated.

(2) Evaluation Item of Bonded State with Bone FIG. 11 shows an evaluation item of the bonded state between the implant implanted in the femur of the rabbit and the bone. As shown in the upper left photograph of FIG. 11, the femur was cut at the dotted line portion of the femur in which the implant was embedded, and a bone section was prepared. Then, using this bone section, i) shear strength measurement, ii) interface observation, iii) implant surface observation / component analysis, and iv) bone tissue observation around the implant (HE staining) were performed.
The results are as follows.

(3) Shear strength measurement In the bone slice prepared above, the time change when a load was applied to the implant was measured, and the maximum load (Fmax (N)) was measured. In addition, the diameter of the implant or rod (D (mm)) and the bone thickness (T (mm)) were also measured, and the shear strength was calculated from the formula of shear strength (σ (MPa)) = Fmax / πDT. . As a comparative example, the same measurement was performed on a titanium rod, and the two were compared. The results are shown in FIGS. 12 and 13 and the following Table 1.

Table 1 shows the measurement results of shear strength and the standard deviation of the implant (CrTi) and titanium rod (Ti) manufactured in Example 1. FIG. 12 is a bar graph showing the results of Table 1. As is apparent from the graph of FIG. 12, the implant (CrTi) produced in Example 1 showed significantly higher shear strength at 4th week, 8th week, and 12th week, and showed strong shear strength. It became clear that it bound to.
FIG. 13 is a chart showing the change over time when a load is applied to the implant (CrTi) or titanium rod (Ti) manufactured in Example 1. The upper chart is after 4 weeks of embedding, and the lower chart is after 8 weeks of embedding. In both the 4th and 8th week charts, the implant manufactured in Example 1 shows elastic behavior in response to changes in load, and elastic regions such as collagen fibers are formed between the bone and the bone. It was shown that

(4) Interface observation Fig. 14 shows the results of observation of the surface state and the state of the interface between the implant and the bone with an SEM (scanning electron microscope) for the 8th week implant implanted in the femur of a rabbit. . The lower left photograph in FIG. 14 is a photograph of the interface between the implant (CrTi) manufactured in Example 1 and the bone taken with an SEM (scanning electron microscope). The lower right photograph in FIG. 14 is a photograph of the surface of the same implant (CrTi) taken with an SEM. The upper left photograph in FIG. 14 is a photograph taken by SEM of an interface between a titanium rod (Ti) and a bone as a comparative example. The upper right photograph in FIG. 14 is a photograph of the surface of the same titanium rod (Ti) taken with an SEM. As shown in the two photographs on the left, neither the titanium lot (Ti) nor the implant manufactured in Example 1 (CrTi) had any voids between the bones. Further, as shown in the two photographs on the right side, only small pieces were seen on the surface of the titanium rod (Ti), but the film was not formed on the surface of the implant (CrTi) manufactured in Example 1. A product was seen.

(5) Component analysis of implant surface The 8th week implant implanted in the femur of a rabbit is described in Michael D. Morris et al., Clinical Orthopaedics and Related Resarch, 2011, vol.496, pp.2160-2169. According to the method, component analysis of the film-like product formed on the surface was performed using a scanning electron microscope and a laser Raman spectrophotometer. As a comparative example, component analysis was performed on small pieces formed on the surface of a titanium rod (Ti). A chart showing the results is shown in FIG. As shown in the upper chart of FIG. 15, for the small pieces formed on the surface of the titanium rod (Ti), peaks of inorganic components such as phosphate and carbonate are seen, and components similar to autologous bone On the other hand, as shown in the lower chart of FIG. 15, the film-like product formed on the surface of the implant (CrTi) has a peak of inorganic components such as phosphate and carbonate. It disappeared.
Next, component analysis by XPS (X-ray photoelectron spectroscopy) was performed on the film-like product formed on the surface of the implant (CrTi) at the eighth week. A chart showing the analysis results is shown in FIG. As shown in the chart of FIG. 16, the spectra of Ca3p, P2p, P2s, Ca2p, and Ca2s were detected, and the presence of calcium and phosphorus atoms was shown. I found out.

(6) Observation of bone tissue around implant For 8 week implant (CrTi) implanted in the femur of a rabbit, the bone tissue around the implant after the shear test was stained with HE (hematoxylin and eosin), and by a biological microscope Observations were made. In addition, as a comparative example, the bone tissue around the rod after the shearing test was observed with the same HE staining for an 8 week titanium rod (Ti) embedded in the femur of a rabbit. The result is shown in FIG. As shown in the upper photograph of FIG. 17, fibrous tissue was not observed in the bone tissue around the titanium rod (Ti), but as shown in the lower photograph of FIG. Collagen fibers having a lamellar plate-like orientation were observed in the bone tissue around (CrTi).

The implant, the implant production method, and the implant surface treatment method of the present invention are useful in the industry for producing medical implants.

DESCRIPTION OF SYMBOLS 1 Implant 2 Base material 3 Implant surface 4 Chromium group having a hydroxyl group 5 Biological tissue 6 Gap between implant and biological tissue 7 Cell 8 Chromium ion 9 Collagen

Claims

In implants that are implanted in vivo for medical purposes,
The implant substrate is a metal, metal alloy, metal oxide or ceramic;
An implant wherein the surface of the substrate is modified with a chromium group having a hydroxyl group.
The chromium group having a hydroxyl group is represented by the following general formula (1)
-O-Cr (OH) R (1)
(Wherein R represents —OH or —O—)
The implant according to claim 1, which is a group represented by:
The implant according to claim 1, wherein the chromium group is a trivalent oxidation chromium group.
The implant according to any one of claims 1 to 3, wherein the implant is a dental implant.
Implanting a substrate selected from the group consisting of metals, metal alloys, metal oxides, and ceramics in a reaction solution containing chromium hydroxide ions, and removing the substrate from the reaction solution Manufacturing method.
The method for producing an implant according to claim 5, wherein the chromium hydroxide ion is a chromium hydroxide ion in which an ion valence of a chromium atom is trivalent.
An implant surface treatment method for improving biocompatibility, comprising bringing a reaction solution containing chromium hydroxide ions into contact with an implant.
The implant surface treatment method according to claim 7, wherein the chromium hydroxide ion is a chromium hydroxide ion having a valence of chromium atom of trivalent.
An implant surface treatment agent characterized by being a solution containing chromium hydroxide ions.
The surface treatment agent for an implant according to claim 9, wherein the chromium hydroxide ion is a chromium hydroxide ion having a valence of chromium atom of trivalent.