KR20120101748A - An implant treatment solution and a method using thereof and an implant manufactured thereby - Google Patents

Abstract

The invention microstructure on the surface of the titanium alloy Immobilization threaded implant - relates to a method for, and then treated with bisphosphonates based drug forming a concave-convex structure of the nanostructure, more specifically, (a) generating nanotube TiO ₂ layer Electrolyte solution containing glycerol or ethylene glycol, ammonium fluoride (NH ₄ F) and water (H ₂ O) for the treatment, (b) bisphosphonates based drugs that inhibit osteoclast formation (e.g. ibandronate) , etidronate, pamidronate, alendronate) and a surface treatment method using the above solution.
Titanium alloy orthopedic implant surface-treated using the solution of the present invention is not only provides a favorable surface conditions for bone adhesion by providing a nanotube TiO ₂ layer on the surface to provide a large surface area during implantation of the implant is also a bisphosphonates system Infiltration of the drug into the nanotubes has the effect of further promoting bone adhesion.

Description

Implant surface treatment solution and surface treatment method using the same and implant manufactured by the same {An implant treatment solution and a method using Julia and an implant manufactured}

The present invention relates to an electrolyte solution for forming a nanotube TiO ₂ layer of an implant made of a titanium alloy for spinal fixation, a surface treatment method using the electrolyte solution, and a bisphosphonates-based drug (eg, ibandronate, etidronate, which inhibits osteoclast formation). Pamidronate, alendronate) or a solution containing antibiotics and a surface treatment method using the above solution. More specifically, the nanotube TiO ₂ layer is formed on the surface to provide a large surface area for implant implantation, providing favorable conditions for bone adhesion, as well as infiltrating bisphosphonates-based drugs into the nanotube TiO ₂ layer. It suppresses the production of osteoclasts and has an effect of promoting the bone adhesion of the implant medium.

An implant is a biomedical medical instrument that is embedded in a living body and exerts its desired function. Therefore, implants should be manufactured using biocompatible materials that are very stable against biological tissues, without side effects and without causing chemical and biochemical reactions.They will only be filled with complete bone without any soft tissue intervening between bone and implant after being implanted in vivo. It should have a high bond with the goal. In addition, the implant must be made of a material that requires good mechanical strength because it must not be deformed or destroyed even when repeatedly acting and momentary acting loads are imposed.

In order to satisfy the above conditions, various metals and alloys have been developed as materials for implants. However, when metal implants are embedded in a living body and placed in the body for a long time, metal ions are eluted from the implants by reacting with the tissue fluids or body fluids in the body, and the metal implants in the living body are in contact with the biological tissues and friction occurs relatively. In addition to damage due to abrasion of the weak biological tissues, elution of metal ions due to corrosion causes macrophage of the living body to react, leading to inflammatory cells or giant cells.

For these reasons, metal implants have a problem that cannot satisfy biocompatibility, chemical compatibility, and mechanical compatibility, which are conditions to be used as biomaterials.

In order to solve the above problems, various kinds of bio-ceramic and the like have been developed, but the ceramic material of these parts has a problem that can not be used alone in the manufacture of implants because they are weak to impact and difficult to process.

Currently, the most widely used implant materials are biocompatible titanium and some titanium alloys. Titanium has a low specific gravity and is relatively lighter than other metal materials. However, it can be improved in strength by using alloys of other metals or by proper treatment. It has a very large corrosion resistance. In addition, it has the great advantage that when the bone is embedded in bone (osteointegration) is the most widely used as an implant material at present.

As an implant material, pure titanium is known to have insufficient strength at a site where high stress occurs, and a Ti-6Al-4V alloy has been studied as a substitute material. Ti-6Al-4V alloy is a representative Ti alloy of the α + β type, and is used as a biomaterial for implants, bone fixation plates, and surgery because of its excellent mechanical properties and corrosion resistance, but the toxicity of V added as an alloying element and Al are Alzheimer's disease. Known to be a cause of interest, interest in a new class of alloys with excellent biocompatibility has emerged.

In order to improve the retention force between the implant and bone tissue, screw formation, sand blasting treatment, electrochemical oxidation, etc. are performed, and anodization, plasma spraying, Surface treatments such as alkali treatments and ion implantation are performed.

Recently, the surface of titanium implant material is coated with hydroxyapatite (HA '), a biocompatible calcium phosphate-based ceramic, to inhibit the dissolution of metal ions in the implant and at the same time biocompatible and mechanical Implants with strength have been developed and widely applied as biomedical medical devices in dentistry, orthopedics and maxillofacial surgery.

Plasma spraying is most commonly used as a method of coating HA on an implant. The plasma spraying method is mainly used for coating a ceramic material having a relatively high melting point, and the HA powder is melted with a plasma flame to implant the implant. It is a method of spraying on and forming an HA film layer. However, although the plasma spray method can obtain a porous coating layer having a high free energy, there are problems such as crack formation or deposition of deposited particles at an interface with a lower substrate. In addition, when HA is sprayed by using a plasma spray method, HA powder is vitrified at a high temperature, so that there is a vulnerability of decomposition or resorption after embedding. In addition, since the HA coating layer is not absorbed by osteoclasts in vivo, it is not possible to induce bone reform, so that the implant and the new bone are isolated. Therefore, the existing HA implant is excellent in the initial reactivity, it can be seen that it is not desirable for long-term application in the clinic.

Recently, research on the method of forming the nanotube TiO ₂ layer by anodizing has been actively conducted. This method is a method of electrochemically treating a titanium or titanium alloy in an electrolyte solution to form a dense nanotube TiO ₂ layer having a completely self-aligned form on the surface, thereby obtaining an oxide layer having a uniform thickness regardless of the surface shape. And, by controlling the factors such as voltage and current, electrolyte composition and pH, there are advantages such as being able to control the length and diameter of the nanotubes in a certain range as well as economical.

Bisphosphonates are known to inhibit the production of osteoclasts in vivo, and are currently {1-hydroxy-3- [methyl (pentyl) amino] propane-1,1-diyl} bis (phosphonic acid (ibabdronate), Ethane-1-hydroxy-1,1-bisphosphonate (etidronate), 3-Amino-1-hydroxy-propylidene bisphosphonate (pamidronate), 4-Amino-1-hydroxy-butylidene bisphosphonate (alendronate) The clinical utility of bisphosphonate has been shown to inhibit the formation and dissolution of HA crystals in and out of the skeletal system, but its mechanism of action is not yet clear. Less than% is absorbed, and food is inhibited by the absorption of the drug and is therefore required to be administered on an empty stomach Pamidronate causes gastrointestinal irritation, which cannot be used as an oral drug, and all currently used agents except etidronate This side effect is that once the drug is absorbed into the body, about half of it accumulates in the bone and the rest is excreted in the urine unchanged, and the portion that binds to the bone, which depends on the rate of bone conversion, usually remains for months. Decreased renal function and peptic ulcer disease are mentioned as major contraindications to medicines.

Bisphosphonates are also used to treat hypercalcemia, osteoporosis and ectopic calcification syndrome associated with malignancies. Only alendronate and risedronate have recently been approved for the treatment of osteoporosis and other bisphosphonates are currently under development. In addition, bisphosphonate also has several effects, including inhibition of intestinal calcium transport, inhibition of 1,25 (OH) ₂ D production, inhibition of glycolysis, inhibition of cell growth, and changes in acidic and alkaline phosphatides. Cause Amino acid bisphosphonate, such as alendronate, is known to block farnesyl pyrophosphate synthase, an important enzyme in the mevalonate pathway that appears to be important for osteoclast survival.

Statins that block mevalonate synthesis have been shown to stimulate bone formation in animal studies. Therefore, the mevalonate pathway plays an important role in osteoblast function and is a new goal in drug development.

SUMMARY OF THE INVENTION An object of the present invention is to solve the above-mentioned problems, and to provide an electrolyte solution for surface treatment and a method for treating the surface, which are required to form a nanotube TiO ₂ layer providing a large surface area on the surface of an implant made of a titanium alloy for spinal fixation. will be.

In addition, another object of the present invention is to infiltrate the nanotube structure of bisphosphonates-based drugs that inhibit the formation of osteoclasts when implanted in the living body to have an effect of promoting bone adhesion when implanted.

In order to achieve the above object, the electrolyte solution according to an embodiment of the present invention comprises glycerol (glycerol), ammonium fluoride (NH ₄ F) and water (H ₂ O).

In the electrolyte solution, ammonium fluoride is 0.4 to 2 wt%, and water (H ₂ O) is 10 to 50 wt%.

In addition, the implant surface treatment method according to the present invention, a titanium or titanium alloy as an anode, platinum, tungsten or silver as a cathode glycerol (glycerol); Ammonium fluoride (NH ₄ F); And anodizing step of oxidizing the positive electrode using a solution containing water as an electrolyte; After the anodizing step comprises the step of infiltration of the bisphosphonates-based drug.

Here, the anodizing step is characterized in that in the constant voltage constant current mode to reach a final voltage of 10 to 40 V at a constant current density of 5 to 50 mA / current density and maintained for 5 minutes to 2 hours at the final voltage conditions .

In addition, the titanium alloy used in the anodizing step is characterized in that the Ti-6Al-4V, Ti-6Al-7Nb, Ti-13Nb-13Zr.

In addition, the bisphosphonates-based drug, ibandronate; etidronate, pamidronate, and alendronate.

In addition, the implant according to the present invention, a titanium or titanium alloy as an anode, platinum, tungsten or silver as a cathode glycerol (glycerol); Ammonium fluoride (NH ₄ F); And anodizing step of oxidizing the positive electrode using a solution containing water as an electrolyte; After the anodizing step is formed comprising the step of infiltration of the bisphosphonates-based drug.

By using an electrolyte solution for implant surface treatment containing glycerol (ethyleneol) or ethylene glycol (glycol), ammonium fluoride (NH ₄ F) and water (H ₂ O) as essential components for the production of TiO ₂ nanotubes of the present invention Titanium implants prepared by forming TiO ₂ nanotubes on the surface of titanium implants and infiltrating bisphosphonates-based drugs (eg, ibandronate; etidronate, pamidronate, alendronate) that inhibit osteoclast formation on these produced TiO ₂ nanotubes In addition to inhibiting the production of osteoclasts to promote bone adhesion, the large surface area provided by the nanotube layer is advantageous in promoting stress adhesion and stress distribution, and thus also in increasing the endurance life of the implant.

1A to 1B are photographs of an orthopedic pedicle screw system made of Ti-6Al-4V ELI alloy used in Example 1, and FIG. 1C is a scanning electron micrograph of its screw surface.
2A to 2B are FE-SEM photographs of the screw surface of Example 1. FIG.
FIG. 3 shows the release amount of ibandronate on the surface of five Ti-6Al-4V ELI alloy plates treated with ibandronate after the formation of the anodized nanotube TiO ₂ layer.
Figure 4a is a scanning electron micrograph of the surface of the implant specimen of Example 2, Figure 4b is a FE-SEM picture of the magnified observation of the screw thread of part A, Figure 4c is a FE-SEM picture of the B portion enlarged observation. .
5A to 5B are photographs observing the shape of the nanotubes produced after anodizing the implant specimen of Example 2. FIG.
6 is a result of measuring the removal torque after embedding the specimens of the spray treatment control group and the drug treatment group of Example 2 in both tibia of each rat for 4 weeks.
7 is a photograph of the implant surface removed after measurement of the removal torque by FE-SEM.

In order to achieve the above object, the present invention (a) glycerol (glycerol) or ethylene glycol (glycol); (b) providing an electrolyte solution for surface treatment necessary for forming a nanotube TiO ₂ layer containing ammonium fluoride (NH ₄ F) and water (H ₂ O).

The present invention also provides an anodic oxidation step of forming a nanotube TiO ₂ layer by (a) oxidizing the anode using a titanium alloy as an anode, platinum or silver as a cathode, and the solution as an electrolyte; And (b) infiltrating bisphosphonates-based drugs into the TiO ₂ nanotube structure formed in the anodization step.

Hereinafter, the present invention will be described in more detail.

Electrolyte solution for forming a nanotube TiO ₂ layer on the surface of the titanium alloy implant for spinal fixation of the present invention is (a) glycerol (glycerol) or ethylene glycol (glycol), (b) ammonium fluoride (NH ₄ F) and (c ) Contains water (H ₂ O) as an essential ingredient.

In this case, the concentration of ammonium fluoride (b) is preferably 0.3 to 3 wt%, and the amount of water (c) is preferably 10 to 30 wt%. If the concentration of (b) ammonium fluoride is less than 0.3 wt% or more than 3 wt%, the nanotube structure becomes incomplete. If the amount of the water (c) is less than 3 wt% or more than 50 wt%, the length of the nanotubes formed on the implant surface may be too long, resulting in damage during preparation and placement of the implant.

In the present invention, the TiO ₂ nanotube structure is treated with a solution of bisphosphonates to promote bone adhesion in a manner of inhibiting osteoclast formation.

The present invention also provides a method for treating the surface of the implant using the above solution. The method will be described in detail below.

In the implant surface treatment method of the present invention, a glycerol solution containing ammonium fluoride and water is used as an electrolyte solution, and a titanium alloy is an anode, and the cathode is platinum, tungsten or silver for 10 minutes to 2 hours. It is a method of forming a nanotube TiO ₂ layer on the surface of the implant by a chemical reaction.

First, when a titanium alloy is used as an anode and platinum, tungsten or silver is used as a cathode, a constant voltage or pulsed constant voltage is flowed in the electrolyte solution under constant current conditions to form a thin oxide layer having a thickness corresponding to an applied voltage.

Subsequently, the surface is activated by the decomposition of fluorine ions released from the soluble fluorine compound contained in the electrolyte solution, thereby generating a large number of pores and increasing the current slightly. Growing into nanotubes that form a regular array at equilibrium.

The reaction condition of this anodization step is performed in the constant voltage constant current mode, and reaches a final voltage of 10 to 50 V at a constant current density of 5 to 50 mA / cm 2, and is maintained for 10 minutes to 2 hours at the final voltage condition. .

At this time, the alloy uses a titanium alloy capable of high-strength anodization, and titanium alloys include Ti-6Al-4V, Ti-6Al-7Nb, and Ti-13Nb-13Zr.

In the case of anodizing according to the above conditions, the titanium-fluorine-based compound generated during dissolution of TiO ₂ by fluorine remains in the nanotube structure, and the TiO ₂ layer formed by anodizing has an amorphous structure. Therefore, heat treatment is performed for 30 minutes to 2 hours at 300-600 ℃ to remove impurities and to crystallize into anatase structure.

In addition, bisphosphonates-based drugs having the effect of inhibiting the production of osteoclasts are diluted at low concentrations and then surface-treated by repeating deposition and drying for a short time or by dipping and drying for 24 hours.

Hereinafter, preferred examples and comparative examples of the present invention are described. The following examples and comparative examples are described for the purpose of more clearly expressing the present invention, but the contents of the present invention are not limited to the following examples and comparative examples.

(Example 1)

Made of Ti-6Al-4V ELI alloy, 6.5 mm in diameter and 45 mm in length, 3 orthopedic pedicle screw systems (Medyssey, Korea) and 10 mm x 10 mm in length and 1 mm thick Ti-6Al-4V ELI alloy Five plates were prepared. Three pedicle screw systems were used as the untreated, anodized, and drug-treated groups, respectively, and five plates were used to measure drug release. Specimens of anodized and drug treated groups were pickled by dipping for 10 seconds in a solution containing 12: 7: 81 HNO3: HF: H2O.

A pedicle screw system and a platinum plate were connected to the anode and cathode of the DC electrostatic source device for anodizing. The two electrodes were placed in the electrolyte so as to face each other at a position about 20 apart, and then a pulsed DC power supply having a period of 0.01 and a voltage of 20 V was applied for 60 minutes at a current density of 20 mA /. The electrolyte solution was prepared by mixing 20 wt% tertiary distilled water and 1 wt% NH ₄ F in a glycerol solution. Anodizing gave a nanotube TiO ₂ layer and dried at 50 for 1 day.

In the drug treatment group, the anodized specimens were heat-treated in 500 electric furnaces for 2 hours, and then immersed in 10 ml of a solution containing 1 ug / ml of ibandronate for 24 hours and stored in a dryer at 50 ° C. for 24 hours.

Surface observation of each test group specimen was observed by a field emission scanning electron microscope (FE-SEM, S800, Hitachi, Japan).

Psalm Shape

A photograph of the spinal fixation screw implant-free group is shown in FIG. 1.

Anodization  Nanotube TiO ₂  Morphological Microstructure of Layers

FIG. 2A is a FE-SEM photograph of the surface of the thread of the anodization group x 50 times, and FIG. 2b is a FE-SEM image of the surface A point x 200,000 times. On the surface of the thread, the nanotubes have a dense self-alignment form in which the smaller diameter tubes are formed in the space between the larger diameter tubes, and the average of the large and small diameter tubes is 132.4 ± 10.5, respectively. nm and 75.5 ± 9.5 nm.

Drug Release Characteristics

FIG. 3 shows the formation of anodized TiO ₂ nanotubes on a Ti-6Al-4V ELI alloy plate of 10 nm × 10 nm × 1 nm, heat treatment at 500 ° C., and immersion in ibandronate solution for 24 hours, followed by release in analogous fluid. The release of ibandronate showed more than 400 ng / ml over 4 days, but then drastically decreased over 2 days.

(Example 2)

Fourteen titanium implants made of Ti-6Al-4V ELI alloy, which were sprayed with a diameter of 2 mm and a length of 5 mm, were prepared. The spray treatment was performed at 4 atmospheres by mixing bioabsorbable HA powder (MCD powder, Hi-Med, USA) so that the ratio of the average particle diameter of 100-150 um and 90 um or less is 50/50 wt%. The surface was then pickled with 20% HNO 3 aqueous solution for 10 minutes, and then ultrasonically washed for 5 minutes in acetone and alcohol solution, followed by deionized water. The surface of the specimen prepared for anodizing was immersed in a solution mixed with HNO ₃ : HF: H ₂ O at 12: 7: 81 for 10 seconds and pickled. One group was randomly divided into two groups, and one group was used as a control group in an untreated state, and the other group was used as an experimental group by treating with ibandronate after anodization and heat treatment.

For the anodization, the implant and the platinum plate were respectively connected to the anode and the cathode of the DC electrostatic source device. The two electrodes were placed in the electrolyte so as to face each other at a position about 20 mm apart, and then a pulsed DC power source having a period of 0.01 ms and a voltage of 20 V was applied for 60 minutes under a current density condition of 20 mA / cm 2. The electrolyte solution was prepared by mixing 20 wt% tertiary distilled water and 1 wt% NH ₄ F in a glycerol solution.

For the heat treatment of the implant specimens, the anodized nanotube TiO ₂ layer was dried for 1 day at 50 and then heat-treated for 2 hours in an electric furnace of 500 ℃.

Implant specimens were immersed in 10 ml of a solution containing 1 mg / ml ibandronate for 24 hours for drug treatment, and then stored for 24 hours in a 50 ℃ dryer for drying and then used for feeding.

Fourteen specimens from the prepared control and drug treatment groups were embedded one by one in the distal side of both tibia diaphysis of 7 rats, and digital torque gauges with precision of 0.1 Ncm (9810P, Aikoh Engineering Co, Japan) was used to measure the removal torque. After removal of the implant, the surface condition was analyzed by FE-SEM and EDS.

Implant Specimen Geometry

The shape of the implant specimen of Example 2 was observed in FE-SEM and is shown in FIG. 4. FIG. 4A is a scanning electron micrograph of the implant specimen of Example 2 observed at 20 ×, and FIG. 4B is a scanning electron micrograph of a 200 × screw observed at the portion A of FIG. 4A, and FIG. 4C is a B of FIG. 4B. Scanning electron microscope photograph of the part observed at × 1,000 times. On the surface of the specimen, high pressure injection of HA powder resulted in slow thread angles and irregular indentation marks.

Anodization  Nanotube TiO ₂  Morphological Microstructure of Layers

Figure 5a is a photograph of the B surface of the thread surface observed in Figure 4b after anodizing the implant specimen of Example 2 by FE-SEM, Figure 5b is the oxide film layer by bending the specimen to observe the shape of the nanotube FE-SEM photographed from the fracture direction after separation and fracture. The nanotubes have a high self-alignment form with a compact structure in which small diameter tubes are formed in the space between the large diameter tubes, and the average is divided into large diameters and small diameters, and the average is 122.9. ± 5.2 nm and average 88.5 ± 9.5 nm. In addition, when viewed in the longitudinal direction, each of the nanotubes formed an independent tube structure and showed an increase in diameter from top to bottom, with an average length of 770.0 ± 24.2 nm.

removal torque  compare

FIG. 6 shows that the injection control and drug treatment groups of Example 2 were each embedded in both tibia rats for 4 weeks, and then the removal torque was measured. As a result, 25.8 Ncm in the drug treatment group and 10.5 Ncm in the injection treatment control group. The drug treated group showed about 2.5 times higher removal torque than the control group.

Of the surface of the removed implant FE - SEM  Photos and EDS  Analysis

7A is a photograph of the surface of the spray treatment control group after the measurement of the removal torque of Example 2 by FE-SEM, and no obvious bone formation was observed on the implant surface. Figure 7b is a photograph of the surface of the drug treatment group by FE-SEM, the bone was closely attached to the implant surface was observed.

As shown in Table 1, as a result of EDS analysis, the peaks of calcium (Ca) and phosphorus (P) deposited on the surface of the drug treatment group were higher than those of the injection control group.

Element \ test group Spray treatment control Drug treatment group        Ti 61.8 0.5         O 25.3 42.9         C 6.7 27.9        Cl 0.3 -       Mg - 0.3       Ca 3.8 18.5         P 2.0 9.9

Claims (8)

Electrolyte solution for implant surface treatment comprising glycerol, ammonium fluoride (NH ₄ F) and water (H ₂ O). The electrolyte solution for implant surface treatment of claim 1, wherein the ammonium fluoride is 0.4 to 2 wt% and the water (H ₂ O) is 10 to 50 wt%. An implant surface treatment method comprising oxidizing an anode using a titanium or a titanium alloy as an anode and platinum, tungsten or silver as a cathode, and using the solution according to claim 1 or 2 as an electrolyte. The method of claim 3,
The anodizing step is an implant, characterized in that the constant voltage in the constant voltage constant current mode to reach a final voltage of 10 to 40 V at a constant current density of 5 to 50 mA / ㎠ and maintained for 5 minutes to 2 hours at the final voltage conditions Surface treatment method. The method of claim 4, wherein
The titanium alloy used in the anodizing step is Ti-6Al-4V, Ti-6Al-7Nb or Ti-13Nb-13Zr. The method of claim 3,
And implanting the bisphosphonates-based drug after the anodizing step. The method of claim 6, wherein the bisphosphonates-based drug is ibandronate, etidronate, pamidronate or alendronate. An implant surface-treated according to any one of claims 3 to 7.

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