KR20160062782A

KR20160062782A - Bone fracture region-specific implant and method for preparing the same

Info

Publication number: KR20160062782A
Application number: KR1020140165154A
Authority: KR
Inventors: 박형호; 김가람; 이해범
Original assignee: 주식회사 비에스코렘
Priority date: 2014-11-25
Filing date: 2014-11-25
Publication date: 2016-06-03

Abstract

The present invention relates to a bone fracture region-specific implant which is surface-improved by using a medicine such as N-acetylcystein (NAC), and a method of preparing the same. More particularly, the present invention relates to a bone fracture region-specific implant which is surface-improved by using a medicine delivery material such as a gold nano particle (GNP), and a method of preparing the same. According to the present invention, a bone fracture region-specific implant has an implant surface coated with medicine such as NAC so that the bone fracture region is effectively prevented from being inflamed, thereby increasing the bone formation to reduce a healing period and enable self-healing. In addition, the implant surface is coated with GNP so that high synostosis between a bone fracture region and the implant is obtained. When the implant is coupled with various medicines having high synostosis such as antioxidant, anti-inflammatory, synostosis drugs and the like, a high medicine delivery effect may be obtained.

Description

TECHNICAL FIELD [0001] The present invention relates to a bone-fracture region-specific implant and a method of manufacturing the same,

The present invention relates to a customized implant with a surface modified with drugs, particularly N-acetylcysteine (NAC), and a method for manufacturing the same.

The present invention also relates to a drug delivery system, in particular, a surface-modified fracture site-customized implant with gold nanoparticles (GNP) and a method for manufacturing the same.

Implant is a biomedical medical device which is implanted in vivo and exhibits a desired function. Therefore, the implants must have mechanical strength to withstand repeated loads and transient pressures, as well as meet biocompatibility and chemical compatibility. Generally, titanium and its alloys having excellent chemical and mechanical properties have been most widely used as implant materials. However, titanium lacks bioactivity to induce osteogenesis positively, resulting in a long period of healing, an inflammatory response, and a low success rate at sites with poor bone quality.

In order to solve these problems, various surface modification methods have been studied as titanium surface characteristics have become important. Recently, a variety of chemical and physical surface treatment methods have been applied, such as coating phosphoric acid or calcium phosphate on the surface of the implant material or forming nanotubes through anodic oxidation to impart bioactivity. Further, after implantation, attempts have been made to bond bone formation proteins such as synthetic peptides or BMPs to the implant material or inject them into the periphery of the implant to suppress inflammation and promote bone formation and bone tissue reaction. However, such bone formation-inducing proteins are very expensive, and there is a problem of immobilization techniques such as loss of bioactive material bound to the surface during implantation. In addition, It is a problem that short-term, one-time consumption is not continuous.

Therefore, there is a desperate need for a research on an implant for surface-modified fracture and dancing for effectively solving such a problem, effectively suppressing the inflammation accompanying the fracture site in the implant treatment, and inducing bone formation.

KR 10-2007-0061993

The inventors of the present invention have confirmed that when a drug, particularly N-acetylcysteine (NAC), is coated on the surface of an implant, inflammation at a fracture site is effectively inhibited and bone formation is promoted while searching for a fracture site-customized implant, . In addition, when the drug carrier, especially the gold nanoparticle (GNP), is coated on the surface of the implant, it exhibits a high bone-binding ability with the fracture site and is coated with various drugs such as antioxidant, anti- And thus, the present invention has been completed.

Accordingly, the present invention provides a fracture-site-customized implant that is surface-modified with drugs, particularly N-acetylcysteine (NAC), and a method for producing the same.

In addition, the present invention provides a drug delivery system, particularly, a fracture-portion-customized implant surface-modified with gold nanoparticles (GNP) and a method of manufacturing the implant.

In order to achieve the above object,

The present invention

A titanium dioxide (TiO ₂ ) nanotube layer formed on the implant surface; And

And a drug or drug delivery system coated on the nanotube layer.

In addition,

(1) forming a titanium dioxide (TiO ₂ ) nanotube layer on the surface of the implant;

(2) heat treating the implant having the nanotube layer formed therein; And

(3) coating a drug or a drug delivery system on the surface of the heat-treated implant.

Hereinafter, the present invention will be described in detail.

The present invention relates to a titanium dioxide (TiO ₂ ) nanotube layer formed on an implant surface; And a drug or drug delivery system coated on the nanotube layer.

In addition,

(1) forming a titanium dioxide (TiO ₂ ) nanotube layer on the surface of the implant; (2) heat treating the implant having the nanotube layer formed therein; And (3) coating a drug or a drug delivery system on the surface of the heat-treated implant.

In the step (1), a titanium dioxide (TiO ₂ ) nanotube layer is formed on the surface of the implant, and the titanium dioxide (TiO ₂ ) nanotube layer is formed by anodizing titanium or a titanium alloy. The thin oxide layer formed on the titanium surface serves to prevent elution and corrosion of metal ions after implantation into the body, and is in contact with the bone tissue, thereby contributing to the biocompatibility of the titanium implant.

The titanium alloy preferably includes at least one selected from the group consisting of aluminum, tantalum, niobium, vanadium, zirconium, platinum, magnesium, and sodium and the titanium.

The step (2) is a step of heat-treating the implant having the nanotube layer formed therein. The heat treatment is preferably performed at 400 to 600 ° C for 1 to 3 hours at a heating rate of 3 to 7 ° C / min, / min at 500 DEG C for 2 hours. Through the heat treatment, the titanium dioxide nanotube layer is structurally stabilized, crystallized, and removed.

The step (3) is a step of coating a drug or a drug delivery system on the surface of the heat-treated implant.

The titanium or titanium alloy used as the implant material has a disadvantage in that it can not actively induce bone formation due to lack of bioactivity, and has a long healing period and a low success rate in a region having poor bone quality. Therefore, it is possible to increase the success rate of implants by increasing the initial binding of the osteoblasts and surrounding tissues in contact with the surface of the implants by coating a drug having antioxidant, anti-inflammatory function or enhancing bone formation.

The drug may be any drug that is effective for improving biocompatibility and bone formation related to antioxidation, antiinflammation, antisstress, antiapoptosis, thrombolysis, etc. However, N-acetylcysteine (NAC) according to an embodiment of the present invention may be used, .

The drug delivery system may be a mediator for delivering a drug to a target site, such as gold nanoparticles (GNP), silver nanoparticles, magnetic nanoparticles, etc. Preferably, the drug delivery system is biodegradable, Gold nanoparticles. The magnetic nanoparticles are magnetic metal nanoparticles having magnetism, such as iron oxide (Fe ₂ O ₃ , Fe ₃ O ₄ ), ferrite (CoFe ₂ O ₄ , MnFe ₂ O _4, etc.), and alloys (FePt, CoPt) But are not limited thereto.

The drug delivery vehicle may sustain release of the delivering drug. The drug delivery system according to the present invention can deliver the drug into the body by binding the drug with the drug delivery system, and at the same time, has the sustained release characteristics of the drug in the body, thereby providing considerable therapeutic convenience to patients in the future.

The coating of the drug or drug delivery vehicle may be performed by immersing and drying the implant having the nanotube layer formed in the solution of the drug or the drug delivery system 2 to 4 times or by applying the drug or the drug carrier onto the surface of the nanotube layer, Lt; / RTI > for 20 to 30 hours.

The implant according to the present invention has a high average torque value of 6 to 9 Ncm when it is placed in the femoral region of a rat and then removed, and has an antioxidant activity, anti-inflammatory activity, or osteogenic activity .

The implant according to the present invention has the effect of effectively inhibiting the inflammation at the fracture site by coating a drug, particularly N-acetylcysteine (NAC) on the surface of the implant, and promoting bone formation and shortening the healing period. In addition, drug carriers, especially gold nanoparticles (GNP), are combined with various drugs such as antioxidants, anti-inflammation, and bone formation and coated on the surface of implants, .

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows (a) the UV spectrum of gold nanoparticles (GNP) and (b) the release of GNP from the implant surface.
FIG. 2 shows (a) N-acetylcysteine (NAC) coated on the surface of an implant with nanotubes formed according to Example 2, and gold nanoparticles coated on the surface of an implant having nanotubes formed according to Example 3 GNP) and (c) cross-sectional structures thereof were observed with an electric field-scanning electron microscope (FE-SEM), respectively.
FIG. 3 is a graph showing the results of implantation of nanotubes (Ti-6Al-4V) according to Example 1, implants surface-modified with N-acetylcysteine (NAC) according to Example 2, and gold nanoparticles ) Was measured 4 weeks after placing the implant on the thigh of the rats and the average torque value when the implant was removed.
FIG. 4 shows (a) Implant (Ti-6Al-4V) with nanotubes formed according to Example 1, (b) Implant surface-modified with N-acetylcysteine (NAC) according to Example 2, and After implantation of gold nanoparticles (GNP) according to Example 3 into the femur of each rat, the implant was rinsed with ultrasonic waves after 4 weeks, and the bone remaining on the surface of the implant was scanned using an electric field-scanning electron microscope FE-SEM).

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the examples.

Example 1. Nanotube anodization

First, a titanium alloy (Ti-6Al-4V) by the implant specimen (1.9mm diameter × length 3mm) prepared the following, a direct current power supply for the titanium dioxide (TiO ₂₎ the creation of nanotubes layer on the sample device (DADP- 1003R, Dow NanoTech, Korea), and a titanium plate and a titanium plate were connected to the positive electrode and the negative electrode, respectively, and a DC voltage of 20 V and a current density of 30 mA / cm ² was applied for 1 hour. The electrolytic solution was mixed with glycerol containing 20 wt% H ₂ O and 1 wt% NH ₄ F.

After the anodizing treatment, the surface of the specimen was washed with tertiary distilled water and then stored in a dryer maintained at 50 ° C for more than 24 hours. The titanium dioxide nanotube layer formed on the surface of the specimen was maintained at 500 DEG C for 2 hours at a rate of 5 DEG C / min for structural stabilization, crystallization and removal of impurities.

Example 2. NAC coating on the surface of a nanotube-formed implant

N-acetylcysteine (NAC) was dissolved in sterilized distilled water to prepare an N-acetylcysteine solution. Thereafter, the implant specimen having the nanotube layer prepared in the above Example 1 was immersed in an N-acetylcysteine (NAC) solution, maintained at room temperature for 24 hours in a vacuum atmosphere, By drying, the NAC was coated on the implant surface.

Example 3 GNP coating on the surface of a nanotube-formed implant

First, chitosan was dissolved in acetic acid to adjust the pH to 5.5. (2) L-NAC, EDC, and NHS were added to modify the chitosan with a positive charge. (3) HAuCl ₄ and NaBH were added and agitated for 3 hours or longer to prepare a gold nanoparticle (GNP) solution. Thereafter, the titanium implant specimen having the titanium dioxide nanotube layer prepared in Example 1 was immersed in a gold nanoparticle (GNP) solution, maintained at room temperature for 24 hours under a vacuum atmosphere, and dried with nitrogen to obtain gold nanoparticles Was coated on the surface of the implant.

EXPERIMENTAL EXAMPLE 1. EXPERIMENTAL EXPERIMENT OF GNP EXPOSURE ON IMPLANT

The release of gold nanoparticles (GNP) from the implant surface was measured indirectly using a UV-VIS spectrophotometer (Jasco V-630, Japan). First, 2.5, 5.0, and 10 uL of GNP were dissolved in 1 mL of distilled water and UV was measured. Then, 10 uL of GNP was coated on the titanium surface with the nanotubes layer, and the release experiment of GNP from the implant surface was performed in distilled water overnight. The concentration of GNP was calculated against the known concentration of GNP. The results are shown in Fig.

As shown in Fig. 1 (a), the GNP exhibited the largest peak at about 520 nm, and the larger the GNP concentration, the greater the peak intensity.

Further, as shown in Fig. 1 (b), it was confirmed that about 70% of the GNP emission was emitted from the surface on which the nanotubes were formed within one hour of the measurement. However, the remaining 30% was found to be released slowly over a long period of time.

Experimental Example 2. SEM Measurement Results of Surface Modified Implant

(a) gold nanoparticles (GNP) coated on an implant surface formed with N-acetylcysteine (NAC) coated on the surface of an implant with nanotubes according to Example 2 and (b) c) and their cross-sectional structures were observed with an electric field-scanning electron microscope (FE-SEM), respectively, and the results are shown in Fig.

As shown in Figs. 2 (a) to 2 (c), it can be seen that N-acetylcysteine (NAC) and gold nanoparticles (GNP) formed a thin film on the surface of the nanotubular implant, It can be confirmed that it is also mounted inside the tube.

Experimental Example 3 Measurement of torque value, SEM and EDS of the implanted implant after placement in the thigh of a mouse

(b) an implant surface-modified with N-acetylcysteine (NAC) according to Example 2, and (c) an implant surface-modified with N-acetylcysteine (NAC) 4 weeks after implantation of gold-nanoparticle (GNP) surface-modified implants in 7-week-old rats, the torque required to remove them was measured, and the results are shown in FIG. .

As shown in Figs. 3 (a) to 3 (c), the NAC coating treatment group and the GNP coating treatment group showed torque values of 8.6 cN.m and 6.7 cN.m respectively, And 330% and 260%, respectively, as compared with 2.6 cN · m of the bone. This suggests that NAC has a remarkable anti-inflammatory function, and thus it is believed that it has enhanced the contact force with the bone by suppressing the surrounding inflammation. In addition, the GNP exhibits a higher bone-binding ability than the untreated group (Ti-6Al-4V), and thus exhibits excellent drug delivery effect at the site of implantation when it is coated with various drugs such as anti-inflammation, bone formation, .

(b) an implant surface-modified with N-acetylcysteine (NAC) according to Example 2, and (c) an implant according to Example 3, Implants that were surface-modified with gold nanoparticles (GNP) were removed by ultrasonography after 4 weeks of implantation at 7 weeks of age in rats, respectively. The bone remaining on the surface of the implants was examined by field-scanning electron microscopy (FE- SEM). The results are shown in FIG. 4 and analyzed by energy dispersion analysis (EDS).

division Ti-6Al-4V GNP NAC Elmt. wt% at% wt% at% wt% at% O 8.84 22.49 42.56 67.21 46.18 69.49 P 0.06 0.07 5.50 4.48 7.88 6.12 Ca 0.09 0.09 8.85 5.58 13.15 7.90 Ti 91.02 77.35 43.09 22.73 32.80 16.49 Total 100 100 100 100 100 100

As shown in FIG. 4 and Table 1, the NAC-coated group and the GNP-coated group show Ca / P ratios of 1.6 and 1.67, respectively, indicating that the attached bone is a natural bone separated from the implantation site.

Ca and P of the untreated group (Ti-6Al-4V) were 0.09 wt.% And 0.06 wt.%, Respectively, indicating that there was almost no residual bone on the surface of the implant. However, Ca and P in the NAC-treated group were 13.15 wt% and 7.88 wt%, respectively, and GNP-coated group showed 8.85 wt% and 5.50 wt%, respectively. You can see many goals. This result is also consistent with the torque value measurement result.

According to the above results, when the NAC for the purpose of inhibiting inflammation is coated on the surface of the implant, the contact of the bone with the bone is improved by suppressing the surrounding inflammation at the implant site, and the GNP having the drug delivery function is coated on the surface of the implant It is expected to exhibit an excellent drug delivery effect at the site of implantation by coating with various drugs such as anti-inflammation, osteogenesis, and antioxidation.

Claims

A titanium dioxide (TiO ₂ ) nanotube layer formed on the implant surface; And
And a drug or drug delivery system coated on the nanotube layer.

The method according to claim 1,
The titanium dioxide (TiO ₂₎ nanotube layer, the fracture site customized implant, characterized in that the positive electrode is formed by oxidizing the titanium or titanium alloy.

3. The method of claim 2,
Wherein the titanium alloy comprises at least one selected from the group consisting of aluminum, tantalum, niobium, vanadium, zirconium, platinum, magnesium and sodium, and titanium.

The method according to claim 1,
The drug is at least one selected from the group consisting of an antioxidant agent, an anti-inflammatory agent, an anti-apoptotic agent, a clot-dissolving agent and a bone-forming agent A customized implant at the fracture site.

The method according to claim 1,
Wherein the drug is N-acetylcysteine (NAC).

The method according to claim 1,
Wherein the drug delivery system is gold nanoparticles (GNP), silver nanoparticles, or magnetic nanoparticles.

The method according to claim 1,
Wherein the drug delivery device emits a drug to be delivered.

The method according to claim 1,
Wherein the coating of the drug or drug delivery system is performed by applying a drug or a drug delivery vehicle onto the surface of the implant having the nanotube layer formed thereon, and then immersing and drying the implantation for 20 to 30 hours in a vacuum atmosphere.

The method according to claim 1,
Wherein the implant adapted to the fracture site has a high average torque value of 6 to 9 cNm when the implant is placed in the femoral region of the rat and then removed.

(1) forming a titanium dioxide (TiO ₂ ) nanotube layer on the surface of the implant;
(2) heat treating the implant having the nanotube layer formed therein; And
(3) coating a drug or drug delivery vehicle on the surface of the heat-treated implant.

[Claim 11] The method according to claim 10, wherein the heat treatment is performed at 400 to 600 DEG C for 1 to 3 hours at a temperature raising rate of 3 to 7 DEG C / min.