JP5026004B2 - Titanium implant material containing phosphorylated saccharide - Google Patents
Titanium implant material containing phosphorylated saccharide Download PDFInfo
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Description
本発明は、リン酸化糖を塗膜したチタンインプラント材ならびにその製造法に関する。 The present invention relates to a titanium implant material coated with phosphorylated sugar and a method for producing the same.
自然歯を無くした場合の治療方法の一つに、顎骨に直接人工歯根を植え込み、人工歯根に義歯を取り付ける、いわゆるインプラント治療がある。インプラント治療においてはバクテリアの制御が困難であり、これが原因となって骨吸収や歯周病の発生が大きな問題となっていた。 One of the treatment methods when natural teeth are eliminated is a so-called implant treatment in which an artificial tooth root is implanted directly into the jawbone and a denture is attached to the artificial tooth root. In implant treatment, it is difficult to control bacteria, and this has led to major problems such as bone resorption and periodontal disease.
本発明はインプラントにリン酸化糖を固定し、骨芽細胞の初期結着性を高め、さらに骨形成速度を高める。これにより、インプラントが顎骨に早く固定されるとともに、バクテリアの繁殖による骨吸収、歯周病の発生も防ぐことも可能となる。 In the present invention, phosphorylated saccharide is fixed to an implant, the initial binding property of osteoblasts is increased, and the bone formation rate is further increased. As a result, the implant is fastened to the jawbone, and bone resorption and periodontal disease due to bacterial growth can be prevented.
チタンインプラントの治療にいて、バクテリアの感染を防ぐ有効な手段はこれまでなかった。そのため、時間経過とともに、骨吸収が生じ、さらには歯周病にまで発展することも頻発していた。これらはやむを得ず放置するか外科的手段により処理するしかなかった。 In the treatment of titanium implants, there has never been an effective means of preventing bacterial infection. For this reason, bone resorption has occurred over time, and it has frequently developed into periodontal disease. These were unavoidably left or treated by surgical means.
チタンインプラントの表面へ、ビスフォスフォネートを固定する方法も知られているが、この物質は抗生物質であるため人によっては副作用を生じ使用するには危険性があった。
現在インプラント治療では、チタンが多く使用されている。インプラント治療で最も重要なことは使用されているチタンとの生体適合性である。すなわち、骨組織とチタンを早く結合させ、しかも長期にわたり安定に結着し続けることである。さらに、骨芽細胞の働きを活発にさせることで、バクテリアの繁殖を抑制する。つまり、チタン表面と生体の結着を早めることはインプラント治療においてきわめて重要である。 At present, titanium is frequently used in implant treatment. The most important thing in implant treatment is biocompatibility with the titanium used. In other words, the bone tissue and titanium are quickly bonded, and are stably bound for a long time. In addition, it activates osteoblasts to suppress bacterial growth. That is, it is extremely important in implant treatment to accelerate the binding between the titanium surface and the living body.
そこで本発明者は、かかる事情に鑑み鋭意検討した結果、リン酸化糖がインプラントチタンの表面に強力に結着し、さらに骨芽細胞の増殖を促進することでインプラントチタンと生体の適合を早めるとの結論に至った。 Therefore, as a result of intensive studies in view of such circumstances, the present inventor found that phosphorylated saccharide strongly binds to the surface of the implant titanium, and further promotes the proliferation of osteoblasts, thereby accelerating the adaptation of the implant titanium and the living body. The conclusion was reached.
本発明によると塩酸処理したチタンをリン酸化糖溶液に浸漬するとリン酸化糖をチタン表面に強力に結合させることができ、さらに骨とインプラントの表面で骨芽細胞の初期接着性を向上させ骨形成を促進する働きがある。これによりインプラントと骨組織を早く適合させることができる。 According to the present invention, when titanium treated with hydrochloric acid is immersed in a phosphorylated saccharide solution, the phosphorylated saccharide can be strongly bonded to the titanium surface, and further, the initial adhesion of osteoblasts is improved on the surface of the bone and the implant, thereby forming bone. There is a work to promote. As a result, the implant and the bone tissue can be quickly fitted.
さらにリン酸化糖は化学修飾することによって、塩基性繊維芽細胞成長因子などの生理活性物質を結合することができ、より生体適合性を高めることができる。 Furthermore, by chemically modifying phosphorylated saccharide, physiologically active substances such as basic fibroblast growth factor can be bound, and biocompatibility can be further enhanced.
本発明でいうリン酸化糖とはリン酸基を持つ分子量１０,０００以下の糖質であればよく、リン酸基に水素が結合しているか、あるいはカルシウム、マグネシウム、カリウム、亜鉛、銅、鉄、アルミニウム、ニッケルあるいはナトリウム等と結合した塩の形態であってもよい。さらには水素と金属が混在して結合していてもよい。糖質部分は特に制限はないが中性糖であっても酸性糖であっても良い。例えばリン酸基を持つ分子量１０,０００以下としてリン酸化デキストリン、リン酸化デキストラン、リン酸化オリゴ糖、リン酸化セルロース、リン酸化セロビオース、リン酸化ペクチン、リン酸化グルクロン酸、などがある。アルドースであってもケトースであってもよく、炭素数は3個のトリオースから10個のデコースがある。構成糖としては例えばアロースおよびそのリン酸化物、アルトロースおよびそのリン酸化物、グルコースおよびそのリン酸化物、マンノースおよびそのリン酸化物、グロースおよびそのリン酸化物、イドースおよびそのリン酸化物、ガラクトースおよびそのリン酸化物、タロースヘプツロースおよびそのリン酸化物、フルクトースおよびそのリン酸化物、ヘキスロースおよびそのリン酸化物、リボースおよびそのリン酸化物、アラビノースおよびそのリン酸化物、キシロースおよびそのリン酸化物、リキソースおよびそのリン酸化物、タロースおよびそのリン酸化物、ガラクトースおよびそのリン酸化物などがあげられる。構成糖は1種類であっても2種類以上の構成糖によりできている糖質であっても良い。リン酸基の数は糖質の重合度と糖質の種類によるが、リン酸基の比率が極端に高い場合は強い酸性となり、生体に用いるに適さない。またリン酸基の比率が極端に低い場合は効果がない。よって構成糖二個ないし十数個にリン酸基がひとつの割合で結合したリン酸化糖が好適である。なかでも特開平８−１０４６９６記載のグルコースおよびそのリン酸化物から構成されているリン酸化糖はインプラントチタンに強力に結合し、さらに細胞増殖の栄養分ともなりえるため好適に用いることができる。 The phosphorylated saccharide referred to in the present invention may be a saccharide having a phosphate group and a molecular weight of 10,000 or less, and hydrogen is bonded to the phosphate group, or calcium, magnesium, potassium, zinc, copper, iron Further, it may be in the form of a salt combined with aluminum, nickel, sodium or the like. Furthermore, hydrogen and metal may be mixed and bonded. The carbohydrate moiety is not particularly limited, and may be a neutral sugar or an acidic sugar. For example, a phosphoric acid group having a molecular weight of 10,000 or less includes phosphorylated dextrin, phosphorylated dextran, phosphorylated oligosaccharide, phosphorylated cellulose, phosphorylated cellobiose, phosphorylated pectin, phosphorylated glucuronic acid, and the like. It can be aldose or ketose, and there are 10 decourses from 3 triose carbons. Examples of the constituent sugar include allose and its phosphate, altrose and its phosphate, glucose and its phosphate, mannose and its phosphate, growth and its phosphate, idose and its phosphate, galactose and Its phosphate, talose heptulose and its phosphate, fructose and its phosphate, hexulose and its phosphate, ribose and its phosphate, arabinose and its phosphate, xylose and its phosphate, Examples include lyxose and its phosphorus oxide, talose and its phosphorus oxide, galactose and its phosphorus oxide, and the like. The constituent sugar may be one kind or a sugar made of two or more kinds of constituent sugars. The number of phosphate groups depends on the degree of polymerization of the saccharide and the type of saccharide, but if the ratio of phosphate groups is extremely high, it becomes strongly acidic and is not suitable for use in living bodies. Further, when the ratio of phosphate groups is extremely low, there is no effect. Accordingly, a phosphorylated saccharide in which a phosphate group is bonded to two to tens of constituent sugars at a ratio of one is preferable. Among them, the phosphorylated saccharide composed of glucose and its phosphate described in JP-A-8-104696 can be suitably used because it binds strongly to implant titanium and can also serve as a nutrient for cell growth.
本発明のようにリン酸化糖をインプラントチタン表面に固定することが可能となれば、口腔内露出部位インプラント表面での骨形成が盛んとなりインプラントと生体への固定が強固にしかも早く行われることとなる。これにより、石灰化抑制やバクテリアの繁殖による種々の疾病発生も予防できることが期待できる。 If it becomes possible to fix the phosphorylated saccharide to the implant titanium surface as in the present invention, the bone formation on the exposed surface of the oral cavity becomes active, and the fixation to the implant and the living body is performed firmly and quickly. Become. Thereby, it can be expected that various diseases caused by calcification inhibition and bacterial propagation can be prevented.
チタンディスクを１０N塩酸にて３０分間超音波処理後、超純水にて３０分間超音波洗浄した。その後５０mＭに調整したグルコースおよびそのリン酸化物から構成されているリン酸化オリゴ糖（平均分子量８００）の溶液に３７℃、１２時間浸漬し、超純水で１０分間超音波洗浄した。このように処理したチタンディスク表面にはX線光電子分光（XPS）分析によりリン酸化オリゴ糖が固定されていることを確認した。 The titanium disk was subjected to ultrasonic treatment with 10N hydrochloric acid for 30 minutes and then ultrasonically washed with ultrapure water for 30 minutes. Thereafter, it was immersed in a solution of phosphorylated oligosaccharide (average molecular weight 800) composed of glucose and its phosphate adjusted to 50 mM at 37 ° C. for 12 hours, and ultrasonically washed with ultrapure water for 10 minutes. It was confirmed by X-ray photoelectron spectroscopy (XPS) analysis that the phosphorylated oligosaccharide was immobilized on the surface of the titanium disk thus treated.
リン酸化オリゴ糖を結合させたチタンディスク上にマウス骨芽細胞様細胞（MC3T3-E1細胞１．０×１０5）懸濁液を静置し、5％ＣＯ2、３７℃条件下にて３０分間培養した。その後チタンディスクを超純水で洗浄し、非接着培養細胞を除去した後、MTS ASSAY試薬を添加し吸光度を測定することにより表面の細胞数を測定した。リン酸化オリゴ糖処理していないチタンディスクへの接着率は36.4％であったが、リン酸化オリゴ糖処理したチタンディスクへの接着率は62.2％と高い接着率を示した。 A mouse osteoblast-like cell (MC3T3-E1 cell 1.0 × 10 5 ) suspension was allowed to stand on a titanium disk to which phosphorylated oligosaccharide was bound, and the suspension was 30% under 5% CO 2 and 37 ° C. conditions. Incubated for 1 minute. Thereafter, the titanium disk was washed with ultrapure water to remove non-adherent cultured cells, and then the number of cells on the surface was measured by adding MTS ASSAY reagent and measuring the absorbance. Although the adhesion rate to the titanium disc not treated with phosphorylated oligosaccharide was 36.4%, the adhesion rate to the titanium disc treated with phosphorylated oligosaccharide was 62.2%, indicating a high adhesion rate.
チタンディスクを１０N塩酸にて３０分間超音波処理後、超純水にて３０分間超音波洗浄した。その後５０mＭに調整したグルコースおよびそのリン酸化物から構成されているリン酸化デキストリン糖（平均分子量５,０００）の溶液に３７℃、１２時間浸漬し、超純水で１０分間超音波洗浄した。このように処理したチタンディスク表面にはX線光電子分光（XPS）分析によりリン酸化オリゴ糖が固定されていることを確認した。 The titanium disk was subjected to ultrasonic treatment with 10N hydrochloric acid for 30 minutes and then ultrasonically washed with ultrapure water for 30 minutes. Thereafter, it was immersed in a solution of phosphorylated dextrin sugar (average molecular weight: 5,000) composed of glucose and its phosphate adjusted to 50 mM at 37 ° C. for 12 hours, and ultrasonically washed with ultrapure water for 10 minutes. It was confirmed by X-ray photoelectron spectroscopy (XPS) analysis that the phosphorylated oligosaccharide was immobilized on the surface of the titanium disk thus treated.
リン酸化デキストリン（平均分子量５,０００）を結合させたチタンディスク上にマウス骨芽細胞様細胞（MC3T3-E1細胞１．０×１０5）懸濁液を静置し、５％
ＣＯ2、３７℃条件下にて３０分間培養した。その後チタンディスクを超純水で洗浄し、非接着培養細胞を除去した後、MTS ASSAY試薬を添加し吸光度を測定することにより表面の細胞数を測定した。リン酸化デキストリン処理していないチタンディスクへの接着率は32.4％であったが、リン酸化オリゴ糖処理したチタンディスクへの接着率は65.2％と高い接着率を示した。
A mouse osteoblast-like cell (MC3T3-E1 cell 1.0 × 10 5 ) suspension was allowed to stand on a titanium disk bound with phosphorylated dextrin (average molecular weight 5,000), and 5%
Cultivation was performed for 30 minutes under conditions of CO 2 and 37 ° C. Thereafter, the titanium disk was washed with ultrapure water to remove non-adherent cultured cells, and then the number of cells on the surface was measured by adding MTS ASSAY reagent and measuring the absorbance. Although the adhesion rate to the titanium disc not treated with phosphorylated dextrin was 32.4%, the adhesion rate to the titanium disc treated with phosphorylated oligosaccharide was 65.2%, indicating a high adhesion rate.
チタンディスクを１０N塩酸にて３０分間超音波処理後、超純水にて３０分間超音波洗浄した。その後５０mＭに調整したグルコースおよびそのリン酸化物から構成されているリン酸化デキストリン糖（平均分子量１０,０００）の溶液に３７℃、１２時間浸漬し、超純水で１０分間超音波洗浄した。このように処理したチタンディスク表面にはX線光電子分光（XPS）分析によりリン酸化オリゴ糖が固定されていることを確認した。 The titanium disk was subjected to ultrasonic treatment with 10N hydrochloric acid for 30 minutes and then ultrasonically washed with ultrapure water for 30 minutes. Thereafter, it was immersed in a solution of phosphorylated dextrin sugar (average molecular weight 10,000) composed of glucose and its phosphate adjusted to 50 mM at 37 ° C. for 12 hours, and ultrasonically washed with ultrapure water for 10 minutes. It was confirmed by X-ray photoelectron spectroscopy (XPS) analysis that the phosphorylated oligosaccharide was immobilized on the surface of the titanium disk thus treated.
リン酸化デキストリン（平均分子量１０,０００）を結合させたチタンディスク上にマウス骨芽細胞様細胞（MC3T3-E1細胞１．０×１０5）懸濁液を静置し、５％
ＣＯ2、３７℃条件下にて３０分間培養した。その後チタンディスクを超純水で洗浄し、非接着培養細胞を除去した後、MTS ASSAY試薬を添加し吸光度を測定することにより表面の細胞数を測定した。リン酸化デキストリン処理していないチタンディスクへの接着率は30.6％であったが、リン酸化オリゴ糖処理したチタンディスクへの接着率は60.4％と高い接着率を示した。
A mouse osteoblast-like cell (MC3T3-E1 cell 1.0 × 10 5 ) suspension was allowed to stand on a titanium disk bound with phosphorylated dextrin (average molecular weight 10,000), and 5%
Cultivation was performed for 30 minutes under conditions of CO 2 and 37 ° C. Thereafter, the titanium disk was washed with ultrapure water to remove non-adherent cultured cells, and then the number of cells on the surface was measured by adding MTS ASSAY reagent and measuring the absorbance. Although the adhesion rate to the titanium disc not treated with phosphorylated dextrin was 30.6%, the adhesion rate to the titanium disc treated with phosphorylated oligosaccharide was 60.4%, indicating a high adhesion rate.
予め10分間のアセトン浸漬をし、100％エタノールで超音波洗浄を10分間行ったチタンディスクをリン酸化オリゴ糖カルシウム（平均分子量800、5％カルシウム含有）1％溶液、10％ポリリン酸溶液、コントロールとしての脱イオン水にそれぞれ24時間浸漬した。脱イオン水で超音波洗浄を3回した後、このチタンディスクをオートクレーブで滅菌した。
このチタンディスクを細胞培養用24wellプレートに設置（n=6/群)した。ヒト間葉系幹細胞hMSCを10％血清添加培養液中（DMEM,SIGMA)で10000個/wellで播種し、５％
ＣＯ2、３７℃条件下にて12時間培養後それぞれ3％血清添加培養液に変更した。1、2、3日後の細胞増殖をMTS ASSAYにより評価した。3日後のAbsorbance (490nm)の結果はリン酸化オリゴ糖カルシウム群が0.306±0.015、10％ポリリン酸が0.245±0.030、コントロール群が0.229±0.016で、リン酸化オリゴ糖カルシウム群が最も細胞が増殖していた。
Titanium disk immersed in acetone for 10 minutes in advance and ultrasonically cleaned with 100% ethanol for 10 minutes. Phosphorylated oligosaccharide calcium (average molecular weight 800, containing 5% calcium) 1% solution, 10% polyphosphate solution, control Each was immersed in deionized water for 24 hours. After ultrasonic cleaning 3 times with deionized water, the titanium disk was sterilized by autoclave.
This titanium disk was placed in a 24-well plate for cell culture (n = 6 / group). Human mesenchymal stem cells hMSCs are seeded at 10,000 cells / well in 10% serum-supplemented culture medium (DMEM, SIGMA), 5%
After culturing for 12 hours under conditions of CO 2 and 37 ° C., each was changed to a 3% serum-added culture medium. Cell proliferation after 1, 2 and 3 days was evaluated by MTS ASSAY. The results of the Absorbance (490nm) after 3 days were 0.306 ± 0.015 for the phosphorylated oligosaccharide calcium group, 0.245 ± 0.030 for 10% polyphosphoric acid, 0.229 ± 0.016 for the control group, and the cells grew most in the phosphorylated oligosaccharide calcium group. It was.
歯科医療の分野で生体への適合性の高いインプラント材の開発が可能となる。
In the field of dentistry, it is possible to develop an implant material that is highly compatible with a living body.
Claims (2)
A method for producing an oral titanium implant material, comprising a step of coating a part or all of a titanium surface with phosphorylated dextrin .
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| ATE271887T1 (en) * | 2000-12-06 | 2004-08-15 | Astra Tech Ab | MEDICAL PROSTHESES AND IMPLANTS COATED WITH METAL HYDRIDES AND BIOMOLECULES WITH IMPROVED BIOCOMPATIBILITY |
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