JP3965204B1 - Bone regeneration treatment kit - Google Patents
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Abstract
【課題】十分な骨誘導能を発揮すると共に、微細な形状であっても所望の形状に正確に骨を再生することができ、あらゆる箇所の骨再生に適用可能な骨再生用治療キットを提供すること。
【解決手段】リン酸カルシウム系セラミックス等の生体適合性材料及び／又は骨等の生体由来の硬組織からなる骨誘導物と、該骨誘導物を内部に収容するための、骨再生域の形状に適合した形状に成形された骨再生用ケーシングとを備えた骨再生用治療キットである。
【選択図】図１[PROBLEMS] To provide a bone regeneration treatment kit that exhibits sufficient osteoinductive ability and can accurately regenerate a bone in a desired shape even in a fine shape, and can be applied to bone regeneration at any location. To do.
A bone guide consisting of a biocompatible material such as calcium phosphate ceramics and / or a hard tissue derived from a living body such as bone, and a shape of a bone regeneration zone for accommodating the bone guide inside. A bone regeneration treatment kit provided with a bone regeneration casing formed into a shaped shape.
[Selection] Figure 1
Description
本発明は、骨の再生治療に用いられる骨再生用治療キット、並びに骨再生用ケーシング及びその製造方法に関する。 The present invention relates to a bone regeneration treatment kit used for bone regeneration treatment, a bone regeneration casing, and a method for manufacturing the same.
外傷、腫瘍、外科的侵襲等による骨欠損部や、抜歯、義歯の長期装用などによる顎骨萎縮部の骨回復治療としては、これまでは、自家骨移植が最善の方法とされてきた。しかしながら、この自家骨移植は骨採取という二次的侵襲に伴う大きな負担を強いるわりには、移植骨が生着し生きた骨に置換されるころには、回復した骨の量は移植した骨の量よりかなり目減りするという問題があった。 Until now, autologous bone transplantation has been the best method for bone recovery treatment of bone defects due to trauma, tumors, surgical invasion, etc., and tooth atrophy due to tooth extraction and long-term denture wear. However, this autologous bone graft imposes a heavy burden associated with the secondary invasion of bone harvesting, but when the transplanted bone is engrafted and replaced with live bone, the amount of recovered bone is the amount of the transplanted bone. There was a problem that it was considerably less than the amount.
また、骨を用いない方法として、リン酸カルシウム系セラミックスによる人工骨の利用がある。本発明者は、リン酸カルシウム系セラミックスからなる骨誘導能を有する多孔質構造体にわずかな量の微細骨粉を含浸させることでその骨誘導能を飛躍的に強化させることができることを明らかにしている（特許文献１参照。）。 In addition, as a method not using bone, there is an artificial bone using calcium phosphate ceramics. The present inventor has clarified that the bone inducing ability can be remarkably enhanced by impregnating a porous structure having an osteoinductive ability made of calcium phosphate ceramics with a small amount of fine bone powder ( (See Patent Document 1).
また、上述のような骨や人工骨を用いることなく、骨を再生しようとする考え方もある。組織再生治療において、目的部位をある種の機械的バリアーを用いて物理的に密封し、その部位の組織再生（治癒）を促進しようとするもので、１９５０年代半ばから様々な組織の再建外科治療に検討されている。骨の欠損部の再生や骨の増幅に対しても検討され、その基本的概念は骨形成を期待する解剖学的部位をバリアーメンブレン（遮蔽膜）で封鎖し、他の組織、特に繊維性結合組織細胞がスペース内に侵入形成するのを阻止することで、そのスペース内に骨由来の骨生成細胞を増殖させその結果スペース内に骨形成を誘導させようとするものである（ＧＢＲ：guided bone regeneration）。この種の研究は主として歯科で行われ、かかる遮蔽膜の材質としては、expanded polytetrafluoroethylene（ｅ−ＰＴＦＥ）が最も多く用いられている。 There is also an idea of trying to regenerate a bone without using the above-described bone or artificial bone. In tissue regeneration treatment, a target site is physically sealed using a certain mechanical barrier to promote tissue regeneration (healing) at the site. Reconstructive surgical treatment of various tissues since the mid-1950s Has been considered. Bone defect regeneration and bone amplification are also studied, and the basic concept is to seal the anatomical site where bone formation is expected with a barrier membrane (shielding membrane), and to connect other tissues, particularly fibrous bonds By blocking the formation of tissue cells invading into the space, bone-derived bone-forming cells are proliferated in the space, and as a result, bone formation is induced in the space (GBR: guided bone). regeneration). This kind of research is mainly performed in dentistry, and expanded polytetrafluoroethylene (e-PTFE) is most frequently used as the material of the shielding film.
このｅ−ＰＴＦＥ膜は、ＧＯＲＥ−ＴＥＸ（登録商標）として製品化されている。この臨床応用では、３壁性骨欠損など狭い範囲の骨再生には膜のみで有効であるが、比較的広い範囲の骨再生には膜のみでは有効ではなく、膜と骨面の間にブロック状の自家骨又は生体適合性材料を添入する必要がある。この自家骨又は生体適合性材料は膜のスペースリテーナーの役割とともに、より良好な骨再生を期待し用いられている。 This e-PTFE membrane is commercialized as GORE-TEX (registered trademark). In this clinical application, only a membrane is effective for bone regeneration in a narrow range such as a three-wall bone defect, but it is not effective only for a membrane in a relatively wide range of bone regeneration, and a block is formed between the membrane and the bone surface. In the form of self-bone or biocompatible material. This autologous bone or biocompatible material is used with the role of a membrane space retainer and expects better bone regeneration.
さらに、ｅ−ＰＴＦＥ膜と同様な概念で、レーザー照射による小孔を有するチタン薄膜（０．０２ｍｍ厚）が製品化されている（FRIOS Bone Shield）。膜を覆う口腔粘膜が破
れた際の膜のコンタミがｅ−ＰＴＦＥ膜に比べ少ないことが利点として挙げられている。
Further, a titanium thin film (thickness 0.02 mm) having a small hole by laser irradiation has been commercialized with the same concept as the e-PTFE film (FRIOS Bone Shield). It is mentioned as an advantage that the contamination of the membrane when the oral mucosa covering the membrane is broken is less than that of the e-PTFE membrane.
しかしながら、いずれの膜も、望まれる骨再生部位に自家骨又は生体適合性材料を添加後、術中に、それらを十分に覆う程度の大きさ・形態にトリミングし、膜の端部を数箇所ビスで骨面に固定して用いられるものであり、術中に、煩雑かつ正確な作業が要求される。また、いずれの膜の使用も、骨壁のない欠損での垂直方向への大きな骨増大、つまり絶対的挙上に際してはその確実性が低い。さらには、外圧に対しても弱く、付与した形態の術後維持が困難という問題がある。 However, after adding autologous bone or a biocompatible material to the desired bone regeneration site, each membrane is trimmed to a size and shape enough to cover them, and the end of the membrane is screwed in several places. In this case, it is used by being fixed to the bone surface, and a complicated and accurate work is required during the operation. In addition, the use of either membrane is less reliable in the case of large bone growth in the vertical direction in a defect without a bone wall, that is, absolute elevation. Furthermore, there is a problem that it is weak against external pressure and it is difficult to maintain the applied form after surgery.
本発明の課題は、十分な骨誘導能を発揮すると共に、微細な形状であっても所望の形状に正確に骨を再生することができ、あらゆる箇所の骨再生に適用可能となる骨再生用治療キット、並びに骨再生用ケーシング及びその製造方法を提供することにある。 An object of the present invention is a bone regeneration device that exhibits sufficient osteoinductive ability and can accurately regenerate a bone to a desired shape even in a fine shape, and can be applied to bone regeneration at any location. A treatment kit, and a bone regeneration casing and a method for manufacturing the same.
本発明者は、まず、アパタイト等の生体適合性材料からなる多孔質構造体やこれに微細骨粉を含浸させた多孔質構造体の骨誘導能が、そのブロックサイズを小さくすることにより低下するという所見を得た。大きなブロックの塊だけの用途は少ない。この所見は、微細な形状を正確に再生する必要がある部位への適用が困難であり、その用途が制限されることを意味する。本発明者は、さらに鋭意研究した結果、この現象は、多孔質構造体の骨誘導は多核細胞が構造体の気孔壁を構成するアパタイト等の生体適合性材料を貪食する過程で骨芽細胞分化因子を産生し、その濃度が気孔内において一定の閾値に達することで、未分化間葉細胞から骨芽細胞への分化が生ずることによりその端を発するが、小さなブロックや粉砕された顆粒等の場合、産生される骨芽細胞分化因子がブロックや顆粒外に離散しやすく相当域が骨形成の起点になりにくいのが原因ではないかという考えに至った。そこで、本発明者は、骨芽細胞分化因子の離散防止が重要であると考え、細かく粉砕した顆粒状の多孔質構造体を、所望の形状に成形したケーシングに収容し、これを用いて骨再生を試みてみたところ、十分な骨誘導能を発揮することができることを見い出し、本発明を完成するに至った。 The inventor firstly said that the osteoinductive ability of a porous structure made of a biocompatible material such as apatite or a porous structure impregnated with fine bone powder is reduced by reducing the block size. I got a finding. There are only a few large blocks. This finding means that it is difficult to apply to a site where a fine shape needs to be accurately reproduced, and its use is limited. As a result of further diligent research, the present inventor has found that this phenomenon is caused by osteoblast differentiation in the process of bone induction of a porous structure by a multinucleated cell phagocytosing a biocompatible material such as apatite constituting the pore wall of the structure. The factor is produced, and its concentration reaches a certain threshold value in the pores, so that its origin is caused by differentiation from undifferentiated mesenchymal cells to osteoblasts, but small blocks, crushed granules, etc. In some cases, the idea was that the osteoblast differentiation factor produced was likely to be scattered outside the block or granule, and that the corresponding region was less likely to be the origin of bone formation. Therefore, the present inventor considers that it is important to prevent the osteoblast differentiation factor from being dispersed, and the finely pulverized granular porous structure is accommodated in a casing molded into a desired shape, and is used for this. As a result of reproduction, it was found that sufficient osteoinductive ability can be exhibited, and the present invention has been completed.
すなわち本発明は、（１）生体適合性材料及び／又は生体由来の硬組織からなる骨誘導物と、該骨誘導物を内部に収容するための、骨再生域の形状に適合した形状に成形された骨再生用ケーシングと、を備え、前記骨誘導物が、粒径０．１〜３ｍｍの顆粒又は粉末状の骨誘導物であり、前記骨再生用ケーシングが、骨形成後に撤去される剛性を有する熱可塑性樹脂からなるケーシングであって、顎骨の絶対的挙上のために用いられることを特徴とする骨再生用治療キットや、（２）生体適合性材料が、リン酸カルシウム系セラミックスの多孔質構造体であることを特徴とする上記（１）に記載の骨再生用治療キット、に関する。 That is, the present invention is (1) formed into a shape suitable for the shape of a bone regenerative region for accommodating a bone inducer comprising a biocompatible material and / or a hard tissue derived from a living body and the bone inducer therein. A bone regenerator casing , wherein the osteoinductive material is a granular or powdery osteoinductive material having a particle diameter of 0.1 to 3 mm, and the bone regenerative casing is rigidly removed after bone formation A bone regeneration treatment kit characterized in that it is used for absolute elevation of the jawbone, and (2) the biocompatible material is a porous calcium phosphate ceramic. bone regeneration treatment kit according to the above (1), which is a structure relates to.
また本発明は、（３）多孔質構造体の気孔率が３〜９５％であることを特徴とする上記（２）に記載の骨再生用治療キットや、（４）生体由来の硬組織が、骨又は歯であることを特徴とする上記（１）〜（３）のいずれかに記載の骨再生用治療キット、に関する。 The present invention also provides (3) a bone regeneration treatment kit according to (2) above, wherein the porosity of the porous structure is 3 to 95%, and (4) a living tissue-derived hard tissue. The bone regeneration treatment kit according to any one of (1) to (3) above, which is a bone or a tooth .
さらに本発明は、（５）骨又は歯が、生のもの又は脱灰物であることを特徴とする上記（４）に記載の骨再生用治療キットや、（６）骨再生用ケーシングが、骨誘導物導入口及び該骨誘導物導入口を覆う蓋を備えていることを特徴とする上記（１）〜（５）のいずれかに記載の骨再生用治療キットに関する。 Furthermore, the present invention provides (5) the bone regeneration treatment kit according to (4) above, wherein the bone or tooth is raw or decalcified, and (6) the bone regeneration casing, The bone regeneration treatment kit according to any one of the above (1) to (5), comprising a bone induction material introduction port and a lid that covers the bone induction material introduction port .
本発明の骨再生用治療キットは、あらゆる箇所の骨再生に適用可能であり、これを用いることにより、十分な骨誘導能を発揮すると共に微細な形状であっても所望の形状に正確に骨を再生することができる。また、本発明の骨再生用治療キットを用いることにより、簡易かつ確実に治療を行うことができる。 Bone regeneration treatment kit of the present invention is applicable to bone regeneration everywhere, by using this, even fine shape with exhibit sufficient osteoinductive exactly into a desired shape Bone can be regenerated. Further, by using the bone regeneration therapy kit of the present invention can be carried out easily and reliably treatment.
本発明の骨再生用治療キットとしては、生体適合性材料及び／又は生体由来の硬組織からなる骨誘導物と、該骨誘導物を内部に収容するための、骨再生域の形状に適合した形状に成形された骨再生用ケーシングとを備えた治療キットであれば特に制限されるものではなく、本発明の骨再生用治療キットを用いて骨再生治療を行うことにより、骨再生用ケーシングにより骨誘導因子の離散を阻止できるので、比較的小径の顆粒状又は粉末状の骨誘導物を用いる場合にも十分な骨誘導能を発揮することができ、また、微細な形状であっても所望の形状に正確に骨を再生することができる。したがって、あらゆる箇所の骨再生に適用することができる。また、比較的大きなブロック状の骨誘導物の場合には、その骨誘導能をより向上させることができ、機械的強度の低い高気孔率のものを用いることも可能となる。本発明の骨再生用治療キットは、具体的には、インプラントのための顎骨の再生の他、外傷、腫瘍、外科的侵襲等による骨欠損部の再生のために使用することができる。 The bone regeneration treatment kit of the present invention is adapted to the shape of the bone regenerative region for accommodating the bone inducer composed of a biocompatible material and / or a hard tissue derived from a living body and the bone inducer therein. The present invention is not particularly limited as long as it is a treatment kit including a bone regeneration casing molded into a shape. By performing bone regeneration treatment using the bone regeneration treatment kit of the present invention, Since it is possible to prevent the dissemination of osteoinductive factors, sufficient osteoinductive ability can be exhibited even when a relatively small-diameter granular or powdery osteoinduct is used. The bones can be regenerated accurately in the shape of. Therefore, it can be applied to bone regeneration at any location. Further, in the case of a relatively large block-shaped bone inducer, the osteoinductive ability can be further improved, and it is also possible to use a high porosity having a low mechanical strength. Specifically, the bone regeneration treatment kit of the present invention can be used for regeneration of a bone defect due to trauma, tumor, surgical invasion, etc. in addition to regeneration of a jawbone for an implant.
本発明における骨誘導物とは、生体適合性材料からなる骨誘導物、生体由来の硬組織からなる骨誘導物、及びこれらの混合物をいう。本発明における骨誘導物は、顆粒状又は粉末状であり、顆粒状又は粉末状の骨誘導物の粒径としては、０．１〜３ｍｍ程度であり、０．５〜２．５ｍｍであることが好ましい。なお、粒径は、ふるい分け法によって測定したものをいう。 The bone inducer in the present invention refers to a bone inducer made of a biocompatible material, a bone inducer made of a hard tissue derived from a living body, and a mixture thereof. Osteoinductive material in the present invention, the condyles granular or powdered der is, as the particle size of the granular or powdered osteoinductive material is about 0.1 to 3 mm, is 0.5~2.5mm It is preferable. The particle size is measured by a sieving method .
骨誘導物における生体適合性材料としては、セラミックス、金属を挙げることができる。セラミックスとしては、例えば、アパタイト、三リン酸カルシウム等のリン酸カルシウム系セラミックス、炭酸カルシウム系セラミックス、動物の焼成骨を挙げることができ、アパタイトが好ましく、ヒドロキシアパタイトがより好ましい。また、金属としては、例えば、チタン合金を挙げることができる。 Examples of the biocompatible material in the osteoinductive material include ceramics and metals. Examples of ceramics include calcium phosphate ceramics such as apatite and calcium triphosphate, calcium carbonate ceramics, and calcined bones of animals. Apatite is preferable, and hydroxyapatite is more preferable. Moreover, as a metal, a titanium alloy can be mentioned, for example.
生体適合性材料からなる骨誘導物は、骨誘導能を有する多孔質のもの（多孔質構造体）が好ましい。多孔質構造体の気孔率は、３〜９５％程度である。また、多孔質構造体は、表面のみに多孔質構造を有するものであってもよい。本発明の骨再生用治療キットによれば、骨再生用ケーシングによって外圧から保護されるので、機械的強度の低い高気孔率の多孔質構造体を用いることが可能となり、これらの多孔質構造体は骨誘導能が高いことから、骨再生をより促進させ、大量の骨形成量を促すことが可能となる。 The osteoinductive material made of a biocompatible material is preferably a porous material having a bone inducing ability (porous structure). The porosity of the porous structure is about 3 to 95%. Moreover, the porous structure may have a porous structure only on the surface. According to the bone regeneration treatment kit of the present invention, since it is protected from external pressure by the bone regeneration casing, it is possible to use a porous structure having a low porosity and a high porosity, and these porous structures. Because of its high osteoinductive ability, it is possible to further promote bone regeneration and promote a large amount of bone formation.
ブロック状の多孔質構造体の具体的な構造としては、構造体の外部表面とつながる平均孔径５０〜１０００μｍ、好ましくは１００〜５００μｍのマクロな連続気孔を構造体の全体にわたって有するとともに、マクロな気孔相互間に存在する生体適合性材料の全体にマクロな気孔と連続する平均孔径０．００５〜５０μｍのミクロな連続気孔を有し、該マクロな連続気孔は構造体の外部表面１０００μｍ平方の範囲内に少なくとも１つ以上存在し、かつ該ミクロな連続気孔はマクロな気孔相互間に存在する生体適合性材料の表面５０μｍ平方の範囲内に少なくとも１つ以上存在している多孔質構造体や、構造体の外部表面とつながる平均孔径５０〜１０００μｍのマクロな連続気孔を構造体の全体にわたって有するとともに、マクロな気孔相互間に存在する生体適合性材料の表面に大きさおよび深さがそれぞれ平均０．００５〜５０μｍのミクロな陥凹部を表面の５０μｍ平方の範囲内に少なくとも一つ以上有し、該マクロな連続気孔は多孔質構造体の外部表面１０００μｍ平方の範囲内に少なくとも１つ以上存在している多孔質構造体を挙げることができる。このブロック状の多孔質構造体の気孔率としては、３０〜９５％程度であり、４０〜９０％であることが好ましい。本発明におけるケーシングは、ブロック状の多孔質構造体の骨誘導能の発現に対しても有効に作用する。 The specific structure of the block-like porous structure includes macro continuous pores having an average pore diameter of 50 to 1000 μm, preferably 100 to 500 μm connected to the outer surface of the structure over the entire structure. The biocompatible material existing between each other has micro continuous pores having an average pore diameter of 0.005 to 50 μm continuous with macro pores, and the macro continuous pores are within a range of 1000 μm square of the outer surface of the structure. And at least one or more of the micro continuous pores are present in the range of 50 μm square of the surface of the biocompatible material existing between the macro pores. It has macro continuous pores with an average pore diameter of 50 to 1000 μm connected to the outer surface of the body throughout the structure, and between macro pores The surface of the existing biocompatible material has at least one micro recess having an average size and depth of 0.005 to 50 μm in the range of 50 μm square of the surface, and the macro continuous pores are porous. Examples of the porous structure include at least one porous structure within the range of 1000 μm square of the outer surface of the porous structure. The porosity of the block-like porous structure is about 30 to 95%, and preferably 40 to 90%. The casing in the present invention effectively acts on the expression of the osteoinductive ability of the block-like porous structure.
また、顆粒状又は粉末状の多孔質構造体としては、上記焼成したブロック状の多孔質構造体を粉砕したもの、ブロック焼成前のグリーンボデイの段階で細片化し焼成したものを挙げることができる。高気孔率ブロックから作製した顆粒の構造は、基本的にブロックの構造と同様である。しかし、低気孔率ブロックから作製した顆粒では、もともとブロック内にマクロ気孔が少ないこととも関連し、顆粒のほとんどの部分が、平均孔径０．００５〜５０μｍのミクロな連続気孔を構造体の全体にわたって有し、該微細な連続気孔は、構造体の外部表面の５０μｍ平方の範囲内に少なくとも１つ以上存在している多孔質構造である。このような顆粒状又は粉末状の多孔質構造体の気孔率は、３〜４０％程度となる。顆粒状又は粉末状の多孔質構造体がケーシングに収容された場合、顆粒や粉末の相互間隙が比較的広く分布し相当域が骨形成の場となり得るので、気孔率の低い多孔質構造体であっても、効果的な骨誘導物になると考えられる。 Examples of the granular or powdery porous structure include those obtained by pulverizing the fired block-like porous structure and those obtained by pulverizing and firing at the stage of the green body before block firing. . The structure of the granules made from the high porosity block is basically the same as the structure of the block. However, in the granule prepared from the low porosity block, it is related to the fact that the block has few macropores in the block, and most of the granule has micro continuous pores having an average pore diameter of 0.005 to 50 μm over the entire structure. The fine continuous pores have a porous structure in which at least one or more pores exist within a range of 50 μm square of the outer surface of the structure. The porosity of such a granular or powdery porous structure is about 3 to 40%. When a granular or powdery porous structure is housed in a casing, the gap between the granules and powder is relatively wide and a considerable area can be a place for bone formation. Even so, it is considered to be an effective bone inducer.
また、本発明の多孔質構造体は、骨又は歯を微細に粉砕したもの（以下、単に、微細骨粉という。）を含浸していてもよい。微細骨粉のサイズとしては、広範囲にかつ分布密度が高い状態で分散することができ、さらに多孔質構造体の内部にまで容易に含浸させられるサイズであることが好ましい。また、多孔質構造体のマクロな気孔内に含浸された微細骨粉が、破骨細胞やマクロファージによって速やかに吸収されるサイズであり、かつ微細骨粉の一部はマクロな気孔相互間に存在する生体適合性材料の全体もしくは表面に分布するミクロな気孔あるいは陥凹部に入り込み細胞攻撃を避けることができるようなサイズであることが好ましい。具体的には、微細骨粉の粒径は、５０μｍ以下であることが好ましく、サブミクロンサイズを含む２０μｍ以下であることがより好ましい。なお、この粒径は、レーザー回折で測定したものをいう。微細骨粉の調製方法及び多孔質構造体への含浸方法等については、特開２００３−３２００１４号公報に記載の通りである。また、多孔質構造体の骨誘導能の向上を目的に上記微細骨粉の他、適切な細胞増殖・分化因子を添加して用いても良い。 The porous structure of the present invention may be impregnated with finely pulverized bone or teeth (hereinafter simply referred to as fine bone powder). The size of the fine bone powder is preferably a size that can be dispersed in a wide range and with a high distribution density, and can be easily impregnated into the porous structure. In addition, the fine bone powder impregnated in the macroscopic pores of the porous structure is a size that can be rapidly absorbed by osteoclasts and macrophages, and a part of the fine bone powder exists between the macroscopic pores. The size is preferably such that it can enter into microscopic pores or depressions distributed on the whole or surface of the compatible material and avoid cell attack. Specifically, the particle size of the fine bone powder is preferably 50 μm or less, and more preferably 20 μm or less including the submicron size. The particle size is measured by laser diffraction. The method for preparing the fine bone powder and the method for impregnating the porous structure are as described in JP-A-2003-320014. In addition to the fine bone powder, an appropriate cell growth / differentiation factor may be added for the purpose of improving the osteoinductive ability of the porous structure.
骨誘導物における生体由来の硬組織としては、例えば、骨、歯を挙げることができる。骨とは、石灰化している部分の骨のみならず骨髄をも含み、また、生体から直接採取した骨のみならず、幹細胞から組織工学的手法を用いて培養下で作製した骨又は骨様組織をも含む。 Examples of the hard tissue derived from the living body in the bone derivative include bone and teeth. Bone includes not only bones that are calcified but also bone marrow, and bones or bone-like tissues prepared not only from bones directly collected from living bodies, but also from stem cells using tissue engineering techniques in culture. Is also included.
骨としては、ヒトの骨以外にも、ウシなどの哺乳類はもとより魚なども含め脊椎動物全般の広範囲な動物の骨も抗原性の減弱化処理により利用することができるが、ヒトの骨が好ましく、自己由来の骨（自家骨）が最も好ましい。骨の採取部位としては、腸骨、顎骨、脛骨、大腿骨等を挙げることができる。なお、ヒトの骨は、米国等より商業的に入手することができる。自家骨の移植には、活性の高い骨髄を含む海綿骨若しくは海綿骨を含む骨が好ましく、一般的に皮質骨は細胞成分が少ないため移植に適さないが、本発明に用いる骨としては、海綿骨に限られず、皮質骨を用いることもできる。 As bones, in addition to human bones, a wide range of vertebrate bones including mammals such as cows as well as fish can be used by antigenic attenuation treatment, but human bones are preferred. Autologous bone (autologous bone) is most preferred. Examples of bone collection sites include the iliac bone, jawbone, tibia, and femur. Human bone can be obtained commercially from the United States and the like. For transplanting autologous bone, cancellous bone containing highly active bone marrow or bone containing cancellous bone is preferable, and cortical bone is generally not suitable for transplantation because it has few cellular components. Cortical bone can also be used without being limited to bone.
また、歯も骨と同様に、ヒト以外の歯を用いることが可能であり、ヒトの歯が好ましく、自己由来の歯が最も好ましい。 In addition, teeth other than humans can be used as well as bones, human teeth are preferable, and self-derived teeth are most preferable.
また、生体由来の硬組織としての骨及び歯は、生の状態に限られず、脱灰処理（酸処理）を施した脱灰物であってもよい。脱灰処理をすることにより、抗原性を減弱化し、また、基質中の分化増殖因子が活性化すると考えられる。 In addition, bones and teeth as a hard tissue derived from a living body are not limited to a raw state, and may be a decalcified product subjected to a decalcification process (acid treatment). By performing the decalcification treatment, it is considered that antigenicity is attenuated and the differentiation growth factor in the substrate is activated.
本発明における骨誘導物を内部に収容するための、骨再生域の形状に適合した形状に成形された骨再生用ケーシングとしては、熱可塑性樹脂製のものを挙げることができ、熱可塑性樹脂としては、例えば、塩化ビニル樹脂、塩化ビニデン樹脂、酢酸ビニル樹脂、ポリビニルアルコール、ポリビニルアセタール、ポリエチレン、ポリエチレンテレフタレート、ポリプロピレン、メタクリル樹脂、酢酸セルロース樹脂、フタル酸樹脂等やこれらの共重合体を挙げることができる。 Examples of the bone regeneration casing molded into a shape suitable for the shape of the bone regeneration area for accommodating the bone inducer in the present invention include those made of thermoplastic resin, is, for example, vinyl chloride resin, Biniden chloride resins, vinyl acetate resins, polyvinyl alcohol, polyvinyl acetal, polyethylene, polyethylene terephthalate, polypropylene, methacrylic resin, cellulose acetate resin, there may be mentioned phthalic acid resins, and copolymers thereof I can .
本発明における骨再生用ケーシングの形状としては、術前に予め骨再生域の形状に適合するよう成形されたものであり、術中に骨再生域の形状に合わせて調製し被覆する従来のｅ-ＰＴＦＥ膜又はチタン薄膜とは異なる。また、ｅ−ＰＴＦＥ膜やチタン薄膜を用いたＧＢＲの概念は、膜によって確保されたスペ−スを骨再生を阻害するとされる軟組織（粘膜組織）から隔絶することによってスペ−ス内に骨から増殖してくるであろう骨形成を得ようとするものであるのに対し、本発明の骨再生用ケーシングは、本来的に異所性骨形成能（骨誘導能）を有する骨誘導物の充填域内若しくはブロック内で産生される骨誘導因子が軟組織内へ拡散することを阻止することで充填域内若しくはブロック内での骨形成を獲得しようとするものであり、従来のＧＢＲとはその基本的な概念が異なる。また、ＧＢＲは傍骨での利用に限定されるのに対し、本発明は必ずしも傍骨での利用にその用途が制限されず、望まれる解剖学的形態の骨再生を異所性に獲得し、その骨を必要部位に移植することも可能である。また、傍骨においても、本発明の骨再生用ケーシングを用いることにより、ｅ−ＰＴＦＥ膜やチタン薄膜と異なり、骨（顎骨）の絶対的挙上が可能となる。 The shape of the casing for bone regeneration in the present invention is a shape that is preliminarily shaped so as to conform to the shape of the bone regeneration zone before surgery, and is prepared and coated in accordance with the shape of the bone regeneration zone during surgery. Different from PTFE membrane or titanium thin film. Moreover, the concept of GBR using an e-PTFE membrane or a titanium thin film is that the space secured by the membrane is separated from the soft tissue (mucosal tissue) that is supposed to inhibit bone regeneration from the bone in the space. Whereas the bone regeneration casing of the present invention is intended to obtain bone formation that will proliferate, the bone regeneration casing of the present invention is inherently an ectopic bone formation ability (bone induction ability). It is intended to acquire bone formation in the filling area or block by preventing the bone inducing factor produced in the filling area or block from diffusing into the soft tissue. Different concepts. In addition, GBR is limited to use in the parasite, whereas the present invention is not necessarily limited to use in the parasite, and ectopically acquires the desired anatomical form of bone regeneration. It is also possible to transplant the bone to a necessary site. Also, in the parabone, by using the bone regeneration casing of the present invention, unlike the e-PTFE membrane and the titanium thin film, the bone (jaw bone) can be lifted up.
また、ｅ−ＰＴＦＥ膜やチタン薄膜で自家骨や生体適合性材料を併用する場合、骨再生が必要な部位に自家骨若しくは生体適合性材料を添加・充填した後、その形状に合わせて膜を調製して被覆し、膜の端部を数箇所ビスで骨面に固定する術式であるため、術中に、適切な再生形状を考慮し、また、それに必要な移植骨や生体適合性材料の量を確保しなければならない。さらに、膜の固定時に充填域の形態が崩れないようにする配慮が求められる。これに対し、本発明の骨再生用ケーシングは、上記のように、術前に適切な形状に成形しており、術時においては、その良好な適合性や機械的強度の高さから、骨面への固定は１〜２箇所のビス固定で十分であり、場合によっては被覆粘膜の縫合閉鎖のみの固定でも可能である。固定後は、決められた形状の骨再生用ケーシング内に骨誘導物を添入するだけでよい。また、骨再生用ケーシング内に骨誘導物を添入した後に固定してもよい。本発明の骨再生用治療キットでは、骨誘導物の量を予め調整しておくことができるので、過剰な骨誘導物の添加、不十分な添入のリスクは少なく、移植手術をスムーズに行うことができる。また、術者に負担の少ないこの術式は、感染のリスクを低減させるとともに患者への負担を軽減する。 Also, when using autologous bone or biocompatible material together with e-PTFE membrane or titanium thin film, add or fill autologous bone or biocompatible material to the site where bone regeneration is necessary, and then apply the membrane according to the shape. Because it is a method of preparation, coating, and fixing the end of the membrane to the bone surface with several screws, consider the appropriate regenerative shape during the operation, and the necessary bone graft and biocompatible material necessary for it The amount must be secured. Furthermore, consideration is required so that the shape of the filling area does not collapse when the membrane is fixed. On the other hand, the bone regeneration casing of the present invention is molded into an appropriate shape before the operation as described above, and at the time of the operation, because of its good compatibility and high mechanical strength, For fixing to the surface, fixing with one or two screws is sufficient, and in some cases, fixing with only suture closure of the coated mucous membrane is also possible. After fixation, it is only necessary to insert a bone inducer into the bone regeneration casing having a predetermined shape. Moreover, you may fix, after inserting a bone inducement in the casing for bone regeneration. In the bone regeneration treatment kit of the present invention, since the amount of the bone inducer can be adjusted in advance, there is little risk of adding excessive bone inducer and insufficient insertion, and the transplantation operation is performed smoothly. be able to. In addition, this method with a low burden on the operator reduces the risk of infection and reduces the burden on the patient.
また、顎骨再建術に際しての骨誘導物の充填域には、術後、口腔機能に伴う様々な外圧の加わることが想定されるが、本発明の骨再生用ケーシングは用途に応じた機械的強度とすることが可能であるため、骨誘導物の充填域を物理的外圧から保護することができる。すなわち、術時に形態を付与するｅ−ＰＴＦＥ膜やチタン薄膜では、その術時に、添加・充填域に沿って被覆できるようなしなやかさや、人の手で変形できるような柔軟性が求められるため、材質やその厚み等が制限され、骨誘導物の充填域を物理的外圧から保護することができないが、本発明の骨再生用ケーシングは、術前に、予め所望の形状に成形されているので、人の手で変形できないような機械的強度（剛性）を付与することが可能となり、骨誘導物の充填域を物理的外圧から保護することができる。 In addition, it is assumed that various external pressures associated with the oral function are applied after the operation to the filling area of the osteoinductive material at the time of jaw reconstruction, but the bone regeneration casing of the present invention has a mechanical strength according to the application. Therefore, it is possible to protect the filling area of the bone inducer from physical external pressure. In other words, the e-PTFE film or titanium thin film that imparts a form at the time of surgery is required to have flexibility that can be coated along the addition / filling area at the time of surgery, and flexibility that can be deformed by human hands. The material, thickness, etc. are limited, and the filling area of the bone inducer cannot be protected from physical external pressure, but the bone regeneration casing of the present invention is pre-shaped into a desired shape before surgery. It is possible to impart mechanical strength (rigidity) that cannot be deformed by human hands, and to protect the filling area of the osteoinductive material from physical external pressure.
また、例えば、頭蓋骨や顎骨などで比較的大型の架橋的骨再生が求められる際には、骨欠損部形態に一致したブロック状の高気孔率の骨誘導物を用いることが好ましく、このような高気孔率のものは一般に機械的強度が低いという問題があるが、本発明の骨再生用ケーシングを用いることにより、機械的強度を補填することができる。 In addition, for example, when relatively large bridging bone regeneration is required in the skull, jaw bone, etc., it is preferable to use a block-like high-porosity bone inducer that matches the shape of the bone defect part. High porosity materials generally have a problem of low mechanical strength, but mechanical strength can be compensated by using the bone regeneration casing of the present invention.
本発明の骨再生用治療キットにおける骨再生用ケーシングとしては、全面が包囲されたケーシングや、骨と直接接触する一方又は両方の側を開口としたケーシングを挙げることができる。全面が包囲されたケーシングの場合はもちろん、一方又は両方の側を開口としたケーシングにおいても、必要に応じて、ケーシング内への栄養血管進入通路を確保のための小孔を設けることができる。 Examples of the bone regeneration casing in the bone regeneration treatment kit of the present invention include a casing that is entirely surrounded, and a casing that is open on one or both sides in direct contact with the bone. In the case of the casing having the entire surface surrounded, as well as the casing having one or both sides opened, a small hole for securing a feeding blood vessel entry passage into the casing can be provided as necessary.
骨と直接接触する一方の側を開口としたケーシングは、骨欠損部や骨陥凹部等の骨面への添加的傍骨移植に用いることができ、特に顎骨再建術に好ましく用いることができる。骨面への添加的傍骨移植では、骨側からの栄養血管や骨原性細胞をケーシング内に取り込むと共に、骨側への分化因子の離散は少ないと考えられ、また、骨形成後の撤去が困難等の理由から、骨面側は開口として移植域の軟組織側のみを遮断することが好ましい。骨と直接接触する両方の側を開口としたケーシングは、架橋的骨再生に用いることができる。なお、骨と直接接触する側を開口としたケーシングは、後述する顆粒状又は粉末状の骨誘導物の導入口及び該導入口を覆う蓋を備えたケーシングであってもよいが、骨と直接接触する側に設けられた開口から骨誘導物を導入することができるので、骨誘導物導入口を必ずしも設ける必要はない。また、単体のブロック状の骨誘導物を使用する際には、適切な形態に成型したブロック状の骨誘導物に密接させたケーシングを作製することで、導入口を必ずしも必要としない。 A casing having an opening on one side in direct contact with bone can be used for additional parabone grafting on a bone surface such as a bone defect or a bone depression, and can be particularly preferably used for jaw reconstruction. In addition to the parasite transplantation to the bone surface, it is thought that nutritional blood vessels and osteogenic cells from the bone side are taken into the casing, and the differentiation of the differentiation factor to the bone side is small, and removal after bone formation For reasons such as difficulty, it is preferable to block only the soft tissue side of the transplant area as an opening on the bone surface side. A casing with openings on both sides in direct contact with bone can be used for bridging bone regeneration. The casing having an opening on the side in direct contact with the bone may be a casing provided with an inlet for a granular or powdered bone inducer, which will be described later, and a lid that covers the inlet, but directly with the bone. Since the bone inducer can be introduced from the opening provided on the contact side, it is not always necessary to provide the bone inducer introduction port. Further, when using a single block-shaped bone guide, a casing close to the block-shaped bone guide molded into an appropriate shape is not necessarily required.
全面が包囲されたケーシングは異所性に骨再生を要する際に使用される。このケーシングを用い、顆粒状又は粉末状の骨誘導物を使用する場合、骨誘導物導入口及び該導入口を覆う蓋を備えることが好ましい。ブロック状の骨誘導物を使用する際には、上述と同様、導入口を必ずしも必要としない。また、このケーシングでは、栄養血管通路の確保のための小孔を多数設けなければならない。 The casing surrounded by the entire surface is used when bone regeneration is required ectopically. When using this casing and using a granular or powdered bone inducer, it is preferable to provide a bone inducer introduction port and a lid covering the introduction port. When using a block-shaped bone guide, an introduction port is not necessarily required as described above. Further, in this casing, a large number of small holes for securing a nutrient blood vessel passage must be provided.
具体的に、上記骨誘導物導入口は、骨誘導物が導入しやすい大きさ及び形状であることが好ましく、例えば、４〜１５０ｍｍ２、好ましくは４〜１００ｍｍ２とすることができる。骨誘導物導入口及び該導入口を覆う蓋を備えたケーシングの場合、ケーシングを適切な位置に固定した後、骨誘導物導入口からケーシング内に顆粒状の骨誘導物を添入し、蓋でケーシングを閉塞することができる。 Specifically, it is preferable that the bone-derived material introduction port has a size and a shape into which the bone-derived material can be easily introduced, for example, 4 to 150 mm 2 , and preferably 4 to 100 mm 2 . In the case of a casing provided with a bone guide introduction port and a lid covering the feed port, after fixing the casing in an appropriate position, a granular bone guide is inserted into the casing from the bone guide introduction port, and the lid With this, the casing can be closed.
また、栄養血管通路の確保のための小孔は、栄養血管が容易に進入可能なように、例えば、直径１００μｍ〜１．０ｍｍとすることができ、これを１ｃｍ２当たり１つ以上設けることが好ましい。 Further, the small holes for securing the feeding blood vessel passage can be, for example, 100 μm to 1.0 mm in diameter so that the feeding blood vessels can easily enter, and one or more of them can be provided per 1 cm 2. preferable.
本発明の骨再生用ケーシングの製造方法としては、予め測定又は印象された骨形状に基づいて決定された骨再生域の形状に適合するよう成形する方法であれば特に制限されるものではなく、具体的には、ＣＴＸ線、ＭＲＩ等を用いて測定された各患者の３Ｄモデル（三次元画像若しくは実模型）から必要な解剖学的骨再生形態（骨再生域の形状）を構築し、これに合わせて骨再生用ケーシングを成形することができる。また、顎骨再建術等においては、骨面を直接印象採得し、これに合わせて骨再生用ケーシングを成形することができる。所望の形状への成形方法としては特に制限されるものではなく、樹脂シートを用いる場合は、例えば、加熱圧迫や加熱吸引等により成形することができる。また、成形時又は成形後に骨誘導物導入口を形成してもよく、この場合、骨誘導物導入口を覆う蓋を別途作製する。また、成形前又は成形後に、栄養血管通路の確保のための小孔を形成することができる。 The method for producing the casing for bone regeneration of the present invention is not particularly limited as long as it is a method of molding so as to conform to the shape of the bone regeneration region determined based on the bone shape measured or impressed in advance. Specifically, a necessary anatomical bone regeneration form (the shape of the bone regeneration area) is constructed from a 3D model (three-dimensional image or actual model) of each patient measured using CTX rays, MRI, etc. The bone regeneration casing can be formed in accordance with the above. Further, in jawbone reconstruction or the like, a bone surface can be directly taken and a bone regeneration casing can be formed in accordance with this. There is no particular restriction on the method of molding into a desired shape, when using a resin sheet, for example, as possible out be formed by heating compression and heating suction or the like. In addition, an osteoinduct introduction port may be formed at the time of molding or after molding. In this case, a lid that covers the osteoinductor introduction port is separately prepared. In addition, a small hole for securing a nutrient blood vessel passage can be formed before or after molding.
上記のような骨再生用ケーシングを用いた治療方法としては、骨再生用ケーシングに、骨誘導物を収容した後、骨再生域に装着する方法や、骨再生用ケーシングを骨再生域に装着した後、該骨再生用ケーシング内に骨誘導物を添入する方法を挙げることができる。 As a treatment method using the bone regeneration casing as described above, a bone regeneration object is accommodated in the bone regeneration casing and then mounted on the bone regeneration area, or the bone regeneration casing is mounted on the bone regeneration area. Thereafter, a method of inserting a bone inducer into the bone regeneration casing can be mentioned.
以下、実施例により本発明をより具体的に説明するが、本発明の技術的範囲はこれらの例示に限定されるものではない。 EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, the technical scope of this invention is not limited to these illustrations.
（参考例１）
ポリエチレンテレフタレートからなる肉厚０．５ｍｍのレジンプレートを用い、加熱真空成型器で、７ｍｍ×７ｍｍ×５ｍｍサイズの気孔率約８５％の多孔質アパタイトブロックをその一面を残し被覆した。このケーシングには、０．５ｍｍ程度の小孔を２．５ｍｍ間隔で設けた。この多孔質アパタイトブロックに微細骨粉を血漿で混ぜた骨濃度約１／２００の懸濁液を含浸後、成犬の背部皮下脂肪組織に埋入した。なお、この多孔質アパタイトブロックは、数十μｍの連通孔を介して連続する約２００μｍのマクロ気孔をブロックの全体に有するとともに、マクロ気孔壁にもマクロ気孔につながるサブμｍから数μｍのミクロ気孔を有する多孔質構造体である。
(Reference Example 1)
Using a resin plate made of polyethylene terephthalate having a thickness of 0.5 mm, a porous apatite block having a porosity of about 85% and having a size of 7 mm × 7 mm × 5 mm was covered with a heating vacuum molding machine, leaving one surface thereof. In this casing, small holes of about 0.5 mm were provided at intervals of 2.5 mm. The porous apatite block was impregnated with a suspension having a bone concentration of about 1/200 in which fine bone powder was mixed with plasma, and then embedded in the dorsal subcutaneous fat tissue of an adult dog. In addition, this porous apatite block has macro pores of about 200 μm continuous through the communication holes of several tens of μm in the entire block, and the micro pores of sub μm to several μm connected to the macro pores on the macro pore wall. Is a porous structure.
移植８週後のケーシング（Ｃ）内の骨形成状態を示す顕微鏡写真を図１に示す。図１に示されるように、多孔質アパタイトブロックがケーシングに囲まれていない領域ではブロックの辺縁部に沿って骨が形成されていないが（Ｎｏ Ｎ．Ｂ）、ケーシング（Ｃ）に被
覆されている領域ではブロックの辺縁に至るまで良好な骨形成が見られる（Ｎ．Ｂ）。この所見は、本発明の骨再生用ケーシングを用いることにより、微細骨粉含浸多孔質アパタイトブロックの骨誘導能を十分に発揮させることができることを示している。なお、図１中、「Ｎ．Ｈ」は栄養血管通路のための小孔を表す。
A photomicrograph showing bone formation in the casing (C) 8 weeks after transplantation is shown in FIG. As shown in FIG. 1, in the region where the porous apatite block is not surrounded by the casing, no bone is formed along the edge of the block (No NB), but the casing (C) is covered. Good bone formation is seen up to the edge of the block in the area (NB). This finding indicates that the osteoinductive ability of the fine bone powder-impregnated porous apatite block can be sufficiently exhibited by using the bone regeneration casing of the present invention. In FIG. 1, “N.H” represents a small hole for a feeding blood vessel passage.
ポリエチレンテレフタレートからなる肉厚０．５ｍｍのレジンプレートを用い、加熱真空成型器で、１０ｍｍ×１０ｍｍ×６ｍｍのボックス状ケーシングを作製した。また、０．５ｍｍ程度の小孔を２．５ｍｍ程度間隔で全面に設けた。かかるボックス状ケーシングに、１ｍｍ３程度の微細骨粉含浸多孔質アパタイト顆粒（骨誘導物）を添入し、成犬の背部皮下脂肪組織に移植した。なお、この多孔質アパタイト顆粒の微細構造は、参考例１で用いたブロックのものと同様であり、微細骨粉含浸多孔質アパタイト顆粒は以下のようにして調製した。 Using a resin plate made of polyethylene terephthalate having a thickness of 0.5 mm, a box-shaped casing of 10 mm × 10 mm × 6 mm was produced with a heating vacuum molding machine. Moreover, small holes of about 0.5 mm were provided on the entire surface at intervals of about 2.5 mm. To this box-shaped casing, fine bone powder-impregnated porous apatite granules (bone derivative) of about 1 mm 3 were inserted and transplanted into the back subcutaneous fat tissue of adult dogs. The fine structure of the porous apatite granules was the same as that of the block used in Reference Example 1 , and the fine bone powder-impregnated porous apatite granules were prepared as follows.
歯科用電気エンジンに取り付けたトレパンバーを用い同一成犬の脛骨から摘出し、フリーザー内で−８０℃にて保存してあった骨小片を適宜取り出し、これを無菌的環境下、粉砕機を用いて一定時間粉砕した。この行程により作成される骨粉のサイズは、レーザー回折により、分布頻度の最高が４μｍ程度であることを確認している。生理的食塩水中で撹拌した骨粉入り生理的食塩水１４ｃｃを１５ｃｃコニカルチューブに入れ、これを遠心分離機で３０００回転（約１０００ｇ）、３０秒間維持した後ブレーキをかけ、生理的食塩水を除去した。この条件で沈殿した骨粉に骨粉体積の２０倍（骨粉作製以前の緻密骨の体積に対し約２００倍）になるまでクエン酸ナトリウム混合全血から分離した血漿を加え、さらに１００Ｗ、２８ｋｈｚの超音波および撹拌機を併用し骨粉を十分に拡散させ、微細骨粉懸濁液を調製した。この骨粉懸濁液を多孔質構造体の入った容器にバイブレーター使用下で滴下し、含浸操作を行った。骨粉含浸後、塩化カルシウムを添加し凝血させた。 Using a trepan bar attached to a dental electric engine, the bone piece that had been removed from the tibia of the same adult dog and stored at −80 ° C. in a freezer was appropriately removed, and this was removed using a pulverizer in an aseptic environment. And pulverized for a certain time. As for the size of the bone powder produced by this process, it has been confirmed by laser diffraction that the maximum distribution frequency is about 4 μm. 14 cc of physiological saline containing bone powder stirred in physiological saline was placed in a 15 cc conical tube, maintained at 3000 rpm (about 1000 g) for 30 seconds with a centrifuge, and then braked to remove the physiological saline. . Plasma separated from sodium citrate mixed whole blood is added to the bone meal precipitated under these conditions until the volume of bone powder is 20 times the volume of bone powder (about 200 times the volume of dense bone before bone powder preparation), and 100 W, 28 kHz ultrasound is added. The bone powder was sufficiently diffused by using a stirrer and a stirrer to prepare a fine bone powder suspension. This bone powder suspension was dropped into a container containing a porous structure under the use of a vibrator, and an impregnation operation was performed. After impregnation with bone powder, calcium chloride was added to clot.
移植８週後のケーシング（Ｃ）内の骨形成状態を示す顕微鏡写真を図２に示す。また、図２におけるケーシング内の顆粒充填域の良好な骨形成が生じている部分の顕微鏡写真を図３に示し、図２におけるケーシング内の顆粒充填域の骨形成が遅れている部分の顕微鏡写真を図４に示す。図２に示されるように、顆粒充填域ではその一部で骨形成が遅れているものの、良好な骨形成が生じていることがわかる。図３に示されるように、良好な骨形成が生じている部分は、新生骨（Ｎ．Ｂ）が顆粒のマクロ気孔壁（Ｍ．Ｐ．Ｗ）に沿って形成されると共に、顆粒相互間にも形成されている。新生骨相互間の骨髄（Ｂ．Ｍ）には、毛細血管（Ｎ．Ｃ）や洞様血管（Ｓ．Ｃ）の形成も見られる。また、図４に示されるように、骨形成が遅れている部分でも、その一部で石灰化している新生骨（Ｎ．Ｂ）が形成されると共に、骨形成が生じていない部でも気孔壁に沿って骨前質（Ｐ．Ｏ）が形成され、また、多核細胞（Ｍ．Ｎ．Ｇ．Ｃ）が出現している。この所見は、本発明の骨再生用ケーシングを用いることにより、微細骨粉含浸多孔質アパタイト顆粒の骨誘導能を異所性において発揮させることが可能であることを示している。なお、図２中、「Ｎ．Ｈ」は栄養血管通路のための小孔を表す。 A photomicrograph showing the bone formation state in the casing (C) 8 weeks after transplantation is shown in FIG. Moreover, the microscope picture of the part in which the favorable bone formation of the granule filling area | region in the casing in FIG. 2 has arisen in FIG. 3, The micrograph of the part in which the bone formation of the granule filling area | region in the casing in FIG. Is shown in FIG. As shown in FIG. 2, it can be seen that in the granule filling region, although bone formation is delayed in a part thereof, good bone formation occurs. As shown in FIG. 3, the portion where good bone formation occurs is that new bone (NB) is formed along the macroporous wall (MPW) of the granule, and between the granules Also formed. Formation of capillaries (NC) and sinusoidal blood vessels (SC) is also observed in the bone marrow (BM) between the new bones. Further, as shown in FIG. 4, even in a portion where bone formation is delayed, a new bone (NB) which is calcified in a part thereof is formed, and a pore wall is also formed in a portion where bone formation has not occurred. Along the pelvic bone (PO) and multinucleated cells (MNGC) have appeared. This finding indicates that by using the bone regeneration casing of the present invention, the osteoinductive ability of the fine bone powder-impregnated porous apatite granules can be exhibited in ectopicity. In FIG. 2, “N.H” represents a small hole for a feeding blood vessel passage.
他方、実施例１のコントロ−ルとして、上記微細骨粉含浸多孔質アパタイト顆粒のみを実施例１と同一の成犬の背部皮下脂肪組織に移植した。移植８週後、顆粒が一部崩れているとともに充填域に骨形成が全く認められなかった。その顕微鏡写真を図５に示す。 On the other hand, the control Example 1 - as Le were implanted only the fine bone powder impregnated porous apatite granules in dorsal subcutaneous adipose tissue of the same dogs as in Example 1. Eight weeks after transplantation, the granules were partially broken and no bone formation was observed in the filling area. The micrograph is shown in FIG.
酢酸セルロース及びフタル酸ジオクチルの共重合体からなる肉厚０．５ｍｍのレジンプレートを用い、加熱真空成型器で、内側１０ｍｍ×１０ｍｍ×６ｍｍのボックス状ケーシングを作製した。ただし、一つの面は開口とし、小孔を設けない無孔のものと参考例１と同様の小孔を設けたものの２種を作製した。ボックス状ケーシング内に、実施例１と同様の微細骨粉含浸多孔質アパタイト顆粒を添入し、犬の下顎骨頬側面に特に固定することなく、ボックス状ケーシングの開口面が骨に接触するように、傍骨移植した。この際、移植相当部緻密骨面に内部海綿骨域に達する孔の穿孔は行わなかった。 Using a resin plate having a thickness of 0.5 mm made of a copolymer of cellulose acetate and dioctyl phthalate, a box-shaped casing having an inner side of 10 mm × 10 mm × 6 mm was produced with a heating vacuum molding machine. However, one surface was an opening, and two types were produced: a non-hole without a small hole and a small hole similar to Reference Example 1 . In the box-shaped casing, the same fine bone powder-impregnated porous apatite granule as in Example 1 is added so that the opening surface of the box-shaped casing is in contact with the bone without being particularly fixed to the buccal side of the mandible of the dog. Paragrafted. At this time, a hole reaching the internal cancellous bone region was not drilled on the dense bone surface of the transplant equivalent part.
無孔性のケーシング（Ｃ）を用いて微細骨粉含浸多孔質アパタイト顆粒を下顎骨頬側面に１２週間傍骨移植した下顎骨前頭断の全体像の顕微鏡写真を図６に示す。また、図６における顆粒移植域の拡大顕微鏡写真を図７に示す。図６及び図７に示されるように、ケーシング（Ｃ）内の顆粒充填域の顆粒内及び顆粒間には多量の新生骨（Ｎ．Ｂ）が形成されている。なお、図６中、「Ｔ．Ｒ」は歯根を表し、「Ｂ．Ｃ．Ｂ」は頬側緻密骨を表し、図７中、「Ｐ．Ａ．Ｇ」は多孔質アパタイト顆粒を表し、「Ｂ．Ｃ．Ｂ」は頬側緻密骨を表す。 FIG. 6 shows a micrograph of an entire image of a mandibular frontal fracture in which a fine bone powder-impregnated porous apatite granule was transplanted to the buccal side of the mandible for 12 weeks using a nonporous casing (C). Moreover, the enlarged micrograph of the granule transplantation area | region in FIG. 6 is shown in FIG. As shown in FIGS. 6 and 7, a large amount of new bone (NB) is formed in and between the granules in the granule filling region in the casing (C). In FIG. 6, “TR” represents a tooth root, “BC” represents a buccal dense bone, and in FIG. 7, “PAG” represents a porous apatite granule, “BC” represents a buccal dense bone.
図８は、有孔性のケーシング（Ｃ）を用いて微細骨粉含浸多孔質アパタイト顆粒を下顎骨頬側面に１２週間傍骨移植した下顎骨前頭断の全体像の顕微鏡写真である。図８に示すように、無孔性のケーシングの場合と同様、有孔性のケーシングを用いた場合にも、ケーシング（Ｃ）内の顆粒充填域には良好な骨形成が生じている。なお、図８中、「Ｎ．Ｈ」は栄養血管通路のための小孔を表す。 FIG. 8 is a photomicrograph of the whole image of a mandibular frontal fracture in which a porous bone apatite granule impregnated with fine bone powder is transplanted to the buccal side of the mandible for 12 weeks using a porous casing (C). As shown in FIG. 8, as in the case of a nonporous casing, even when a porous casing is used, good bone formation occurs in the granule filling region in the casing (C). In FIG. 8, “N.H” represents a small hole for a feeding blood vessel passage.
成犬の下顎骨下面を印象し、その石膏模型上で、下顎骨下面を前後２０ｍｍ程度に渡って肉厚４ｍｍ程度増幅・挙上させる形態を、即時重合レジンでモウルドし、その形態を覆い、骨と直接接触する一方の側を開口としたケーシングを、実施例２と同様に、酢酸セルロース及びフタル酸ジオクチルの共重合体からなる肉厚０．５ｍｍのレジンプレートを用い、加熱吸引成型器で作製した。このケーシングの一部に、５ｍｍ×５ｍｍの窓を開けるとともに同寸の蓋を用意した。また、このケーシングには、参考例１と同様の小孔を設けた。移植に際しては、移植相当部緻密骨面に内部海綿骨域に達する小孔の穿孔を数箇所行った後、ケーシングを適切な位置で２箇所ネジ止めし、窓部から微細骨粉含浸多孔質アパタイト顆粒を添入し、蓋で充填域を閉鎖した。用いた多孔質アパタイト顆粒は実施例１，２と異なり、気孔率約４０％の低気孔率多孔質アパタイトのブロックを粉砕した大きさ１．５ｍｍ前後のもので、顆粒内の一部に散在するマクロ気孔を除く大半の部分はサブμｍから数μｍのミクロ気孔のみを有する気孔率約２０％の多孔質構造体である。 Impressing the lower surface of the mandible of an adult dog, on the gypsum model, the form that amplifies and raises the lower surface of the mandible about 20 mm back and forth about 4 mm thick is molded with an immediate polymerization resin, and the form is covered. A casing having an opening on one side in direct contact with the bone was used in the same manner as in Example 2 using a resin plate having a wall thickness of 0.5 mm made of a copolymer of cellulose acetate and dioctyl phthalate. Produced. A 5 mm × 5 mm window was opened in a part of this casing, and a lid of the same size was prepared. Further, the casing was provided with small holes similar to those in Reference Example 1 . At the time of transplantation, several small holes reaching the internal cancellous bone area were drilled on the dense bone surface corresponding to the transplanted part, and then the casing was screwed at two positions at appropriate positions, and the porous apatite granules impregnated with fine bone powder from the window part And the filling area was closed with a lid. The porous apatite granules used were different from those in Examples 1 and 2 and were obtained by pulverizing a low-porosity porous apatite block having a porosity of about 40%, which was about 1.5 mm in size and scattered in a part of the granules. Most of the parts excluding macropores are porous structures having a porosity of about 20% having only micropores of sub-μm to several μm.
移植１１週後のケーシング（Ｃ）内の骨形成状態を示す顕微鏡写真を図９に示す。図９に示されるように、ケーシング内（Ｃ）には、既存骨面に一致して連続する多量の新生骨（Ｎ．Ｂ）が密に形成されている。なお、図９中、「Ｃ．Ｂ」は緻密骨を表し、「Ｐ．Ａ．Ｇ」は多孔質アパタイト顆粒を表し、「Ｃ」はケーシングの蓋部分を表す。 A micrograph showing the bone formation state in the casing (C) 11 weeks after transplantation is shown in FIG. As shown in FIG. 9, a large amount of new bone (NB) that is continuous with the existing bone surface is densely formed in the casing (C). In FIG. 9, “CB” represents dense bone, “PAG” represents porous apatite granules, and “C” represents the lid portion of the casing.
Claims (6)
前記骨誘導物が、粒径０．１〜３ｍｍの顆粒又は粉末状の骨誘導物であり、
前記骨再生用ケーシングが、骨形成後に撤去される剛性を有する熱可塑性樹脂からなるケーシングであって、
顎骨の絶対的挙上のために用いられることを特徴とする骨再生用治療キット。 A bone regenerative material composed of a biocompatible material and / or a hard tissue derived from a living body, and a bone regeneration casing formed in a shape suitable for the shape of the bone regeneration region for accommodating the bone reductant therein; equipped with a,
The bone inducer is a granule or powdered bone inducer having a particle size of 0.1 to 3 mm,
The casing for bone regeneration is a casing made of a thermoplastic resin having rigidity to be removed after bone formation,
A treatment kit for bone regeneration, which is used for absolute elevation of the jawbone .
The bone regeneration treatment kit according to any one of claims 1 to 5 , wherein the bone regeneration casing includes a bone guide introduction port and a lid that covers the bone guide introduction port.
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