JP4206282B2

JP4206282B2 - Method for producing filler in bone defect or void, method for producing porous cured body, and porous cured body produced by the method

Info

Publication number: JP4206282B2
Application number: JP2003060879A
Authority: JP
Inventors: 智広梅田
Original assignee: Hoya Corp
Current assignee: Hoya Corp
Priority date: 2003-03-07
Filing date: 2003-03-07
Publication date: 2009-01-07
Anticipated expiration: 2023-03-07
Also published as: JP2004269393A

Description

【０００１】
【発明の属する技術分野】
本発明は、医科、歯科などで骨の欠損部又は空隙部に充填して当該箇所を修復するために用いられる充填材の製造方法に関するものである。また、本発明は、口腔外科を含む医科の分野において骨補修治療に用いられ、自在な形状形成が可能な多孔質硬化体の製造方法及びこの方法により製造される多孔質硬化体に関するものである。
【０００２】
【従来の技術】
一般に、骨補修用材料には、（１）生体に対する高い親和性と優れた骨修復性、（２）生体組織が侵入し同化するのに適した多孔質体であること、及び（３）補修すべき骨欠損の形状に適合する賦形性等が要求される。例えば、（１）及び（２）を満足するものとして、アパタイトに代表されるセラミック人工骨が頻用されてきた。また、（１）及び（３）を満足するものとして、リン酸カルシウムセメントが知られている（例えば、特許文献１参照。）。しかしながら、アパタイト人工骨には賦形性がなく、リン酸カルシウムセメントには多孔質体を形成することができず、この両方を兼ね備えた材料が待望されていた。
このような上記問題点を解決する方策として、本出願人は、リン酸カルシウム化合物が硬化液によりペースト状に調製された生体用セメントに、サイズが５０μｍ以上１ｍｍ以下のカルシウム化合物又はカルシウムとリンを含む化合物のいずれか一方又は双方が生体用セメント１００体積％に対して５〜９００体積％分散してなる骨の欠損部又は空隙部への充填材を提案した（例えば、特許文献２参照。）。また、生体内における適合性及び周囲の骨形成が良好な第１無機化合物と生体内において毒性がなくかつ高い吸収性を有する第２無機化合物とを含み、その含有割合が第２無機化合物１００体積％に対して第１無機化合物１〜１００００体積％であることを特徴とする骨の欠損部等への充填材を提案した（例えば、特許文献３参照。）。
【０００３】
【特許文献１】
特開昭６４−３７４４５号公報
【特許文献２】
特開２００１−９０２１号公報
【特許文献３】
特開２００１−５４５６５号公報
【０００４】
【発明が解決しようとする課題】
しかし、上記特許文献２及び特許文献３に示された充填材では、充填する前に所望の気孔率及び気孔径となるように充填材を調製しておかなければならず、充填した後の気孔率、気孔径の制御が困難であった。
本発明の第１の目的は、種々の気孔率及び気孔径が得られる骨の欠損部又は空隙部への充填材の製造方法を提供することにある。
本発明の第２の目的は、補修すべき骨欠損の形状に適合する賦形性を有する、骨の欠損部又は空隙部への充填材の製造方法を提供することにある。
本発明の第３の目的は、種々の気孔率及び気孔径を有する多孔質硬化体を容易に得ることができる、多孔質硬化体の製造方法を提供することにある。
本発明の第４の目的は、生体に対する高い親和性と優れた骨修復性を有し、生体組織が侵入し同化するのに適した、多孔質硬化体を提供することにある。
本発明の第５の目的は、補修すべき骨欠損の形状に適合する賦形性を有する、多孔質硬化体の製造方法及び該製造方法により得られる多孔質硬化体を提供することにある。
【０００５】
【課題を解決するための手段】
請求項１に係る発明は、平均粒径２．０μｍ〜８．０μｍのα型第３リン酸カルシウム（以下、α−ＴＣＰという。）、平均粒径２．０μｍ〜８．０μｍの第４リン酸カルシウム（以下、ＴｅＣＰという。）及び平均粒径２．０μｍ〜８．０μｍの第２リン酸カルシウム（以下、ＤＣＰＤという。）をそれぞれ主成分として含み、ＴｅＣＰが１０〜２５重量％、ＤＣＰＤが３〜１０重量％及びα−ＴＣＰを含む成分が６５〜８７重量％の組成比を有するセメント粉末（以下、セメント粉末という。）を調製する工程と、セメント粉末と硬化用液体とをセメント粉末と硬化用液体の重量混合比（粉末／液体）が４．５〜６．５の割合で混合する工程と、混合物を遠心造粒して平均粒径１．０ｍｍ〜５．０ｍｍの粒子状物質を成形する工程とを含む骨の欠損部又は空隙部への充填材の製造方法である。
請求項１に係る発明では、上記工程を経ることにより、種々の気孔率、気孔径が得られ、補修すべき骨欠損の形状に適合する賦形性を有する充填材が得られる。
【０００６】
請求項２に係る発明は、請求項１に係る発明であって、硬化用液体が水を主成分とする液体、骨髄液及び血液からなる群より選ばれた１種又は２種以上を含む液体である製造方法である。
請求項３に係る発明は、請求項１又は２に係る発明であって、遠心造粒が混合物を貯留した容器に公転回転及び自転回転の双方を同時に加えて混合物中のセメント粉末と硬化用液体を練和することにより行われ、公転回転が１０００ｒｐｍ〜３０００ｒｐｍ、自転回転が２００ｒｐｍ〜６００ｒｐｍの条件で１０秒〜６０秒間行われる製造方法である。
【０００７】
請求項４に係る発明は、平均粒径２．０μｍ〜８．０μｍのα−ＴＣＰ、平均粒径２．０μｍ〜８．０μｍのＴｅＣＰ及び平均粒径２．０μｍ〜８．０μｍのＤＣＰＤをそれぞれ主成分として含み、ＴｅＣＰが１０〜２５重量％、ＤＣＰＤが３〜１０重量％及びα−ＴＣＰを含む成分が６５〜８７重量％の組成比を有するセメント粉末を調製する工程と、セメント粉末と硬化用液体とをセメント粉末と硬化用液体の重量混合比（粉末／液体）が４．５〜６．５の割合で混合する工程と、混合物を遠心造粒して平均粒径１．０ｍｍ〜５．０ｍｍの粒子状物質を成形する工程と、粒子状物質をゲル状物質に混合してゲル状混合物を形成する工程と、ゲル状混合物を所定の形状にプレス成形する工程と、プレス成形物を養生して硬化させ、多孔質硬化体を形成する工程とを含む多孔質硬化体の製造方法である。
請求項４に係る発明では、上記工程を経ることにより、種々の気孔率、気孔径を有し、補修すべき骨欠損の形状に適合する賦形性を有する、多孔質硬化体を容易に得ることができる。
【０００８】
請求項５に係る発明は、請求項４に係る発明であって、硬化用液体が水を主成分とする液体、骨髄液及び血液からなる群より選ばれた１種又は２種以上を含む液体である製造方法である。
請求項６に係る発明は、請求項４又は５に係る発明であって、遠心造粒が混合物を貯留した容器に公転回転及び自転回転の双方を同時に加えて混合物中のセメント粉末と硬化用液体を練和することにより行われ、公転回転が１０００ｒｐｍ〜３０００ｒｐｍ、自転回転が２００ｒｐｍ〜６００ｒｐｍの条件で１０秒〜６０秒間行われる製造方法である。
請求項７に係る発明は、請求項４に係る発明であって、プレス成形が３００ｇ／ｃｍ²〜２ｋｇ／ｃｍ²の範囲内で行われる製造方法である。
【０００９】
請求項８に係る発明は、請求項４に係る発明であって、プレス成形物の養生が１０℃〜４０℃で、１５分以上の条件で行われる製造方法である。
請求項９に係る発明は、請求項４に係る発明であって、プレス成形物の表面をゲル状物質により被覆する工程を更に含む製造方法である。
請求項１０に係る発明は、請求項４又は９に係る発明であって、粒子状物質とゲル状物質との混合割合が重量比（粒子状物質／ゲル状物質）で０．５〜５．０である製造方法である。
請求項１１に係る発明は、請求項４，９又は１０に係る発明であって、ゲル状物質がコラーゲン水溶液、フィブリン、カルボキシルメチルキチン（以下、ＣＭキチンという。）、フィブロネクチン、アルギン酸及びヒアルロン酸からなる群より選ばれた１種又は２種以上の物質である製造方法である。
【００１０】
請求項１２に係る発明は、請求項１ないし３いずれか１項に記載の方法により製造される充填材を所定の形状にプレス成形し、得られたプレス成形物を養生して硬化させた硬化体が、気孔率が５０％〜７０％、気孔径が０．５ｍｍ〜２．０ｍｍ及びその圧縮強度が１ＭＰａ〜１０ＭＰａであることを特徴とする多孔質硬化体である。
請求項１２に係る発明では、上記物性を有する多孔質硬化体は、骨欠損部又は空隙部に充填した際に、生体に対する高い親和性と優れた骨修復性を有し、生体組織が侵入し同化するのに適した気孔を有し、かつ、補修すべき骨欠損の形状に適合する賦形性を有することができる。
【００１１】
請求項１３に係る発明は、請求項４ないし１１いずれか１項に記載の方法により製造される硬化体であって、気孔率が５０％〜７０％、気孔径が０．５ｍｍ〜２．０ｍｍ及びその圧縮強度が１ＭＰａ〜１０ＭＰａであることを特徴とする多孔質硬化体である。
請求項１３に係る発明では、上記物性を有する多孔質硬化体は、骨欠損部又は空隙部に充填した際に、生体に対する高い親和性と優れた骨修復性を有し、生体組織が侵入し同化するのに適した気孔を有し、かつ、補修すべき骨欠損の形状に適合する賦形性を有することができる。
【００１２】
【発明の実施の形態】
本発明者らは上述の観点から鋭意研究を進めた結果、骨欠損部又は空隙部に充填する充填材の形状を所定の平均粒径を有する粒子状物質とすることで、骨補修用材料に要求される前述の（１）〜（３）の全ての要件を満足することができるという研究結果を得た。
本発明の骨欠損部又は空隙部への充填材の製造方法は、平均粒径２．０μｍ〜８．０μｍのα−ＴＣＰ、平均粒径２．０μｍ〜８．０μｍのＴｅＣＰ及び平均粒径２．０μｍ〜８．０μｍのＤＣＰＤをそれぞれ主成分として含み、ＴｅＣＰが１０〜２５重量％、ＤＣＰＤが３〜１０重量％及びα−ＴＣＰを含む成分が６５〜８７重量％の組成比を有するセメント粉末を調製する工程と、セメント粉末と硬化用液体とをセメント粉末と硬化用液体の重量混合比（粉末／液体）が４．５〜６．５の割合で混合する工程と、混合物を遠心造粒して平均粒径１．０ｍｍ〜５．０ｍｍの粒子状物質を成形する工程とを含む。
本発明のセメント粉末は、平均粒径２．０μｍ〜８．０μｍのα−ＴＣＰ、平均粒径２．０μｍ〜８．０μｍのＴｅＣＰ及び平均粒径２．０μｍ〜８．０μｍのＤＣＰＤをそれぞれ主成分として含む。各成分の平均粒径が下限値未満であると作業性が低下し、強度が低下するため好ましくない。α−ＴＣＰの好ましい平均粒径は２．０μｍ〜５．０μｍであり、ＴｅＣＰの好ましい平均粒径は２．０μｍ〜５．０μｍであり、ＤＣＰＤの好ましい平均粒径は２．０μｍ〜５．０μｍである。
【００１３】
ＴｅＣＰには、硬化体が生体骨へ再生する吸収置換性を促進する作用がある。このＴｅＣＰのセメント粉末への組成比割合は１０重量％〜２５重量％である。組成比割合が１０重量％未満であると充分な促進作用が得られず、２５重量％を越えると硬化体の強度が低下する。ＴｅＣＰの製造方法は、次の通りである。先ず、水酸化カルシウム４モルを１０リットルの水に懸濁させて懸濁液を調製する。この懸濁液にリン酸２モルを水で希釈してなる４０重量％リン酸水溶液を攪拌しながらゆっくり滴下し、滴下終了後、室温下で１日間放置する。次いで、乾燥器で１１０℃に加熱してこの温度で２４時間保持することにより乾燥させて凝集体を形成する。次に、得られた凝集体を９００℃に３時間保持して仮焼結し、引き続いて仮焼結したものを均一に粉砕し、粉砕物を１４００℃で３時間保持して焼結する。次に、焼成生成物を粉砕し、篩い分けにて篩目が１００μｍ以下（平均粒径８．０μｍ）とする。上記工程を経ることにより、ＴｅＣＰの含有割合が９０．５％で残りが実質的に不可避な不純物としての水酸アパタイトからなる混合生成物が得られる。
【００１４】
ＤＣＰＤには、スラリーの硬化体への凝結を促進する作用がある。このＤＣＰＤのセメント粉末への組成比割合は３重量％〜１０重量％である。組成比割合が３重量％未満では、十分な凝結促進作用を確保することができず、１０重量％を越えると、硬化時間が短くなりすぎてしまい、作業性が低下する。α−ＴＣＰは、良好な水和活性を有し、硬化する。このα−ＴＣＰを含む成分のセメント粉末への組成比割合は６５重量％〜８７重量％である。６５重量％未満であると、操作性が低下し、８７重量％を越えると強度低下するため好ましくない。α−ＴＣＰの製造方法は、次の通りである。先ず、水酸化カルシウム３モルを１０リットルの水に懸濁させて懸濁液を調製する。この懸濁液にリン酸２モルを水で希釈してなる４０重量％リン酸水溶液を攪拌しながらゆっくり滴下し、滴下終了後、室温下で１日間放置する。次いで、乾燥器で１１０℃に加熱してこの温度で２４時間保持することにより乾燥させて凝集体を形成する。次に、得られた凝集体を１４００℃で３時間保持して焼成する。次に、焼成生成物を粉砕し、篩い分けにて篩目が１００μｍ以下（平均粒径８．０μｍ）とする。上記工程を経ることにより、純度９９．９％のα−ＴＣＰが得られる。
ＴｅＣＰ、ＤＣＰＤ及びα−ＴＣＰを含む成分をそれぞれ上記割合、即ちＴｅＣＰが１０〜２５重量％、ＤＣＰＤが３〜１０重量％及びα−ＴＣＰを含む成分が６５〜８７重量％となるように混合してセメント粉末を調製する。
【００１５】
次いで、セメント粉末と硬化用液体とをセメント粉末と硬化用液体の重量混合比（粉末／液体）が４．５〜６．５の割合で混合する。硬化用液体としては、硬化用液体が水を主成分とする液体、骨髄液及び血液からなる群より選ばれた１種又は２種以上を含む液体が挙げられる。セメント粉末と硬化用液体の重量混合比（粉末／液体）が４．５未満、即ち硬化用液体の割合が高くなると、後に続く工程において形成される粒子状物質はゆるい粒子となってしまい、このゆるい粒子を充填材として骨の欠損部又は空隙部へ充填した場合、体液との接触によって崩壊しやすくなるため好ましくない。また重量混合比（粉末／液体）が６．５を越える、即ち硬化用液体の割合が低くなると、後に続く工程において形成される粒子状物質が短い時間で完全に硬化してしまうため、所定の形態を付与することが困難となる。
【００１６】
次に、混合物を遠心造粒して平均粒径１．０ｍｍ〜５．０ｍｍの粒子状物質を成形する。本発明に使用する遠心造粒装置は、例えば「スピンクル」（商品名：モリタ東京製作所製）や「あわとり練太郎」（商品名：シンキー社製）や「ハイブリッドミキサー」（商品名：株式会社キーエンス）を挙げることができる。これらの遠心造粒装置を使用して混合物を遠心造粒して平均粒径１．０ｍｍ〜５．０ｍｍの粒子状物質を成形する。遠心造粒は混合物を貯留した容器に公転回転及び自転回転の双方を同時に加えて混合物中のセメント粉末と硬化用液体を練和することにより行われる。公転回転は１０００ｒｐｍ〜３０００ｒｐｍ、自転回転は２００ｒｐｍ〜６００ｒｐｍ、上記公転回転及び自転回転を１０秒〜６０秒間行う。公転回転が１５００ｒｐｍ〜２５００ｒｐｍ、自転回転が３００ｒｐｍ〜５００ｒｐｍ、上記公転回転及び自転回転を２０秒〜４０秒間行うことが好ましい。この遠心造粒作用によってセメント粉末と硬化用液体がほぼ球状に造粒される。得られる粒子状物質の粒子径は、粉体と液体の混合割合により、自在に制御することが可能である。
【００１７】
図１に遠心造粒装置に装着する二重容器の断面図を示す。
遠心造粒装置に装着する二重容器１１は、外容器本体１２ａとその上部開口を脱着可能に覆う外蓋１２ｂとからなる外容器１２と、該外容器１２内に収容可能な内容器本体１３とその上部開口を脱着可能に覆うツマミ１４付きの内蓋１３ｂとからなる内容器１３から構成されている。内容器１３は、内蓋１３ｂを取り付けた状態で外容器本体１２ａ内に収容され、外蓋１２ｂを取り付けた状態で、内容器１３のツマミ１４の上端が外蓋１２ｂ内面に近接するか又は接触するようになっている。外容器本体１２ａの内方側底面には、十文字の凹部が設けられ、一方、内容器本体１３ａの外方側底面には、その十文字の凹部に嵌入される十文字の突起（ロック機構）が設けられ、外容器１２内に内容器１３を収容し、突起１６を凹部に嵌入することによって、外容器１２内で内容器１３が回転することなく保持できるようになっている。
このような構成を有する二重容器１１では、先ず、滅菌処理した内容器本体１３ａに、滅菌済みのセメント粉末と硬化用液体とを所定の割合で混合した混合物を入れ、内蓋１３ｂを閉じる。次いで内容器１３を滅菌処理した外容器１２内に収容し、突起１６を凹部に嵌入した後、外蓋１２ｂを閉める。次に、混合物を入れた二重容器１１を前述した遠心造粒装置（図示せず）に装着する。二重容器を装着した遠心造粒装置に、公転回転と自転回転とを同時に加えて遠心造粒する。遠心造粒終了後は、二重容器１１の外蓋１２ｂを開けて外容器１２内部から内容器１３を取出し、内蓋１３ｂを開けて形成した平均粒径１．０ｍｍ〜５．０ｍｍの粒子状物質を取出す。この得られた粒子状物質を骨の欠損部又は空隙部への充填材とする。
【００１８】
上記本発明の方法により製造される充填材を所定の形状にプレス成形し、得られたプレス成形物を養生して硬化させた本発明の多孔質硬化体は、気孔率が５０％〜７０％、気孔径が０．５ｍｍ〜２．０ｍｍ及びその圧縮強度が１ＭＰａ〜１０ＭＰａであることを特徴とする。上記物性を有することで、骨欠損部又は空隙部に充填した際に、生体に対する高い親和性と優れた骨修復性を有し、生体組織が侵入し同化するのに適した気孔を有し、かつ、補修すべき骨欠損の形状に適合する賦形性を有することができる。
【００１９】
続いて、多孔質硬化体の製造方法を説明する。
先ず、本発明の骨欠損部又は空隙部への充填材の製造方法において得られた粒子状物質を用い、図２に示すように、骨２１の欠損部２２又は空隙部に粒子状物質２３を所定量充填する（図２（ａ）及び図２（ｂ））。次いで、骨欠損部又は空隙部に充填した充填物２３をプレス成形する（図２（ｃ））。このプレス成形により骨２１の欠損部２２又は空隙部へ充填した充填物２３の気孔率及び気孔径を容易に制御することができる。プレス成形は３００ｇ／ｃｍ²〜２ｋｇ／ｃｍ²の範囲内で行われる。３００ｇ／ｃｍ²未満であると骨欠損部又は空隙部表面と充填物との界面結合が弱くなり、２ｋｇ／ｃｍ²を越えると粒子状物質自体がプレス成形により潰れてしまい、気孔の形成、気孔率、気孔径の制御がそれぞれ困難になる。プレス成形は５００ｇ／ｃｍ²〜１．５ｋｇ／ｃｍ²の範囲内が好ましい。
次に、プレス成形物を養生して硬化させ、多孔質硬化体を形成する。プレス成形物の養生は１０℃〜４０℃で、１５分以上の条件で行われる。好ましくは２０℃〜３０℃で、３０分〜６０分である。このようにして得られた多孔質硬化体は、種々の気孔率及び気孔径を容易に形成することができ、補修すべき骨欠損の形状に適合する賦形性を有することができる。
【００２０】
また、プレス成形物の表面をゲル状物質により被覆することで多孔質硬化体の形状制御が容易になる、操作性が向上するなどの効果が期待できる。ゲル状物質としては、コラーゲン水溶液（高研社製など）、フィブリン（三菱ウェルファーマ社製など）、ＣＭキチン（片倉チッカリン社製など）、フィブロネクチン（タカラバイオ社製など）、アルギン酸及びヒアルロン酸（和光純薬工業社製など）からなる群より選ばれた１種又は２種以上の物質を使用できるが、上記記載した物質に限らず、医療分野で広く使用されているゲル状の物質を使用することができる。粒子状物質とゲル状物質との混合割合は重量比（粒子状物質／ゲル状物質）で０．５〜５．０である。好ましい重量比（粒子状物質／ゲル状物質）は１．０〜４．０である。これらのゲル状物質は硬化反応過程における炎症反応等、生体への悪影響もない。
【００２１】
本発明の多孔質硬化体の製造方法では、遠心造粒により粒子状物質を成形した後、粒子状物質をゲル状物質に混合してゲル状混合物を形成し、このゲル状混合物を所定の形状に充填してプレス成形する。ゲル状混合物を用い、更にゲル状物質の割合を高くしたり、ゲルの粘度調整を行うと、骨欠損部への注入器での補填も可能となり、患者への負担を軽減できる。
【００２２】
上記本発明の方法により製造される本発明の多孔質硬化体は、気孔率が５０％〜７０％、気孔径が０．５ｍｍ〜２．０ｍｍ及びその圧縮強度が１ＭＰａ〜１０ＭＰａであることを特徴とする。上記物性を有することで、骨欠損部又は空隙部に充填した際に、生体に対する高い親和性と優れた骨修復性を有し、生体組織が侵入し同化するのに適した気孔を有し、かつ、補修すべき骨欠損の形状に適合する賦形性を有することができる。
本発明の多孔質硬化体は、マイクロサージャリー技術による血管柄（束）付き移植を可能とするものであり、腫瘍切除後等の比較的大きな欠損に対する新たな再建法として期待できる。このように本発明の製造方法で得られる多孔質硬化体は組織工学、再生医療分野での応用も可能とするものである。
【００２３】
【実施例】
次に本発明の実施例を説明する。
＜実施例１＞
先ず、平均粒径２．０μｍ〜８．０μｍのα−ＴＣＰ、平均粒径２．０μｍ〜８．０μｍのＴｅＣＰ及び平均粒径２．０μｍ〜８．０μｍのＤＣＰＤをそれぞれ用意した。次にα−ＴＣＰ、ＴｅＣＰ及びＤＣＰＤを次の表１に示される配合割合にそれぞれ混合し、セメント粉末ａ〜粉末ｄをそれぞれ調製した。
【００２４】
【表１】

【００２５】
次いで、硬化用液体として水、採血したばかりの新鮮な血液、及び水と血液の混合液をそれぞれ用意した。この硬化用液体と粉体ａ〜粉末ｄとを次の表２に示す割合でそれぞれ混合して混合物を調製した。次に、遠心造粒装置「スピンクル」（東京モリタ製作所製）を用意し、この混合物を遠心造粒した。遠心造粒の条件は、公転回転２０００ｒｐｍ、自転回転５００ｒｐｍを２０秒間である。得られた造粒物は、ほぼ均一な粒径を有し、平均粒径が１．０ｍｍ〜５．０ｍｍの粒子状物質であった。次に、粒子状物質を内径φ２０ｍｍ、高さ３０ｍｍの型枠に充填し、充填物の上から外径φ２０ｍｍの円柱で押しつける方法でプレス成形した。プレス成形条件は５００ｇ／ｃｍ²であった。このプレス成形物を３７℃、４０分の条件で養生し、多孔質硬化体を得た。それぞれ得られた多孔質硬化体の気孔率及び気孔径を全気孔率測定法及びマイクロメーター、光学顕微鏡観察により測定した。次の表２にその結果を示す。
【００２６】
【表２】

【００２７】
表２より明らかなように、本発明の製造方法により種々の気孔率及び気孔径を有する多孔質硬化体が容易に得られた。このことから本発明の多孔質硬化体の製造方法では、生体組織が侵入し同化するのに適した多孔質体を容易に製造することができ、得られた多孔質硬化体は、補修すべき骨欠損の形状に適合する賦形性を有することが判る。
【００２８】
【発明の効果】
以上述べたように、本発明の骨の欠損部又は空隙部への充填材の製造方法は、平均粒径２．０μｍ〜８．０μｍのα−ＴＣＰ、平均粒径２．０μｍ〜８．０μｍのＴｅＣＰ及び平均粒径２．０μｍ〜８．０μｍのＤＣＰＤをそれぞれ主成分として含み、ＴｅＣＰが１０〜２５重量％、ＤＣＰＤが３〜１０重量％及びα−ＴＣＰを含む成分が６５〜８７重量％の組成比を有するセメント粉末を調製する工程と、セメント粉末と硬化用液体とをセメント粉末と硬化用液体の重量混合比（粉末／液体）が４．５〜６．５の割合で混合する工程と、混合物を遠心造粒して平均粒径１．０ｍｍ〜５．０ｍｍの粒子状物質を成形する工程とを含む。上記工程を経ることにより、種々の気孔率、気孔径が得られ、生体に対する高い親和性と優れた骨修復性を有し、生体組織が侵入し同化するのに適した充填材が得られる。
【００２９】
また、本発明の多孔質硬化体の製造方法は、平均粒径２．０μｍ〜８．０μｍのα−ＴＣＰ、平均粒径２．０μｍ〜８．０μｍのＴｅＣＰ及び平均粒径２．０μｍ〜８．０μｍのＤＣＰＤをそれぞれ主成分として含み、ＴｅＣＰが１０〜２５重量％、ＤＣＰＤが３〜１０重量％及びα−ＴＣＰを含む成分が６５〜８７重量％の組成比を有するセメント粉末を調製する工程と、セメント粉末と硬化用液体とをセメント粉末と硬化用液体の重量混合比（粉末／液体）が４．５〜６．５の割合で混合する工程と、混合物を遠心造粒して平均粒径１．０ｍｍ〜５．０ｍｍの粒子状物質を成形する工程と、粒子状物質をゲル状物質に混合してゲル状混合物を形成し、このゲル状混合物を所定の形状に充填してプレス成形する工程と、プレス成形物を養生して硬化させ、多孔質硬化体を形成する工程とを含む。上記工程を経ることにより、種々の気孔率、気孔径を有し、補修すべき骨欠損の形状に適合する賦形性を有する、多孔質硬化体を容易に得ることができる。
【図面の簡単な説明】
【図１】遠心造粒装置に装着する二重容器の断面図。
【図２】骨欠損部に粒子状物質を充填し、プレス成形する工程を示す断面図。
【符号の説明】
１１二重容器
１２外容器
１２ａ外容器本体
１２ｂ外蓋
１３内容器
１３ａ内容器本体
１３ｂ内蓋
１４ツマミ
１６突起[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing a filler used for filling a bone defect or void in a medical department, dentistry, or the like and repairing the part. The present invention also relates to a method for producing a porous cured body that can be used for bone repair treatment in the medical field including oral surgery and capable of forming a free shape, and a porous cured body produced by this method. .
[0002]
[Prior art]
In general, bone repair materials include (1) a high affinity for the living body and excellent bone repairability, (2) a porous body suitable for invasion and assimilation of living tissue, and (3) repair. The shapeability etc. which match the shape of the bone defect which should be required are requested | required. For example, a ceramic artificial bone typified by apatite has been frequently used as satisfying (1) and (2). Moreover, calcium phosphate cement is known as what satisfies (1) and (3) (for example, refer patent document 1). However, the apatite artificial bone has no formability, and the calcium phosphate cement cannot form a porous body, and a material having both of these has been awaited.
As a measure for solving the above-mentioned problems, the applicant of the present invention has proposed that a calcium compound having a size of 50 μm or more and 1 mm or less, or a compound containing calcium and phosphorus, in a biological cement in which a calcium phosphate compound is prepared in a paste form with a hardening liquid. One or both of these proposed a filler for bone defects or voids in which 5 to 900% by volume is dispersed with respect to 100% by volume of biological cement (see, for example, Patent Document 2). In addition, the first inorganic compound having good compatibility in vivo and surrounding bone formation and the second inorganic compound having no toxicity and high absorbability in the living body, the content ratio of which is 100 volume of the second inorganic compound. 1% to 10000% by volume of the first inorganic compound with respect to%, a filler for bone defects or the like has been proposed (see, for example, Patent Document 3).
[0003]
[Patent Document 1]
Japanese Patent Laid-Open No. 64-37445 [Patent Document 2]
JP 2001-9021 [Patent Document 3]
Japanese Patent Laid-Open No. 2001-54565
[Problems to be solved by the invention]
However, in the fillers disclosed in Patent Document 2 and Patent Document 3, the filler must be prepared so as to have a desired porosity and pore diameter before filling. It was difficult to control the rate and pore diameter.
A first object of the present invention is to provide a method for producing a filler in a bone defect or void that can provide various porosity and pore diameter.
A second object of the present invention is to provide a method for producing a filler in a bone defect or void having a shape that matches the shape of the bone defect to be repaired.
A third object of the present invention is to provide a method for producing a porous cured body, which can easily obtain a porous cured body having various porosities and pore sizes.
A fourth object of the present invention is to provide a porous cured body having high affinity for a living body and excellent bone repairability, and suitable for invading and assimilating a living tissue.
A fifth object of the present invention is to provide a method for producing a porous cured body and a porous cured body obtained by the production method, which have a formability suitable for the shape of the bone defect to be repaired.
[0005]
[Means for Solving the Problems]
The invention according to claim 1 is an α-type tricalcium phosphate (hereinafter referred to as α-TCP) having an average particle size of 2.0 μm to 8.0 μm, and a quaternary calcium phosphate having an average particle size of 2.0 μm to 8.0 μm (hereinafter referred to as “α-TCP”). , TeCP) and dicalcium phosphate having an average particle size of 2.0 μm to 8.0 μm (hereinafter referred to as DCPD) as main components, TeCP is 10 to 25% by weight, DCPD is 3 to 10% by weight, and A step of preparing a cement powder (hereinafter referred to as a cement powder) in which a component containing α-TCP has a composition ratio of 65 to 87% by weight, and the cement powder and the hardening liquid are mixed by weight. A step of mixing at a ratio (powder / liquid) of 4.5 to 6.5 , and a step of centrifugally granulating the mixture to form a particulate material having an average particle size of 1.0 mm to 5.0 mm Bone A method for producing a filler to loss portion or void portion.
In the invention according to claim 1, through the above-described steps, various porosity and pore diameter can be obtained, and a filler having a formability suitable for the shape of the bone defect to be repaired can be obtained.
[0006]
The invention according to claim 2 is the invention according to claim 1, wherein the curable liquid contains one or more selected from the group consisting of a liquid mainly composed of water, bone marrow fluid and blood. This is a manufacturing method.
The invention according to claim 3 is the invention according to claim 1 or 2, wherein the centrifugal granulation simultaneously applies both rotation and rotation to the container in which the mixture is stored, and cement powder and hardening liquid in the mixture In which the revolution rotation is 1000 rpm to 3000 rpm and the rotation rotation is 200 rpm to 600 rpm for 10 seconds to 60 seconds.
[0007]
The invention according to 請 Motomeko 4, alpha-TCP having an average particle size 2.0Myuemu～8.0Myuemu, a DCPD of TeCP and average particle size 2.0Myuemu～8.0Myuemu an average particle diameter of 2.0Myuemu～8.0Myuemu A step of preparing a cement powder having a composition ratio of 10 to 25% by weight of TeCP, 3 to 10% by weight of DCPD, and 65 to 87% by weight of a component containing α-TCP, A step of mixing the curing liquid with a cement powder and a curing liquid in a weight mixing ratio (powder / liquid) of 4.5 to 6.5, and centrifugally granulating the mixture to obtain an average particle size of 1.0 mm to A step of forming a 5.0 mm particulate material, a step of mixing the particulate material with a gel material to form a gel mixture, a step of pressing the gel mixture into a predetermined shape, and a press molded product Curing and curing the porous cured body And a step of forming the porous cured body.
In the invention which concerns on Claim 4, by passing through the said process, the porous hardened | cured material which has various porosity, a pore diameter, and has the shaping property which adapts the shape of the bone defect which should be repaired is obtained easily. be able to.
[0008]
The invention according to claim 5 is the invention according to claim 4 , wherein the curable liquid contains one or more selected from the group consisting of a liquid mainly composed of water, bone marrow fluid and blood. This is a manufacturing method.
The invention according to claim 6 is the invention according to claim 4 or 5 , wherein the centrifugal granulation simultaneously applies both revolution rotation and rotation rotation to the container storing the mixture, and cement powder and hardening liquid in the mixture In which the revolution rotation is 1000 rpm to 3000 rpm and the rotation rotation is 200 rpm to 600 rpm for 10 seconds to 60 seconds.
The invention according to claim 7 is the manufacturing method according to claim 4 , wherein the press molding is performed within a range of 300 g / cm ^{2 to 2} kg / cm ² .
[0009]
The invention according to claim 8 is the method according to claim 4 , wherein the press-molded product is cured at 10 ° C. to 40 ° C. for 15 minutes or more.
The invention according to claim 9 is the manufacturing method according to claim 4, further comprising a step of coating the surface of the press-molded product with a gel substance.
The invention according to claim 10 is the invention according to claim 4 or 9 , wherein the mixing ratio of the particulate substance and the gel substance is 0.5 to 5. wt% (particulate substance / gel substance). The production method is zero.
The invention according to claim 11 is the invention according to claim 4 , 9 or 10 , wherein the gel-like substance is an aqueous collagen solution, fibrin, carboxymethyl chitin (hereinafter referred to as CM chitin), fibronectin, alginic acid and hyaluronic acid. It is a manufacturing method which is 1 type, or 2 or more types of substances chosen from the group which consists of.
[0010]
The invention according to claim 12 is a curing in which the filler manufactured by the method according to any one of claims 1 to 3 is press-molded into a predetermined shape, and the obtained press-molded product is cured and cured. The body is a porous cured body having a porosity of 50% to 70%, a pore diameter of 0.5 mm to 2.0 mm, and a compressive strength of 1 MPa to 10 MPa.
In the invention according to claim 12 , the porous cured body having the above physical properties has a high affinity for a living body and excellent bone repairability when the bone defect or void is filled, and the living tissue enters. It has pores suitable for assimilation and can be shaped to match the shape of the bone defect to be repaired.
[0011]
The invention according to claim 13 is a cured product produced by the method according to any one of claims 4 to 11 , wherein the porosity is 50% to 70% and the pore diameter is 0.5 mm to 2.0 mm. And the compressive strength is 1 MPa-10 MPa, It is a porous hardening body characterized by the above-mentioned.
In a thirteenth aspect of the present invention, the porous cured body having the above physical properties has a high affinity for a living body and excellent bone repairability when the bone defect or void is filled, and the living tissue enters. It has pores suitable for assimilation and can be shaped to match the shape of the bone defect to be repaired.
[0012]
DETAILED DESCRIPTION OF THE INVENTION
As a result of intensive studies from the above viewpoint, the present inventors have made the bone repair material by making the shape of the filler filling the bone defect or void into a particulate substance having a predetermined average particle size. The research result that it was possible to satisfy all the requirements (1) to (3) described above was obtained.
The method for producing a filler in a bone defect or void according to the present invention includes α-TCP having an average particle diameter of 2.0 μm to 8.0 μm, TeCP having an average particle diameter of 2.0 μm to 8.0 μm, and an average particle diameter of 2 Cement powder containing 0.0 μm to 8.0 μm of DCPD as a main component, TeCP being 10 to 25% by weight, DCPD being 3 to 10% by weight, and a component containing α-TCP being 65 to 87% by weight A step of mixing the cement powder and the hardening liquid with a weight mixing ratio (powder / liquid) of the cement powder and the hardening liquid of 4.5 to 6.5 , and centrifugally granulating the mixture. And forming a particulate material having an average particle diameter of 1.0 mm to 5.0 mm.
The cement powder of the present invention is mainly composed of α-TCP having an average particle size of 2.0 μm to 8.0 μm, TeCP having an average particle size of 2.0 μm to 8.0 μm, and DCPD having an average particle size of 2.0 μm to 8.0 μm. Contains as an ingredient. If the average particle size of each component is less than the lower limit, the workability is lowered and the strength is lowered. The preferable average particle diameter of α-TCP is 2.0 μm to 5.0 μm, the preferable average particle diameter of TeCP is 2.0 μm to 5.0 μm, and the preferable average particle diameter of DCPD is 2.0 μm to 5.0 μm. It is.
[0013]
TeCP has an action of promoting the absorption replacement property that the cured body regenerates into living bone. The composition ratio of TeCP to cement powder is 10% to 25% by weight. If the composition ratio is less than 10% by weight, a sufficient accelerating effect cannot be obtained, and if it exceeds 25% by weight, the strength of the cured product is lowered. The manufacturing method of TeCP is as follows. First, 4 mol of calcium hydroxide is suspended in 10 liters of water to prepare a suspension. To this suspension, a 40 wt% aqueous phosphoric acid solution prepared by diluting 2 mol of phosphoric acid with water is slowly added dropwise with stirring. After completion of the addition, the mixture is allowed to stand at room temperature for 1 day. Subsequently, it heats at 110 degreeC with a dryer, and it is made to dry by hold | maintaining at this temperature for 24 hours, and forms an aggregate. Next, the obtained aggregate is preliminarily sintered by holding at 900 ° C. for 3 hours, and then the pre-sintered one is uniformly pulverized, and the pulverized product is held at 1400 ° C. for 3 hours to sinter. Next, the fired product is pulverized and sieved to 100 μm or less (average particle size 8.0 μm). By passing through the said process, the mixed product which consists of a hydroxyapatite as a content rate which TeCP is 90.5% and the remainder is substantially inevitable is obtained.
[0014]
DCPD has the effect of promoting the aggregation of the slurry into the cured body. The composition ratio of DCPD to cement powder is 3% to 10% by weight. When the composition ratio is less than 3% by weight, a sufficient setting acceleration effect cannot be ensured, and when it exceeds 10% by weight, the curing time becomes too short and workability is lowered. α-TCP has good hydration activity and cures. The composition ratio of the component containing α-TCP to the cement powder is 65% by weight to 87% by weight. If it is less than 65% by weight, the operability is lowered, and if it exceeds 87% by weight, the strength is lowered. The manufacturing method of α-TCP is as follows. First, 3 mol of calcium hydroxide is suspended in 10 liters of water to prepare a suspension. To this suspension, a 40 wt% aqueous phosphoric acid solution prepared by diluting 2 mol of phosphoric acid with water is slowly added dropwise with stirring. After completion of the addition, the mixture is allowed to stand at room temperature for 1 day. Subsequently, it heats at 110 degreeC with a dryer, and it is made to dry by hold | maintaining at this temperature for 24 hours, and forms an aggregate. Next, the obtained aggregate is baked by holding at 1400 ° C. for 3 hours. Next, the fired product is pulverized and sieved to 100 μm or less (average particle size 8.0 μm). By passing through the above steps, α-TCP having a purity of 99.9% is obtained.
Components containing TeCP, DCPD and α-TCP are mixed in the above proportions, that is, TeCP is 10 to 25% by weight, DCPD is 3 to 10% by weight and components containing α-TCP are 65 to 87% by weight. To prepare cement powder.
[0015]
Next, the cement powder and the hardening liquid are mixed at a weight mixing ratio (powder / liquid) of the cement powder and the hardening liquid of 4.5 to 6.5 . Examples of the curable liquid include a liquid containing one or more selected from the group consisting of a liquid mainly composed of water, a bone marrow fluid, and blood. When the weight mixing ratio (powder / liquid) of the cement powder and the hardening liquid is less than 4.5 , that is, when the ratio of the hardening liquid becomes high, the particulate matter formed in the subsequent process becomes loose particles. When loose particles are filled into a bone defect or void as a filler, it is not preferable because it easily collapses due to contact with body fluids. In addition, when the weight mixing ratio (powder / liquid) exceeds 6.5 , that is, when the ratio of the curing liquid is low, the particulate matter formed in the subsequent process is completely cured in a short time. It becomes difficult to give form .
[0016]
Next, the mixture is centrifuged to form a particulate material having an average particle size of 1.0 mm to 5.0 mm. Centrifugal granulators used in the present invention include, for example, “Spinkle” (trade name: manufactured by Morita Tokyo Seisakusho), “Awatori Nerita” (trade name: manufactured by Shinky Corporation), and “Hybrid Mixer” (trade name: Co., Ltd.). Keyence). Using these centrifugal granulators, the mixture is centrifugally granulated to form particulate matter having an average particle size of 1.0 mm to 5.0 mm. Centrifugal granulation is performed by simultaneously adding both revolution rotation and rotation rotation to a container storing the mixture to knead the cement powder and the hardening liquid in the mixture. The revolution rotation is 1000 rpm to 3000 rpm, the rotation rotation is 200 rpm to 600 rpm, and the revolution rotation and rotation rotation are performed for 10 seconds to 60 seconds. It is preferable that the revolution rotation is 1500 rpm to 2500 rpm, the rotation rotation is 300 rpm to 500 rpm, and the revolution rotation and rotation rotation are performed for 20 seconds to 40 seconds. By this centrifugal granulation action, the cement powder and the hardening liquid are granulated almost spherically. The particle size of the obtained particulate substance can be freely controlled by the mixing ratio of the powder and liquid.
[0017]
FIG. 1 shows a cross-sectional view of a double container to be attached to the centrifugal granulator.
The double container 11 to be mounted on the centrifugal granulation apparatus includes an outer container 12 comprising an outer container body 12a and an outer lid 12b that detachably covers an upper opening thereof, and an inner container body 13 that can be accommodated in the outer container 12. And an inner lid 13b having a knob 14 that covers the upper opening thereof in a detachable manner. The inner container 13 is accommodated in the outer container body 12a with the inner lid 13b attached, and the upper end of the knob 14 of the inner container 13 is close to or in contact with the inner surface of the outer lid 12b with the outer lid 12b attached. It is supposed to be. A cross-shaped recess is provided on the inner bottom surface of the outer container body 12a, while a cross-shaped projection (lock mechanism) that is inserted into the cross-shaped recess is provided on the outer bottom surface of the inner container body 13a. The inner container 13 is accommodated in the outer container 12 and the protrusion 16 is fitted into the recess so that the inner container 13 can be held in the outer container 12 without rotating.
In the double container 11 having such a configuration, first, a mixture obtained by mixing a sterilized cement powder and a hardening liquid in a predetermined ratio is put into a sterilized inner container body 13a, and the inner lid 13b is closed. Next, the inner container 13 is accommodated in the sterilized outer container 12, and the protrusion 16 is inserted into the recess, and then the outer lid 12b is closed. Next, the double container 11 containing the mixture is attached to the centrifugal granulator (not shown) described above. Centrifugal granulation is performed by simultaneously applying revolution rotation and rotation rotation to a centrifugal granulation apparatus equipped with a double container. After the end of centrifugal granulation, the outer container 12b of the double container 11 is opened, the inner container 13 is taken out of the outer container 12, and the inner cover 13b is opened to form particles having an average particle diameter of 1.0 mm to 5.0 mm. Remove material. The obtained particulate material is used as a filler for a bone defect or void.
[0018]
The porous cured body of the present invention obtained by press-molding the filler produced by the above-described method of the present invention into a predetermined shape and curing the obtained press-molded product has a porosity of 50% to 70%. The pore diameter is 0.5 mm to 2.0 mm and the compressive strength is 1 MPa to 10 MPa. By having the above physical properties, when filled into a bone defect or void, it has a high affinity for the living body and excellent bone repairability, and has pores suitable for invasion and assimilation of living tissue, And it can have the shaping property which adapts to the shape of the bone defect to be repaired.
[0019]
Next, the manufacturing method of the multi-porous cured material.
First, using the particulate material obtained in the method for producing a filler in a bone defect or void of the present invention, as shown in FIG. A predetermined amount is filled (FIGS. 2A and 2B). Next, the filling material 23 filled in the bone defect or void is press-molded (FIG. 2C). By this press molding, the porosity and the pore diameter of the filler 23 filled in the defect 22 or the void of the bone 21 can be easily controlled. The press molding is performed within a range of 300 g / cm ^{2 to 2} kg / cm ² . If it is less than 300 g / cm ² , the interface between the bone defect or void surface and the filler is weak, and if it exceeds ² kg / cm ² , the particulate matter itself is crushed by press molding, forming pores, It becomes difficult to control the rate and the pore diameter. The press molding is preferably in the range of 500 g / cm ^{2 to} 1.5 kg / cm ² .
Next, the press-molded product is cured and cured to form a porous cured body. Curing of the press-molded product is performed at 10 ° C. to 40 ° C. for 15 minutes or more. Preferably it is 20 to 30 ° C. and 30 to 60 minutes. The porous cured body thus obtained can easily form various porosities and pore sizes, and can have a formability suitable for the shape of the bone defect to be repaired.
[0020]
Further, by coating the surface of the press-molded product with a gel substance, it is possible to expect effects such as easy shape control of the porous cured body and improved operability. Examples of gel substances include collagen aqueous solutions (such as those manufactured by Koken), fibrin (such as manufactured by Mitsubishi Pharma Corporation), CM chitin (such as manufactured by Katakura Chikkarin), fibronectin (such as manufactured by Takara Bio), alginic acid and hyaluronic acid ( One or two or more substances selected from the group consisting of, for example, manufactured by Kojun Pharmaceutical Co., Ltd. can be used, but not only the substances described above but also gel-like substances widely used in the medical field are used. be able to. The mixing ratio of the particulate substance and the gel substance is 0.5 to 5.0 by weight ratio (particulate substance / gel substance). A preferable weight ratio (particulate matter / gel-like matter) is 1.0 to 4.0. These gel-like substances have no adverse effects on the living body such as an inflammatory reaction in the curing reaction process.
[0021]
In the method for producing a porous cured body of the present invention, after forming a particulate material by centrifugal granulation, the particulate material is mixed with the gel material to form a gel mixture, and the gel mixture is formed into a predetermined shape. It was filled in a press molding. If the gel-like mixture is used and the proportion of the gel-like substance is further increased or the viscosity of the gel is adjusted, the bone defect can be compensated with an injector, and the burden on the patient can be reduced.
[0022]
The porous cured body of the present invention produced by the method of the present invention has a porosity of 50% to 70%, a pore diameter of 0.5 mm to 2.0 mm, and a compressive strength of 1 MPa to 10 MPa. And By having the above physical properties, when filled into a bone defect or void, it has a high affinity for the living body and excellent bone repairability, and has pores suitable for invasion and assimilation of living tissue, And it can have the shaping property which adapts to the shape of the bone defect to be repaired.
The porous cured body of the present invention enables transplantation with a vascular pattern (bundle) by microsurgery technology, and can be expected as a new reconstruction method for relatively large defects such as after tumor resection. As described above, the porous cured body obtained by the production method of the present invention can be applied in the fields of tissue engineering and regenerative medicine.
[0023]
【Example】
Next, examples of the present invention will be described.
<Example 1>
First, α-TCP having an average particle size of 2.0 μm to 8.0 μm, TeCP having an average particle size of 2.0 μm to 8.0 μm, and DCPD having an average particle size of 2.0 μm to 8.0 μm were prepared. Next, α-TCP, TeCP, and DCPD were mixed at the blending ratios shown in Table 1 below to prepare cement powder a to powder d, respectively.
[0024]
[Table 1]

[0025]
Next, water, fresh blood just collected, and a mixture of water and blood were prepared as curable liquids. The curing liquid and powders a to d were mixed at the ratios shown in Table 2 to prepare a mixture. Next, a centrifugal granulator “Spincle” (manufactured by Tokyo Morita Manufacturing Co., Ltd.) was prepared, and this mixture was subjected to centrifugal granulation. The conditions for centrifugal granulation are a revolution rotation of 2000 rpm and a rotation speed of 500 rpm for 20 seconds. The obtained granulated product was a particulate material having a substantially uniform particle size and an average particle size of 1.0 mm to 5.0 mm. Next, the particulate matter was filled into a mold having an inner diameter of 20 mm and a height of 30 mm, and press-molded by pressing the filled material with a cylinder having an outer diameter of 20 mm. The press molding condition was 500 g / cm ² . This press-molded product was cured at 37 ° C. for 40 minutes to obtain a porous cured body. The porosity and the pore diameter of each of the obtained porous cured bodies were measured by a total porosity measurement method, a micrometer, and an optical microscope observation. The results are shown in Table 2 below.
[0026]
[Table 2]

[0027]
As apparent from Table 2, porous cured bodies having various porosities and pore diameters were easily obtained by the production method of the present invention. Therefore, in the method for producing a porous cured body of the present invention, a porous body suitable for invading and assimilating a living tissue can be easily produced, and the obtained porous cured body should be repaired. It can be seen that it has a formability that matches the shape of the bone defect.
[0028]
【The invention's effect】
As described above, the method for producing a filler in a bone defect or void according to the present invention includes α-TCP having an average particle size of 2.0 μm to 8.0 μm and an average particle size of 2.0 μm to 8.0 μm. Of TeCP and DCPD having an average particle size of 2.0 μm to 8.0 μm as main components, TeCP is 10 to 25% by weight, DCPD is 3 to 10% by weight, and a component containing α-TCP is 65 to 87% by weight. A step of preparing a cement powder having a composition ratio of: a step of mixing the cement powder and the hardening liquid at a weight mixing ratio (powder / liquid) of the cement powder and the hardening liquid of 4.5 to 6.5. And centrifugal granulating the mixture to form a particulate material having an average particle size of 1.0 mm to 5.0 mm. By passing through the above steps, various porosity and pore diameter can be obtained, and a filler having high affinity for a living body and excellent bone repairability and suitable for invading and assimilating living tissue can be obtained.
[0029]
In addition, the method for producing the porous cured body of the present invention includes α-TCP having an average particle diameter of 2.0 μm to 8.0 μm, TeCP having an average particle diameter of 2.0 μm to 8.0 μm, and an average particle diameter of 2.0 μm to 8 μm. A step of preparing cement powder containing 0.0 μm DCPD as a main component, TeCP being 10 to 25% by weight, DCPD being 3 to 10% by weight, and a component containing α-TCP being 65 to 87% by weight And a step of mixing the cement powder and the hardening liquid in a weight mixing ratio (powder / liquid) of the cement powder and the hardening liquid of 4.5 to 6.5, and the mixture is centrifuged and averaged A step of forming a particulate material having a diameter of 1.0 mm to 5.0 mm, and mixing the particulate material with a gel material to form a gel mixture, filling the gel mixture into a predetermined shape, and press molding Process and curing the press-molded product And forming a porous cured body. By passing through the above steps, it is possible to easily obtain a porous cured body having various porosities and pore diameters and having a formability suitable for the shape of the bone defect to be repaired.
[Brief description of the drawings]
FIG. 1 is a cross-sectional view of a double container attached to a centrifugal granulator.
FIG. 2 is a cross-sectional view showing a process of filling a bone defect with a particulate substance and press-molding.
[Explanation of symbols]
11 Double container 12 Outer container 12a Outer container body 12b Outer cover 13 Inner container 13a Inner container body 13b Inner cover 14 Knob 16 Projection

Claims

Α-type tribasic calcium phosphate having an average particle size of 2.0 μm to 8.0 μm, quaternary calcium phosphate having an average particle size of 2.0 μm to 8.0 μm, and dibasic calcium phosphate having an average particle size of 2.0 μm to 8.0 μm, respectively. A calcium phosphate cement powder having a composition ratio of 10 to 25% by weight of the fourth calcium phosphate, 3 to 10% by weight of the second calcium phosphate and 65 to 87% by weight of the component containing the α-type third calcium phosphate. And a process of
A step of mixing the calcium phosphate cement powder and the hardening liquid in a weight mixing ratio of the calcium phosphate cement powder and the hardening liquid (powder / liquid) of 4.5 to 6.5;
And a step of forming the mixture by centrifugal granulation to form a particulate material having an average particle size of 1.0 mm to 5.0 mm.

2. The method according to claim 1, wherein the curable liquid is a liquid containing one or more selected from the group consisting of a liquid mainly composed of water, bone marrow fluid, and blood.

Centrifugal granulation is performed by simultaneously adding both rotation and rotation to the container storing the mixture to knead the calcium phosphate cement powder and the hardening liquid in the mixture, and the rotation is 1000 rpm to 3000 rpm. The production method according to claim 1 or 2, wherein the rotation is performed for 10 seconds to 60 seconds under a condition of 200 rpm to 600 rpm.

Α-type tribasic calcium phosphate having an average particle size of 2.0 μm to 8.0 μm, quaternary calcium phosphate having an average particle size of 2.0 μm to 8.0 μm, and dibasic calcium phosphate having an average particle size of 2.0 μm to 8.0 μm, respectively. A calcium phosphate cement powder having a composition ratio of 10 to 25% by weight of the fourth calcium phosphate, 3 to 10% by weight of the second calcium phosphate and 65 to 87% by weight of the component containing the α-type third calcium phosphate. And a process of
A step of mixing the calcium phosphate cement powder and the hardening liquid in a weight mixing ratio of the calcium phosphate cement powder and the hardening liquid (powder / liquid) of 4.5 to 6.5;
Centrifuge granulating the mixture to form a particulate material having an average particle size of 1.0 mm to 5.0 mm;
Mixing the particulate material with a gel material to form a gel mixture;
Pressing the gel-like mixture into a predetermined shape;
A process for producing a porous cured body, comprising: curing and curing the press-molded product to form a porous cured body.

Liquid curing liquid containing water as a main component, one or Claim 4 Symbol mounting method of manufacturing a liquid containing two or more selected from the group consisting of bone marrow and blood.

Centrifugal granulation is performed by simultaneously adding both rotation and rotation to a container storing the mixture to knead the calcium phosphate cement powder and the hardening liquid in the mixture, and the rotation is 1000 rpm to 3000 rpm. according to claim 4 or 5 Symbol mounting method for manufacturing the rotation rotation is carried out 10 seconds to 60 seconds under the conditions of 200Rpm～600rpm.

4. Symbol mounting method of manufacturing a press-molding is carried out in the range of ^{^{300g / cm 2 ~2kg / cm 2}} .

In curing is 10 ° C. to 40 ° C. of the press molded product, according to claim 4 Symbol mounting method of manufacturing takes place in conditions of more than 15 minutes.

The method according to claim 4 Symbol mounting surface of the press-molded product further comprises a step of coating the gel-like material.

The production method according to claim 4 or 9 , wherein a mixing ratio of the particulate substance and the gel substance is 0.5 to 5.0 by weight ratio (particulate substance / gel substance).

The method according to claim 4 , 9 or 10 , wherein the gel substance is one or more substances selected from the group consisting of an aqueous collagen solution, fibrin, carboxymethylchitin, fibronectin, alginic acid and hyaluronic acid.

A cured product obtained by press-molding a filler produced by the method according to any one of claims 1 to 3 into a predetermined shape and curing the obtained press-molded product by curing has a porosity of 50. % To 70%, a pore size of 0.5 mm to 2.0 mm, and a compressive strength of 1 MPa to 10 MPa.

A cured product produced by the process according to any one of claims 4 to 11, 50% to 70% porosity, pore diameter 0.5mm~2.0mm and compression strength is 1MPa~10MPa A porous cured body characterized by the above.