JP5658008B2 - Artificial blood vessel forming substrate with valve, production method of artificial blood vessel with valve using the same, and artificial blood vessel with valve - Google Patents
Artificial blood vessel forming substrate with valve, production method of artificial blood vessel with valve using the same, and artificial blood vessel with valve Download PDFInfo
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- JP5658008B2 JP5658008B2 JP2010257821A JP2010257821A JP5658008B2 JP 5658008 B2 JP5658008 B2 JP 5658008B2 JP 2010257821 A JP2010257821 A JP 2010257821A JP 2010257821 A JP2010257821 A JP 2010257821A JP 5658008 B2 JP5658008 B2 JP 5658008B2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/24—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body
- A61F2/2412—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body with soft flexible valve members, e.g. tissue valves shaped like natural valves
- A61F2/2415—Manufacturing methods
Description
本発明は、欠損組織の代替となる弁付き人工血管を形成するための基材、それを用いた弁付き人工血管の生産方法及び弁付き人工血管に関する。 The present invention relates to a base material for forming a valved artificial blood vessel that substitutes for a defective tissue, a valved artificial blood vessel production method using the same, and a valved artificial blood vessel.
病気や事故で失われた細胞、組織、器官を、人工素材や細胞により再び蘇らせる再生医療の研究が数多くなされている。通常、身体には自己防衛機能があり、体内の浅い位置にトゲ等の異物が侵入した場合には体外へ押し出そうとするが、体内の深い位置に異物が侵入した場合にはその周りに繊維芽細胞が集まってきて、主に繊維芽細胞とコラーゲンからなる結合組織体のカプセルを形成し異物を覆うことにより、体内において隔離することが知られている。このような後者の自己防衛反応を利用して、生体内において生細胞を用いた管状の生体由来組織を形成する方法が複数報告されている（特許文献１〜３参照）。 There have been many studies on regenerative medicine in which cells, tissues, and organs lost due to illness and accidents are revived by artificial materials and cells. Normally, the body has a self-defense function, and when a foreign object such as a thorn enters a shallow position inside the body, it tries to push it out of the body, but when a foreign object enters a deep position inside the body, It is known that fibroblasts gather and sequester in the body by forming a capsule of connective tissue composed mainly of fibroblasts and collagen and covering foreign matter. A plurality of methods for forming a tubular living body tissue using living cells in the living body using the latter self-defense reaction have been reported (see Patent Documents 1 to 3).
特許文献１（特開２００７−３１２８２１）には、棒状構造体の表面に螺旋状溝を形成し、この棒状構造体を生体内に埋入することにより、棒状構造体の表面に膜状の結合組織体を形成し、結合組織体の機械的強度を増加させる点が開示されている。 In Patent Document 1 (Japanese Patent Application Laid-Open No. 2007-312821), a spiral groove is formed on the surface of a rod-like structure, and the rod-like structure is embedded in a living body, whereby a membrane-like bond is formed on the surface of the rod-like structure. It is disclosed that it forms a tissue and increases the mechanical strength of the connective tissue.
特許文献２（特開２００８−２３７８９６）には、棒状構造部材の外周に沿って外郭部材を螺旋形に形成し、これを生体に埋入して、棒状構造部材の外縁に結合組織体を形成する点が開示されている。結合組織体が外郭部材と棒状構造部材の表面との間に侵入し、結合組織体の内面形状が棒状構造部材の表面と同様の平滑面に形成される。結合組織体が、外郭部材を包埋する厚さに形成される。 In Patent Document 2 (Japanese Patent Laid-Open No. 2008-237896), an outer shell member is formed in a spiral shape along the outer periphery of a rod-shaped structural member, and this is embedded in a living body to form a connective tissue body on the outer edge of the rod-shaped structural member. This is disclosed. The connective tissue body enters between the outer member and the surface of the rod-shaped structural member, and the inner surface shape of the connective tissue body is formed on the same smooth surface as the surface of the rod-shaped structural member. A connective tissue body is formed to a thickness that embeds the shell member.
特許文献３（特開２０１０−０９４４７６）には、棒状構造部材の表面に外郭部材を形成し、これを結合組織形成用基材とする点が開示されている。この基材を生体内に埋入することにより、基材表面に膜状の組織体を形成する。その際、外郭部材の材料として、生体適合性に優れるが組織体やその構成成分に侵襲されにくい材料を使用することにより、外郭部材は組織体と癒着し結合組織体の機械的強度が増加されるとともに外郭部材の内面に組織体やその構成成分が露出しない人工血管が得られる。 Patent Document 3 (Japanese Patent Application Laid-Open No. 2010-094476) discloses that an outer member is formed on the surface of a rod-like structural member, and this is used as a connective tissue forming substrate. By embedding this base material in the living body, a film-like tissue body is formed on the surface of the base material. At that time, by using a material that is excellent in biocompatibility as a material of the outer member but is not easily invaded by the tissue body or its constituent components, the outer member adheres to the tissue body and the mechanical strength of the connective tissue body is increased. In addition, an artificial blood vessel in which the tissue body and its constituent components are not exposed on the inner surface of the outer member is obtained.
また、上記特許文献１〜３の人工血管よりも構造が複雑化した、例えば大動脈の大動脈洞（バルサルバ洞）のように、血管壁が半径外方向に膨出した膨大部と、その血流方向上流側の内部において半径方向内側に突出して血流方向に開閉する複数の弁葉と、を有する血管の生産も求められている。膨大部は、弁が開く際には血液の逃げ道となり、閉じた時には血液の溜まり場として機能し、弁の開閉を行いやすくすると共に血液の逆流を防ぐ働きをしている。 In addition, the structure is more complicated than that of the artificial blood vessels of Patent Documents 1 to 3, for example, an aortic sinus (valsalva sinus) of an aorta, and a blood vessel wall bulging in a radially outward direction, and its blood flow direction There is also a need for the production of a blood vessel having a plurality of leaflets that project radially inward and open and close in the direction of blood flow inside the upstream side. The enormous portion serves as a blood escape when the valve is opened, and functions as a blood pool when the valve is closed, facilitating the opening and closing of the valve and preventing the backflow of blood.
このような膨大部及び弁を備えた弁付き人工血管の作成について、特許文献４に開示されている。特許文献４は、生体適合性ブロックコポリマーを含む人工心臓弁及び血管構造のためのスキャフォールドに関するものである。すなわち、複数のモデルパーツからなるバルブモデル上に、エレクトロスピニグ法によりファイバーを堆積させてメッシュ構造を構築する。そこからモデルパーツを離型することにより、バルブモデルのスキャフォールドが完成する。このスキャフォールドは、ポリマー繊維によって形成されたメッシュ様の構造を有する。スキャフォールド上で細胞（内皮細胞や筋線維芽細胞）を培養すると、メッシュ構造が足場となり、その内部で細胞が成長する。このようにして、弁付き人工血管を形成することができる。 Patent Document 4 discloses the creation of a valve-provided artificial blood vessel having such enormous parts and valves. U.S. Patent No. 6,099,059 relates to a scaffold for prosthetic heart valves and vascular structures comprising biocompatible block copolymers. That is, a mesh structure is constructed by depositing fibers on a valve model composed of a plurality of model parts by an electrospinning method. By releasing the model parts from there, the scaffold of the valve model is completed. This scaffold has a mesh-like structure formed by polymer fibers. When cells (endothelial cells and myofibroblasts) are cultured on the scaffold, the mesh structure becomes a scaffold, and the cells grow inside. In this way, a valved artificial blood vessel can be formed.
また、非特許文献１には、スキャフォールドを用いた弁付き人工血管の作成について開示されている。スキャフォールド（高分子のスポンジ材の型）を作り、そこで細胞培養することにより、弁付き人工血管を形成することができる。 Non-Patent Document 1 discloses creation of a valved artificial blood vessel using a scaffold. An artificial blood vessel with a valve can be formed by making a scaffold (polymer sponge material type) and culturing cells there.
しかしながら、特許文献４記載及び非特許文献１の弁付き人工血管は、人工的なスキャフォールド（異物）を足場としてその内部に細胞が一体化したものであるため、体内へ移植した後、スキャフォールドが分解されるまでの間、拒絶反応や炎症反応が起こるおそれがある。また、特許文献４及び非特許文献１記載の弁付き人工血管は、人工物を内包しているため、移植後に体の成長に伴って大きくならず、特に小児患者の場合には永久的に使用することが困難であり、再度移植の必要性がある。 However, since the artificial blood vessel with a valve described in Patent Document 4 and Non-Patent Document 1 has an artificial scaffold (foreign substance) as a scaffold and cells are integrated therein, after being transplanted into the body, the scaffold There may be a rejection or inflammatory reaction until is decomposed. In addition, since the artificial blood vessel with valve described in Patent Document 4 and Non-Patent Document 1 contains an artificial object, it does not increase with the growth of the body after transplantation, and is permanently used particularly in the case of a pediatric patient. It is difficult to do and there is a need for transplantation again.
さらにまた、特許文献４によると、第２モデルパーツの遊離端部分における３つの端面と、これに相補的な第１モデルパーツの遊離端領域における端面との間で弁葉が形成されることになるが、図３４に示すように、形成されたスキャフォールド３１は各弁葉が連続しているため、後で３枚の弁葉に切断する工程が必要となり手間がかかる（特許文献４の段落００４５参照）。 Furthermore, according to Patent Document 4, a leaflet is formed between three end surfaces in the free end portion of the second model part and an end surface in the free end region of the first model part that is complementary thereto. However, as shown in FIG. 34, since the formed scaffold 31 has each leaflet continuous, a process of cutting into three leaflets later is required, which is troublesome (paragraph of Patent Document 4). 0045).
本発明は、上記に鑑み、生体組織から構成される膨大部及び弁を備えた弁付き人工血管を形成することのできる基材、これを用いた弁付き人工血管の生産方法及び弁付き人工血管を提供することを目的とする。 In view of the above, the present invention provides a base material capable of forming an artificial blood vessel with a valve provided with enormous parts composed of living tissue and a valve, a method for producing an artificial blood vessel with a valve using the same, and an artificial blood vessel with a valve The purpose is to provide.
本発明にかかる人工血管形成用基材は、生体組織材料の存在する環境下におくことにより、その表面に膜状の組織体を形成し、組織体を剥離して弁付き人工血管を形成するための基材であって、血管の上流側管状部を形成する第１柱状体と、血管の下流側管状部を形成する第２柱状体と、上流側管状部と下流側管状部の間にあって血管壁が半径外方向に膨出する膨大部、及びその内部において半径方向内側に突出して血流方向に開閉可能な弁葉を形成するための複数の膨出体と、膨出体を第１柱状体および／または第２柱状体に着脱自在に係止する係止手段とを備え、係止手段は、第１柱状体及び第２柱状体の一方又は両方の軸方向端面に形成され軸方向に凹んだ凹部と、膨出体の本体から半径方向内側に張り出して凹部に係止することにより、膨出体が第１柱状体及び第２柱状体に対して半径方向、周方向及び軸方向に位置ずれするのを規制する係止部とを備え、膨出体は、その本体の外周面が膨大部形成面となり、膨出体本体と第１柱状体及び／又は第２柱状体との間に設けられた隙間が弁葉形成部となることを特徴とするものである。第１柱状体及び第２柱状体はその外周面が血管の形成面となるため、その大部分を円柱状とするのが好ましい。 The artificial blood vessel forming substrate according to the present invention forms a membrane-like tissue body on the surface thereof by placing it in an environment where a biological tissue material exists, and peels the tissue body to form a valved artificial blood vessel. A first columnar body that forms an upstream tubular portion of a blood vessel, a second columnar body that forms a downstream tubular portion of the blood vessel, and an upstream tubular portion and a downstream tubular portion. A plurality of bulging bodies for forming a bulge part in which a blood vessel wall bulges in a radially outward direction, a valve leaf that projects inward in the radial direction and can be opened and closed in a blood flow direction, and A locking means for detachably locking the columnar body and / or the second columnar body, and the locking means is formed on one or both axial end surfaces of the first columnar body and the second columnar body and is axially And a recess recessed inward and projecting radially inward from the body of the bulging body The bulging body is provided with a locking portion for restricting displacement of the bulging body in the radial direction, the circumferential direction, and the axial direction with respect to the first columnar body and the second columnar body, and the bulging body is an outer peripheral surface of the main body. Is an enormous portion forming surface, and a gap provided between the bulging body main body and the first columnar body and / or the second columnar body serves as a leaflet forming portion. Since the outer peripheral surface of the first columnar body and the second columnar body serves as a blood vessel forming surface, most of the first columnar body and the second columnar body are preferably cylindrical.
このような弁付き人工血管形成用基材を、生体組織材料の存在する環境下に所定期間おいた後（設置工程）、環境下から組織体で被覆された弁付き人工血管形成用基材を取り出し（取り出し工程）、組織体から弁付き人工血管形成用基材を取り出す（分離工程）ことにより、生体組織から構成される膨大部及び弁を有する弁付き人工血管を形成することができる。また、分離工程において、基材の周りに形成された組織体から弁付き人工血管形成用基材を取り出す際には、基材を分解して取り出すことができるので、組織体を傷つけずに簡単に抜き出すことができる。このように形成された弁付き人工血管は、大動脈洞（バルサルバ洞）、肺動脈洞、頚動脈洞、上錐体動脈洞、横静脈洞、下垂体静脈洞等の膨大部及び弁を有する血管に適用可能である。 After such a valved artificial blood vessel forming base material is placed in an environment where biological tissue material exists for a predetermined period (installation step), the valved artificial blood vessel forming base material covered with a tissue body from the environment is used. By taking out (extracting step) and taking out the valved artificial blood vessel forming base material from the tissue body (separating step), it is possible to form a valved artificial blood vessel having an enormous portion composed of living tissue and a valve. Also, in the separation step, when removing the valved artificial blood vessel forming base material from the tissue body formed around the base material, the base material can be disassembled and taken out, so that the tissue body is not damaged. Can be extracted. The artificial blood vessel with a valve formed in this way is applied to a blood vessel having a large part and a valve such as aortic sinus (valsalva sinus), pulmonary sinus, carotid sinus, superior cone sinus, lateral venous sinus, pituitary sinus Is possible.
膨出体の係止部は、膨出体本体よりも半径内側方向に飛び出すようにして張り出しているので、係止部が第１柱状体及び／又は第２柱上体の凹部に係止されることにより、膨出体本体が第１柱状体及び第２柱上体の表面から飛び出した状態となる。この膨出体本体の外周面が膨大部形成面となり、膨出体本体と第１柱状体及び／又は第２柱状体との間に設けられた隙間（弁葉形成部）で弁葉を形成することができる。弁葉形成部で１つの完成した弁葉を形成することができるので、切断作業を行わずとも弁葉を完成することができる。 Since the locking portion of the bulging body protrudes so as to protrude radially inward from the bulging body main body, the locking portion is locked to the concave portion of the first columnar body and / or the second column upper body. As a result, the bulging body main body protrudes from the surfaces of the first columnar body and the second columnar body. The outer peripheral surface of the bulging body main body becomes the enormous portion forming surface, and a leaflet is formed by a gap (valve forming portion) provided between the bulging body main body and the first columnar body and / or the second columnar body. can do. Since one complete leaflet can be formed by the leaflet forming portion, the leaflet can be completed without performing a cutting operation.
係止手段の凹部は、第１柱状体又は第２柱状体のいずれか一方に設けてもよいが、第１柱状体及び第２柱状体の両方に設けて両凹部を重ね合わせ、その重ね合わせた凹部内に膨出体の係止部を収納するようにしてもよい。 The concave portion of the locking means may be provided in either the first columnar body or the second columnar body, but is provided in both the first columnar body and the second columnar body, and the both concave portions are overlapped, and the overlapping You may make it accommodate the latching | locking part of a bulging body in the recessed part.
また、係止手段は係止部を凹部に収納しながら、第１柱状体及び第２柱状体で軸方向上下から挟みこんで係止するようにするのが好ましい。組織体から弁付き人工血管形成用基材を取り出す分離工程において、第１柱状体及び第２柱状体を膨出体から上下に分解して、組織体の内腔より取り出した後、複数の膨出体を内腔から取り出すようにすれば、全ての基材を軸方向に抜き出すことができるので、周囲に形成されている組織体を傷つけずに行うことができる。 Further, it is preferable that the locking means is locked by being sandwiched from above and below in the axial direction between the first columnar body and the second columnar body while the locking portion is housed in the recess. In the separation step of removing the valved artificial blood vessel forming base material from the tissue body, the first columnar body and the second columnar body are disassembled up and down from the bulge body and taken out from the lumen of the tissue body, and then a plurality of bulges are separated. If the extracted body is taken out from the lumen, all the base materials can be extracted in the axial direction, so that it is possible to carry out without damaging the surrounding tissue body.
第１柱状体、第２柱状体及び膨出体を一体的に固定する固定手段を備えるのが好ましい。一体化された第１柱状体、第２柱状体及び膨出体のユニットを、生体組織材料の存在する環境下に安定しておくことができる。 It is preferable to provide fixing means for fixing the first columnar body, the second columnar body, and the bulging body integrally. The integrated unit of the first columnar body, the second columnar body, and the bulging body can be kept stable in an environment where the biological tissue material exists.
固定手段は様々な態様をとることができる。１つの態様として、固定手段は、第１柱状体及び第２柱状体の中心を軸方向に貫通するように形成された貫通孔と、貫通孔を挿通して膨出体の係止部、第１柱状体及び第２柱状体を一体的に固定する貫通軸と、を備える構成とすることができる。貫通軸は、棒状体、ネジ、磁石など貫通孔に挿通可能な構造であればいずれの形態をとってよい。例えば、固定手段は、貫通軸の外周に刻設された雄ネジと、該雄ネジに螺合するよう第１柱状体及び／又は第２柱状体の貫通孔の周面に形成された雌ネジとを備えるように構成すればよい。雄ネジを貫通孔の雌ネジにねじ込めば、膨出体の係止部、第１柱状体及び第２柱状体を一体的に固定することができる。 The fixing means can take various forms. As one aspect, the fixing means includes a through-hole formed so as to penetrate the centers of the first columnar body and the second columnar body in the axial direction, a locking portion of the bulging body through the through-hole, And a through shaft that integrally fixes the first columnar body and the second columnar body. The through shaft may take any form as long as it has a structure that can be inserted into the through hole, such as a rod-like body, a screw, or a magnet. For example, the fixing means includes a male screw engraved on the outer periphery of the through shaft and a female screw formed on the peripheral surface of the through hole of the first columnar body and / or the second columnar body so as to be screwed into the male screw. May be provided. If the male screw is screwed into the female screw of the through hole, the locking portion of the bulging body, the first columnar body, and the second columnar body can be fixed integrally.
また、２つ目の態様として、固定手段は、第１柱状体及び第２柱状体のうちの一方に形成された雄ネジと、該雄ネジに螺合するよう第１柱状体及び第２柱状体のうちの他方に形成された雌ネジとを備える構成とすることができる。一方の柱状体の雄ネジを他方の柱状体の雌ネジに螺合することにより、両柱状体及び膨出体を一体的に固定することができる。 As a second aspect, the fixing means includes a male screw formed on one of the first columnar body and the second columnar body, and the first columnar body and the second columnar body so as to be screwed to the male screw. It can be set as the structure provided with the internal thread formed in the other of the bodies. By screwing the male screw of one columnar body into the female screw of the other columnar body, both the columnar body and the bulging body can be fixed integrally.
さらに３つ目の態様として、固定手段は、第１柱状体及び第２柱状体のうちの一方に配置された磁性体と、第１柱状体及び第２柱状体のうちの他方に配置され磁性体に吸着する被磁性体とを備える構成とすることができる。一方の柱状体の磁性体に他方の柱状体の被磁性体を吸着させることにより、両柱状体及び膨出体を一体的に固定することができる。 Furthermore, as a third aspect, the fixing means is a magnetic body disposed on one of the first columnar body and the second columnar body and a magnetic body disposed on the other of the first columnar body and the second columnar body. It can be set as the structure provided with the to-be-magnetized body adsorb | sucked to a body. By adsorbing the magnetic body of one columnar body to the magnetic body of the other columnar body, both the columnar bodies and the bulging body can be fixed integrally.
４つ目の態様として、固定手段は、第１柱状体及び第２柱状体のうちの一方に配置された係合爪と、該係合爪に係脱自在に係合するよう第１柱状体及び第２柱状体のうちの他方に形成された係合穴とを備える構成とすることができる。一方の柱状体の係合爪を他方の柱状体の係合穴に係合することにより、両柱状体及び膨出体を一体的に固定することができる。 As a fourth aspect, the fixing means includes an engaging claw disposed on one of the first columnar body and the second columnar body, and the first columnar body so as to be detachably engaged with the engaging claw. And an engagement hole formed in the other of the second columnar bodies. By engaging the engaging claws of one columnar body with the engaging holes of the other columnar body, both the columnar body and the bulging body can be fixed integrally.
弁葉形成部の半径方向の厚みは、０．３〜１.０ｍｍとするのが好ましい。生体における弁葉の厚みは約０．２ｍｍであるが、弁付き人工血管の弁葉を生体と同じ０．２ｍｍとすると、体内へ移植した後、安定するまでの間血流によって弁葉が薄くなって破けてしまい、弁としての機能を損なってしまうおそれがある。そこで、弁葉形成部の厚み、すなわち弁葉の厚みを０．３〜１．０ｍｍ、より好ましくは０．３〜０．８ｍｍとすれば、移植後に弁葉が薄くなっても最終的に約０．２ｍｍで落ち着くので、弁の働きを持続させることができる。 The radial thickness of the leaflet forming portion is preferably 0.3 to 1.0 mm. The thickness of the leaflets in the living body is about 0.2 mm. However, if the valve leaflet of the artificial blood vessel with a valve is 0.2 mm, which is the same as that of the living body, the leaflets are thinned by the blood flow until it becomes stable after transplantation into the body. It may be broken and the function as a valve may be impaired. Therefore, if the thickness of the leaflet forming part, that is, the thickness of the leaflet is 0.3 to 1.0 mm, more preferably 0.3 to 0.8 mm, even if the leaflet becomes thin after transplantation, the thickness is finally about Since it settles at 0.2 mm, the function of the valve can be maintained.
膨出体本体は、膨出体本体の半径方向外側面と弁葉形成部とを連通して、組織体を弁葉形成部側に侵入しやすくする侵入孔を有するのが好ましい。組織体が弁葉形成部に侵入しやすくなるため、分厚い弁葉の形成を早めることができる。なお、侵入孔の数は１つでもよいし、よりたくさん組織体を侵入させるために複数設けるようにしてもよい。 The bulging body main body preferably has an intrusion hole that allows the radially outer surface of the bulging body main body and the leaflet forming portion to communicate with each other so that the tissue body can easily enter the leaflet forming portion side. Since the tissue easily enters the leaflet forming part, the formation of thick leaflets can be accelerated. Note that the number of intrusion holes may be one, or a plurality of intrusion holes may be provided in order to infiltrate more tissues.
１又は複数の膨出体本体の外面に接続される第３の柱状体を備え、第３の柱状体の外周面が膨大部から分岐する血管の形成面とすることができる。例えば、心臓の血管の場合は、第３の柱状体の周りに形成される血管を冠動脈とすることができる。また、第３の柱状体は、膨出体本体の外面に着脱自在とされるのが好ましい。 A third columnar body connected to the outer surface of one or a plurality of bulging body bodies may be provided, and the outer peripheral surface of the third columnar body may be a blood vessel formation surface that branches off from the enormous portion. For example, in the case of a blood vessel of the heart, a blood vessel formed around the third columnar body can be a coronary artery. Moreover, it is preferable that the third columnar body is detachable from the outer surface of the bulging body main body.
第１柱状体及び第２柱状体の素材は限定されるものではなくアクリル樹脂などの素材を用いてもよいが、第１柱状体及び／又は第２柱状体の少なくとも表面がシリコーン樹脂等の弾性体であるのが好ましい。弾性体の表面には生体組織による膜が厚く形成されるため、安定した生体組織を形成することができる。 The material of the first columnar body and the second columnar body is not limited, and a material such as acrylic resin may be used, but at least the surface of the first columnar body and / or the second columnar body is elastic such as silicone resin. The body is preferred. Since a film made of biological tissue is formed thick on the surface of the elastic body, a stable biological tissue can be formed.
基材の表面粗さ（Ｒａ）が、５０μｍ以下とするのが好ましい。表面粗さ（Ｒａ）を５０μｍ以下とすることにより、基材の周囲に形成される組織体の厚みをより厚く形成することができる。表面粗さ（Ｒａ）が０．１μｍと、鏡面に近い基材であっても、その周囲に厚みの大きい組織体を形成することができる。なお、平均粗さ（Ｒａ）とは、「算術平均粗さ」のことであり、ＪＩＳ Ｂ ０６０１−１９９４「表面粗さ−定義」に規定されている「算術平均粗さ（Ｒａ）」を示す。 The surface roughness (Ra) of the substrate is preferably 50 μm or less. By setting the surface roughness (Ra) to 50 μm or less, the thickness of the tissue formed around the substrate can be increased. Even if the surface roughness (Ra) is 0.1 μm and the substrate is close to a mirror surface, a thick tissue body can be formed around the substrate. The average roughness (Ra) is “arithmetic average roughness” and indicates “arithmetic average roughness (Ra)” defined in JIS B 0601-1994 “Surface Roughness—Definition”. .
なお、この基材の表面粗さについては、弁及び膨大部を有する血管に限定されるものではなく、弁又は膨大部を有しない血管を含む管状組織、膜状組織等の結合組織を形成するための基材にも適用することができる。すなわち、本発明は、基材の表面粗さ（Ｒａ）が５０μｍ以下である生体由来組織形成用基材も提供することができる。形成された生体由来組織は、管状組織、膜状組織及び弁状組織を含む結合組織となる。管状組織としては、血管、リンパ管、気管、胆管、腸管、尿道管、尿管、卵管等が挙げられる。膜状組織としては、心膜、硬膜、角膜、皮膚、心膜等が挙げられ、表層を覆うあるいは膜状で機能する平面状の組織である。弁状組織としては、心臓弁、静脈弁等が挙げられる。 The surface roughness of the base material is not limited to a valve and a blood vessel having an enormous portion, but forms a connective tissue such as a tubular tissue or a membrane-like tissue including a blood vessel having no valve or an enormous portion. It can also be applied to a substrate for this purpose. That is, the present invention can also provide a biological tissue-forming base material having a surface roughness (Ra) of 50 μm or less. The formed biological tissue becomes a connective tissue including a tubular tissue, a membranous tissue, and a valve-like tissue. Examples of the tubular tissue include blood vessels, lymphatic vessels, trachea, bile ducts, intestinal tracts, urethral tubes, ureters, oviducts, and the like. Examples of the membranous tissue include pericardium, dura mater, cornea, skin, pericardium and the like, and are planar tissues that cover the surface layer or function in a membranous form. Examples of valve-like tissues include heart valves and venous valves.
また、本発明において、「生体組織材料」とは、所望の生体由来組織を形成するうえで必要な物質のことであり、例えば、線維芽細胞、平滑筋細胞、内皮細胞、幹細胞、ＥＳ細胞、ｉＰＳ細胞等の動物細胞、各種たんぱく質類（コラーゲン、エラスチン）、ヒアルロン酸等の糖類、その他、細胞成長因子、サイトカイン等の生体内に存在する各種の生理活性物質が挙げられる。 In the present invention, the “biological tissue material” refers to a substance necessary for forming a desired biological tissue. For example, fibroblasts, smooth muscle cells, endothelial cells, stem cells, ES cells, Examples include animal cells such as iPS cells, various proteins (collagen, elastin), saccharides such as hyaluronic acid, and other various physiologically active substances existing in vivo such as cell growth factors and cytokines.
また、本発明において、「生体組織材料」には、ヒト、イヌ、ウシ、ブタ、ヤギ、ヒツジ等の哺乳類動物、鳥類、魚類、その他の動物に由来するもの、又はこれと同等の人工材料が含まれる。また、移植対象者に対して、自家移植、同種移植、異種移植のいずれでもよいが、拒絶反応を避ける観点からなるべく自家移植か同種移植が好ましい。また、異種移植の場合には、拒絶反応を避けるため公知の脱細胞化処理などの免疫源除去処理を施すのが好ましい。 In the present invention, the “biological tissue material” is derived from mammals such as humans, dogs, cows, pigs, goats and sheep, birds, fish and other animals, or artificial materials equivalent thereto. included. In addition, autotransplantation, allotransplantation, and xenotransplantation may be performed for the transplant recipient, but autotransplantation or allotransplantation is preferable from the viewpoint of avoiding rejection. In the case of xenotransplantation, it is preferable to perform an immunogen removal process such as a known decellularization process in order to avoid rejection.
また、「生体組織材料の存在する環境下」とは、動物（ヒト、イヌ、ウシ、ブタ、ヤギ、ヒツジ等の哺乳類動物、鳥類、魚類、その他の動物）の生体内（例えば、四肢部、腰部、背部又は腹部などの皮下、もしくは腹腔内への埋入）、又は、動物の生体外において、生体組織材料を含有する人工環境内を表す。また、動物へ埋入の方法をとる場合には低侵襲な方法で行うことと、動物愛護の精神を尊重し、十分な麻酔下で最小限の切開術で行うことが好ましい。 In addition, “in the environment where biological tissue material is present” means in vivo (for example, limbs, mammals such as humans, dogs, cows, pigs, goats, sheep, birds, fish, and other animals). It represents the inside of an artificial environment containing a biological tissue material outside the living body of an animal). In addition, it is preferable to use a minimally invasive method under the sufficient anesthesia with respect to the spirit of animal welfare when taking the method of implantation into animals.
本発明の弁付き人工血管形成用基材によれば、基材の周りに形成された組織体から弁付き人工血管形成用基材を取り出す際に、基材を分解して取り出すことができるので、組織体を傷つけずに簡単に抜き出すことができる。そして、生体組織から構成される膨大部及び弁を有する弁付き人工血管を形成することができる。 According to the valved artificial blood vessel forming base material of the present invention, when the valved artificial blood vessel forming base material is taken out from the tissue formed around the base material, the base material can be disassembled and taken out. It can be easily extracted without damaging the tissue. And the artificial blood vessel with a valve which has the enormous part comprised from a biological tissue and a valve can be formed.
また、膨出体本体と第１柱状体及び／又は第２柱状体との間に設けられた隙間（弁葉形成部）で、１つの完成した弁葉を形成することができ、切断作業が不要となる。 In addition, one completed leaflet can be formed in the gap (leaflet forming portion) provided between the bulging body main body and the first columnar body and / or the second columnar body, and the cutting operation can be performed. It becomes unnecessary.
本発明の弁付き人工血管形成用基材１は、生体組織材料の存在する環境下におくことにより、その表面に膜状の組織体２を形成し、組織体２を剥離して弁付き人工血管３を形成するための基材である。なお、図１５において、２点鎖線は弁葉が閉じた状態を示す仮想線である。また、図１９〜図２３は血管３の内部構造を見やすくするために切り開いたものであり、実際の生産工程において切り開き作業を行う必要はない。また、血流方向を矢印Ｂで示す。 The artificial blood vessel forming substrate 1 with a valve according to the present invention is placed in an environment in which a biological tissue material exists, thereby forming a membrane-like tissue body 2 on the surface, and peeling the tissue body 2 to provide an artificial valved device. This is a base material for forming the blood vessel 3. In FIG. 15, a two-dot chain line is a virtual line indicating a state where the leaflets are closed. 19 to 23 are cut to make the internal structure of the blood vessel 3 easier to see, and it is not necessary to perform the cutting operation in the actual production process. The direction of blood flow is indicated by arrow B.
弁付き人工血管形成用基材１は、図１、図２及び図１０に示すように、血管３の血流方向上流側部分である上流側管状部４を形成する第１柱状体５と、血管３の血流方向下流側部分である下流側管状部６を形成する第２柱状体７と、上流側管状部４と下流側管状部６の間にあって血管壁が半径外方向に膨出する膨大部８、及びその内部において半径方向内側に突出して血流方向に開閉可能な弁葉９を形成するための複数の膨出体１０と、膨出体１０を第１柱状体５および第２柱状体７に着脱自在に係止する係止手段１１と、第１柱状体５、第２柱状体７及び膨出体１０を一体的に固定する固定手段１２を備える。 As shown in FIGS. 1, 2, and 10, the artificial blood vessel forming substrate 1 with a valve includes a first columnar body 5 that forms an upstream tubular portion 4 that is an upstream side portion of the blood vessel 3 in the blood flow direction, Between the second columnar body 7 forming the downstream tubular portion 6, which is the downstream portion of the blood vessel 3 in the blood flow direction, and between the upstream tubular portion 4 and the downstream tubular portion 6, the blood vessel wall bulges radially outward. A plurality of bulges 10 for forming the enormous portion 8 and a valve leaf 9 projecting inward in the radial direction and opening and closing in the blood flow direction, and the bulges 10 are formed into the first columnar body 5 and the second columnar body 10. Locking means 11 detachably locked to the columnar body 7 and fixing means 12 for fixing the first columnar body 5, the second columnar body 7 and the bulging body 10 integrally are provided.
弁付き人工血管形成用基材１の材料は、生体に埋入した際に大きく変形することが無い強度（硬度）を有しており、化学的安定性があり、滅菌などの負荷に耐性があり、生体を刺激する溶出物が無いまたは少ない樹脂が好ましく、例えばシリコーン樹脂、アクリル樹脂等が挙げられるがこれに限定されるものではない。なお、弾性の高いシリコーン樹脂等の弾性体を用いると、その表面に形成される組織体２の厚みが厚くなる傾向がある。したがって、弁付き人工血管形成用基材１の全て、または、少なくとも組織体２と接触する第１柱状体５、第２柱状体７及び膨出体１０の表面をシリコーン樹脂等の弾性体から構成するのが好ましい。 The material of the artificial blood vessel forming substrate 1 with a valve has a strength (hardness) that does not greatly deform when implanted into a living body, has chemical stability, and is resistant to a load such as sterilization. Yes, a resin with no or little eluate that stimulates the living body is preferable, and examples thereof include, but are not limited to, a silicone resin and an acrylic resin. In addition, when elastic bodies, such as a highly elastic silicone resin, are used, there exists a tendency for the thickness of the structure | tissue 2 formed in the surface to become thick. Therefore, the whole surface of the valve-provided artificial blood vessel forming substrate 1 or the surfaces of the first columnar body 5, the second columnar body 7 and the bulging body 10 in contact with at least the tissue body 2 is made of an elastic body such as silicone resin. It is preferable to do this.
また、弁付き人工血管形成用基材１の表面粗さ（Ｒａ）は、０．１〜５０μｍとされる。基材１の表面粗さ（Ｒａ）が９０μｍのとき、その基材１表面に形成される組織体２の厚みは４０．９±１０．５μｍ、基材１の表面粗さ（Ｒａ）が５０μｍのとき、その基材１表面に形成される組織体２の厚みは１２４．４±１７．４μｍ、基材１の表面粗さ（Ｒａ）が２０μｍのとき、その基材１表面に形成される組織体２の厚みは１５７．４±３９．５μｍとなった。したがって、弁付き人工血管形成用基材１の表面粗さ（Ｒａ）を５０μｍ以下とすれば、その基材１表面に形成される組織体２の厚みが十分に厚いものとなり好ましい。組織体２の厚みが厚ければ、形成される血管３の自立性が高まり、生体内の血管との吻合操作が行いやすい。本実施形態においては、基材１の表面粗さ（Ｒａ）を２０μｍとした。 Further, the surface roughness (Ra) of the valved artificial blood vessel forming substrate 1 is set to 0.1 to 50 μm. When the surface roughness (Ra) of the substrate 1 is 90 μm, the thickness of the tissue 2 formed on the surface of the substrate 1 is 40.9 ± 10.5 μm, and the surface roughness (Ra) of the substrate 1 is 50 μm. In this case, when the thickness of the tissue body 2 formed on the surface of the substrate 1 is 124.4 ± 17.4 μm and the surface roughness (Ra) of the substrate 1 is 20 μm, the thickness is formed on the surface of the substrate 1. The thickness of the tissue body 2 was 157.4 ± 39.5 μm. Therefore, if the surface roughness (Ra) of the valve-provided artificial blood vessel forming substrate 1 is 50 μm or less, the thickness of the tissue body 2 formed on the surface of the substrate 1 is preferably sufficiently thick. If the thickness of the tissue body 2 is large, the self-sustainability of the blood vessel 3 to be formed increases, and an anastomosis operation with the blood vessel in the living body is easy to perform. In the present embodiment, the surface roughness (Ra) of the substrate 1 is 20 μm.
第１柱状体５は、シリコーン樹脂製、第２柱状体７は、アクリル樹脂製の円柱状に形成され、それぞれ外径２０ｍｍ、全長約３０ｍｍとされる。また、第１柱状体５及び第２柱状体７の各中心部分には、直径１０ｍｍ程度の貫通孔１３が形成される。第１柱状体５及び第２柱状体７は、半径外方向に突出する部材がなく、その外周面が人工血管３の管状部の内腔面を形成する。第１柱状体５及び第２柱状体７の表面には軸方向に延びる浅い細溝１４が複数形成されている。細溝１４により組織体２を引き抜くときに空気が入るため、抜きやすくなる。なお、第１柱状体５及び第２柱状体７の外径により血管３の太さが決定されるため、目的の太さによってその直径を変更可能である。 The first columnar body 5 is made of silicone resin, and the second columnar body 7 is formed in a cylindrical shape made of acrylic resin, and each has an outer diameter of 20 mm and a total length of about 30 mm. In addition, a through hole 13 having a diameter of about 10 mm is formed in each central portion of the first columnar body 5 and the second columnar body 7. The first columnar body 5 and the second columnar body 7 do not have a member projecting radially outward, and the outer peripheral surface thereof forms the lumen surface of the tubular portion of the artificial blood vessel 3. A plurality of shallow narrow grooves 14 extending in the axial direction are formed on the surfaces of the first columnar body 5 and the second columnar body 7. Since air enters when the tissue body 2 is pulled out by the narrow groove 14, it is easy to pull out. In addition, since the thickness of the blood vessel 3 is determined by the outer diameters of the first columnar body 5 and the second columnar body 7, the diameter can be changed depending on the target thickness.
第１柱状体５及び第２柱状体７は、それぞれの合わせ面側の端面に、軸方向に凹んだ凹部１５ａ、１５ｂが複数形成される。凹部１５ａ、１５ｂは、弁葉９の数に合わせて本実施形態においては３つずつ形成され、第１柱状体５及び第２柱状体７の間で対応する位置に形成される。また、凹部１５ａ、１５ｂは、半径内方向側が幅広に形成された係止溝１６を有する。 The first columnar body 5 and the second columnar body 7 are formed with a plurality of recesses 15a and 15b that are recessed in the axial direction on the end surfaces of the respective mating surfaces. In the present embodiment, three recesses 15 a and 15 b are formed according to the number of leaflets 9, and are formed at corresponding positions between the first columnar body 5 and the second columnar body 7. Moreover, the recessed parts 15a and 15b have the locking groove | channel 16 in which the radial inner side was formed wide.
膨出体１０は、アクリル樹脂製であり、図４〜図９に示すように、膨出体本体１７と、膨出体本体１７から半径方向内側に張り出した係止部１８とから構成される。膨出体１０は、弁葉９の数に合わせて本実施形態においては３つ設けられる。係止部１８は、膨出体本体１７よりも半径内側方向に飛び出すようにして張り出しており、これが第１柱状体５の凹部１５ａと第２柱状体７の凹部１５ｂとを重ね合わせた部分に係止されることにより、膨出体本体１７が第１柱状体５及び第２柱状体７の表面から飛び出した状態となる。 As shown in FIGS. 4 to 9, the bulging body 10 is made of an acrylic resin and includes a bulging body main body 17 and a locking portion 18 projecting radially inward from the bulging body main body 17. . In the present embodiment, three bulging bodies 10 are provided in accordance with the number of leaflets 9. The locking portion 18 protrudes so as to protrude radially inward from the bulging body main body 17, and this is a portion where the concave portion 15 a of the first columnar body 5 and the concave portion 15 b of the second columnar body 7 are overlapped. By being locked, the bulging body body 17 protrudes from the surfaces of the first columnar body 5 and the second columnar body 7.
係止部１８は、図１０に示すように、第１柱状体５の凹部１５ａと第２柱状体７の凹部１５ｂとを重ね合わせた部分の形状と相補的な形状に形成される。したがって、膨出体１０が第１柱状体５及び第２柱状体７に対して周方向及び軸方向に位置ずれするのを規制する。また、係止部１８は、その半径内側の先端がフランジ状に拡大した幅広部１９を備えており、この幅広部１９が凹部１５ａ、１５ｂの係止溝１６に嵌まることにより、膨出体１０が第１柱状体５及び第２柱状体７に対して半径方向に位置ずれするのを規制する。 As shown in FIG. 10, the locking portion 18 is formed in a shape complementary to the shape of the overlapping portion of the concave portion 15 a of the first columnar body 5 and the concave portion 15 b of the second columnar body 7. Therefore, displacement of the bulging body 10 in the circumferential direction and the axial direction with respect to the first columnar body 5 and the second columnar body 7 is restricted. Moreover, the latching | locking part 18 is equipped with the wide part 19 which the front-end | tip inside the radius expanded to the flange shape, and when this wide part 19 fits into the latching groove | channel 16 of recessed part 15a, 15b, a bulging body 10 is restricted from being displaced in the radial direction with respect to the first columnar body 5 and the second columnar body 7.
膨出体本体１７は、図３に示すように、第１柱状体５及び第２柱状体７の側方へ膨出するような湾曲面を有しており、この湾曲した外周面が膨大部８の内腔面を形作る膨大部形成面２０となる。膨出体本体１７は、図４及び図５に示すように、その上流側縁がＵ字状に湾曲して形成される。３つの膨出体本体１７は、図３に示すように、周方向にわたって連続するように設けられる。また、膨出体本体１７は、係止部１８の下縁（上流側縁）よりも上側（血流方向下流側）の部位１７ａは、第１柱状体５及び第２柱状体７と密着可能とされる。この構造によって、第１柱状体５と第２柱状体７との間の隙間を覆い隠すことができ、隙間への組織体２の余分な侵入を防止できる。なお、図３３に示すように、膨出体本体１７で第１柱状体５と第２柱状体との境界を周方向にわたって覆うようにしてもよい。この構造によると、第１柱状体５及び第２柱状体７の隙間を全て覆い隠すことができる。 As shown in FIG. 3, the bulging body main body 17 has a curved surface that bulges to the side of the first columnar body 5 and the second columnar body 7, and the curved outer peripheral surface is a huge portion. It becomes the enormous part formation surface 20 which forms the 8 lumen surfaces. As shown in FIGS. 4 and 5, the bulging body main body 17 is formed such that its upstream edge is curved in a U shape. As shown in FIG. 3, the three bulging body main bodies 17 are provided so as to be continuous over the circumferential direction. Further, the bulging body main body 17 can be in close contact with the first columnar body 5 and the second columnar body 7 at a portion 17a on the upper side (downstream side in the blood flow direction) of the lower edge (upstream side edge) of the locking portion 18. It is said. With this structure, the gap between the first columnar body 5 and the second columnar body 7 can be obscured, and extra entry of the tissue body 2 into the gap can be prevented. As shown in FIG. 33, the bulging body main body 17 may cover the boundary between the first columnar body 5 and the second columnar body in the circumferential direction. According to this structure, all the gaps between the first columnar body 5 and the second columnar body 7 can be covered.
また、図２、図５、図９及び図１１に示すように、膨出体本体１７の上側の部位１７ａは第１柱状体５及び第２柱状体７と密着しているが、その下部（上流側）が薄肉となるように段落ちしており、この段落ち部分２１と第１柱状体５との間に設けられた隙間が弁葉形成部２２となる。図１２（ａ）、（ｂ）に示すように、この弁葉形成部２２に形成された組織体２は半径外内方向へ往復動することにより、弁葉９として機能することができる。 Moreover, as shown in FIGS. 2, 5, 9 and 11, the upper portion 17a of the bulging body 17 is in close contact with the first columnar body 5 and the second columnar body 7, but the lower part ( The upstream side) is stepped down so as to be thin, and the gap provided between the stepped portion 21 and the first columnar body 5 becomes the leaflet forming portion 22. As shown in FIGS. 12A and 12B, the tissue body 2 formed in the leaflet forming portion 22 can function as the leaflet 9 by reciprocating in the radially outward and inward directions.
また、図５に示すように、段落ち部分２１の下流側縁２１ａは、弁葉９の下流側縁（先端形状）を形作る。その段落ち部分２１の下流側縁２１ａは弁葉下流側へ向かって尖った形状に形成されているため、弁葉９の先端も尖った角形状となる。弁葉形成部２２の半径方向の厚みは、０．３〜１.０ｍｍ、より好ましくは０．３〜０．８ｍｍとするのが好ましい。 Further, as shown in FIG. 5, the downstream edge 21 a of the stepped portion 21 forms the downstream edge (tip shape) of the leaflet 9. Since the downstream edge 21a of the stepped portion 21 is formed in a sharp shape toward the leaflet downstream side, the tip of the leaflet 9 also has a sharp corner shape. The radial thickness of the leaflet forming portion 22 is preferably 0.3 to 1.0 mm, more preferably 0.3 to 0.8 mm.
弁葉９は、膨出体本体１７の下縁（上流側縁）と第１柱状体５との隙間２２から侵入する組織体２によって形成されるが、厚みのある弁葉９をより短期間に形成するために、図２５に示すように、膨出体本体１７に半径方向に貫通した侵入孔２３を形成してもよい。侵入孔２３によって、膨出体本体１７の半径方向外側面と弁葉形成部２２とを連通させることができるので、組織体２を弁葉形成部２２側に侵入させやすくなる。侵入孔２３の数は単数でもよいが、複数形成した方が組織体２を弁葉形成部２２へ侵入させやすいので好ましい。なお、侵入孔２３を設けた場合は、基材１の表面に形成された組織体２から膨出体１０を抜き出す際には、侵入孔２３の少なくとも片側で組織体２を切断する必要がある。また、侵入孔２３の口径は０．５〜１．０ｍｍとすることが望ましい。０．５ｍｍよりも小さいと細胞の侵入が困難となり、１．０ｍｍよりも大きいと組織体２を切断するのが困難になるためである。 The leaflet 9 is formed by the tissue body 2 that enters from the gap 22 between the lower edge (upstream side edge) of the bulging body main body 17 and the first columnar body 5. In order to form it, as shown in FIG. 25, you may form the penetration hole 23 penetrated to the bulging body main body 17 in the radial direction. The intrusion hole 23 allows the radially outer surface of the bulging body main body 17 and the leaflet forming portion 22 to communicate with each other, so that the tissue body 2 can easily enter the leaflet forming portion 22 side. Although the number of intrusion holes 23 may be singular, it is preferable to form a plurality of intrusion holes 23 because the tissue body 2 can easily enter the leaflet forming portion 22. When the intrusion hole 23 is provided, the tissue body 2 needs to be cut on at least one side of the intrusion hole 23 when the bulging body 10 is extracted from the tissue body 2 formed on the surface of the substrate 1. . In addition, the diameter of the intrusion hole 23 is desirably 0.5 to 1.0 mm. This is because if it is smaller than 0.5 mm, it is difficult for cells to enter, and if it is larger than 1.0 mm, it is difficult to cut the tissue body 2.
また、弁葉形成部２２（すなわち、膨出体本体１７の内面と、これに対応する第１柱状体５の表面の形状）は円弧状に形成される。弁葉９を半径外内方向へ往復動させやすい。 Further, the leaflet forming portion 22 (that is, the inner surface of the bulging body main body 17 and the shape of the surface of the first columnar body 5 corresponding thereto) is formed in an arc shape. It is easy to reciprocate the leaflets 9 in the radially outward and inward directions.
係止手段１１は、上記第１柱状体５及び第２柱状体７の軸方向端面に形成され軸方向に凹んだ凹部１５ａ、１５ｂと、上記膨出体１０の係止部１８とから構成され、図１０に示すように、係止部１８を第１柱状体５の凹部１５ａと第２柱状体７の凹部１５ｂとを重ね合わせた部分に収納しながら、第１柱状体５及び第２柱状体７で軸方向上下から挟みこんで係止することにより、膨出体１０を第１柱状体５および第２柱状体７に着脱自在に係止する。なお、係止手段１１の構成は、膨出体１０が第１柱状体５及び第２柱状体７に対して半径方向、周方向及び軸方向のいずれの方向にも位置ずれするのを規制する構造であれば、上記形態に限定されるものではない。 The locking means 11 includes concave portions 15 a and 15 b formed on the axial end surfaces of the first columnar body 5 and the second columnar body 7 and recessed in the axial direction, and a locking portion 18 of the bulging body 10. As shown in FIG. 10, the first columnar body 5 and the second columnar shape are accommodated while the locking portion 18 is housed in a portion where the concave portion 15 a of the first columnar body 5 and the concave portion 15 b of the second columnar body 7 are overlapped. The bulging body 10 is detachably locked to the first columnar body 5 and the second columnar body 7 by being sandwiched and locked by the body 7 from above and below in the axial direction. In addition, the structure of the latching means 11 restricts the bulging body 10 from being displaced in any of the radial direction, the circumferential direction, and the axial direction with respect to the first columnar body 5 and the second columnar body 7. If it is a structure, it is not limited to the said form.
固定手段１２は、第１柱状体５及び第２柱状体７の中心を軸方向に貫通するように形成された上記の貫通孔１３と、貫通孔１３を挿通して膨出体１０の係止部１８、第１柱状体５及び第２柱状体７を一体的に固定する貫通軸２４とを備える。 The fixing means 12 includes the through hole 13 formed so as to penetrate the centers of the first columnar body 5 and the second columnar body 7 in the axial direction, and the locking of the bulging body 10 through the through hole 13. And a through-shaft 24 that integrally fixes the first columnar body 5 and the second columnar body 7.
貫通軸２４は、アクリル樹脂製であり、図２及び図１０に示すように、第１柱状体５及び第２柱状体７の貫通孔１３と相補的に形成された円柱状の軸部２５と、軸部２５が立設される円板状の軸台２６と、貫通軸２４の固定をロックするロック部２７と、から構成される。軸台２６の外径は、第１柱状体５及び第２柱状体７の外径と同一とされ、軸台２６の外周面が弁付き人工血管３の内腔面の一部を形成する。ロック部２７は、軸部２５の先端側に形成されたロック孔２８と、該ロック孔２８に貫通可能な挿入体２９とから構成され、軸部２５を貫通孔１３に通した後、その先端のロック孔２８に挿入体２９を挿入することにより、挿入体２９と軸台２６とで第１柱状体５、第２柱状体７及び膨出体１０とを挟み込んで固定することができる。このように、固定手段１２にて、第１柱状体５、第２柱状体７及び膨出体１０を完全に固定することにより、それぞれの合わせ面や、貫通孔１３内に組織体２が形成されないですむ。 The through shaft 24 is made of acrylic resin, and, as shown in FIGS. 2 and 10, a cylindrical shaft portion 25 formed in a complementary manner with the through holes 13 of the first columnar body 5 and the second columnar body 7. The disk-shaped shaft base 26 on which the shaft portion 25 is erected and the lock portion 27 that locks the through shaft 24 are fixed. The outer diameter of the shaft 26 is the same as the outer diameter of the first columnar body 5 and the second columnar body 7, and the outer peripheral surface of the shaft 26 forms a part of the lumen surface of the valved artificial blood vessel 3. The lock portion 27 includes a lock hole 28 formed on the distal end side of the shaft portion 25 and an insertion body 29 that can penetrate the lock hole 28, and after passing the shaft portion 25 through the through hole 13, By inserting the insertion body 29 into the lock hole 28, the first columnar body 5, the second columnar body 7 and the bulging body 10 can be sandwiched and fixed by the insertion body 29 and the shaft base 26. As described above, the first columnar body 5, the second columnar body 7, and the bulging body 10 are completely fixed by the fixing means 12, whereby the tissue body 2 is formed in the respective mating surfaces and the through holes 13. You don't have to.
次に、上記のような弁付き人工血管形成用基材１を用いて弁付き人工血管３を生産する方法について説明する。生産方法は、生体組織材料の存在する環境下におく「設置工程」と、環境下から組織体２で被覆された弁付き人工血管形成用基材１を取り出す「取り出し工程」と、組織体２から弁付き人工血管形成用基材１を取り出す「分離工程」とからなる。 Next, a method for producing the valved artificial blood vessel 3 using the valved artificial blood vessel forming substrate 1 will be described. The production method includes an “installation step” in an environment where biological tissue material exists, a “takeout step” in which the valved artificial blood vessel forming base material 1 covered with the tissue body 2 is removed from the environment, and the tissue body 2. The “separation process” is a step of taking out the valve-equipped artificial blood vessel forming base material 1 from the above.
＜設置工程＞
まず、弁付き人工血管形成用基材１を生体組織材料の存在する環境下へ置く。生体組織材料の存在する環境下とは、動物の生体内（例えば、皮下や腹腔内への埋入）、又は、動物の生体外において生体組織材料が浮遊する溶液中等の人工環境内が挙げられる。生体組織材料としては、ヒト、イヌ、ウシ、ブタ、ヤギ、ウサギ、ヒツジなどの他の哺乳類動物由来のものや、鳥類、魚類、その他の動物由来のもの、又は人工材料を用いることもできる。
<Installation process>
First, the artificial blood vessel forming substrate 1 with a valve is placed in an environment where a biological tissue material exists. The environment in which the biological tissue material exists includes in an animal's living body (for example, subcutaneously or intraperitoneally embedded) or in an artificial environment such as a solution in which the biological tissue material floats outside the animal's body. . As biological tissue materials, materials derived from other mammals such as humans, dogs, cows, pigs, goats, rabbits, sheep, birds, fish, other animals, or artificial materials can be used.
弁付き人工血管形成用基材１を動物に埋入する場合には、十分な麻酔下で最小限の切開術で行い、埋入後は傷口を縫合する。弁付き人工血管形成用基材１の埋入部位としては例えば、結合組織形成用基材１を受け入れる容積を有する腹腔内、あるいは四肢部、賢部又は背部、腹部などの皮下が好ましい。また、埋入には低侵襲な方法で行うことと動物愛護の精神を尊重し、十分な麻酔下で最小限の切開術で行うことが好ましい。 When the artificial blood vessel forming substrate 1 with a valve is implanted in an animal, it is performed with a minimum of incision under sufficient anesthesia, and the wound is sutured after implantation. As an implantation site of the artificial blood vessel forming base material 1 with a valve, for example, intraperitoneal cavity having a volume for receiving the connective tissue forming base material 1 or subcutaneous such as an extremity, a genital part or a back part, and an abdomen are preferable. In addition, it is preferable that the implantation is performed by a minimally invasive method and the spirit of animal welfare is respected, and is performed with a minimum of incision under sufficient anesthesia.
また、弁付き人工血管形成用基材１を生体組織材料の存在する環境下へ置く場合には、種々の培養条件を整えてクリーンな環境下で公知の方法に従って細胞培養を行えばよい。 In addition, when placing the valved artificial blood vessel forming substrate 1 in an environment where biological tissue materials are present, various culture conditions may be prepared and cell culture performed in a clean environment according to a known method.
＜取り出し工程＞
所定時間の設置工程に置いた後、弁付き人工血管形成用基材１を生体組織材料の存在する環境下から取り出す取り出し工程を行う。生体組織材料の存在する環境下から取り出された弁付き人工血管形成用基材１は、全体を生体組織による膜に覆われている（図１６）組織体２は、繊維芽細胞とコラーゲンなどの細胞外マトリックスで構成され、組織体２は弁付き人工血管形成用基材１の外周表面に癒着しているが、基材１の内側には侵入していない。
<Removal process>
After being placed in the installation step for a predetermined time, a removal step of taking out the valved artificial blood vessel forming base material 1 from the environment in which the biological tissue material exists is performed. The artificial blood vessel forming base material 1 with a valve taken out from the environment where the biological tissue material exists is entirely covered with a membrane made of biological tissue (FIG. 16). The tissue body 2 includes fibroblasts, collagen, and the like. It is composed of an extracellular matrix, and the tissue body 2 is adhered to the outer peripheral surface of the valved artificial blood vessel forming base material 1, but does not enter the base material 1.
＜分離工程＞
そして、分離工程において、一端側の生体組織を取り除き（図１７）、ロック孔２８から挿入体２９を引き抜いてロック部２７によるロック状態を解除する。そして、他端側の生体組織を取り除いた後、軸台２６をもって軸部２５を第１柱状体５及び第２柱状体７の貫通軸２４から抜き出す（図１８）。第１柱状体５及び第２柱状体７を膨出体１０から軸方向上下に分解して、それぞれを組織体２の内腔の上下端から抜き出す。
<Separation process>
In the separation step, the living tissue on one end side is removed (FIG. 17), and the insert 29 is pulled out from the lock hole 28 to release the locked state by the lock portion 27. Then, after removing the living tissue on the other end side, the shaft portion 25 is extracted from the penetrating shaft 24 of the first columnar body 5 and the second columnar body 7 with the shaft 26 (FIG. 18). The first columnar body 5 and the second columnar body 7 are disassembled from the bulging body 10 in the axial direction and are respectively extracted from the upper and lower ends of the lumen of the tissue body 2.
次に、３つの膨出体１０を抜き出す。図１９及び図２０の血管３を縦に切り開いた状態を示す写真に示すように、膨出体１０は、弁葉形成部２２と膨大部８との間のポケットに収納されている状態となっている。この膨出体１０を下流側へ抜き出すことにより、生体組織から構成される弁付き人工血管３を生産することができる。剥離された組織体２の内面は、基材１の表面に接しているので平滑になる。 Next, the three bulging bodies 10 are extracted. As shown in the photograph showing the state in which the blood vessel 3 in FIG. 19 and FIG. 20 is opened vertically, the bulging body 10 is in a state of being accommodated in the pocket between the leaflet forming portion 22 and the enormous portion 8. ing. By extracting the bulging body 10 to the downstream side, it is possible to produce a valved artificial blood vessel 3 composed of a living tissue. Since the peeled inner surface of the tissue body 2 is in contact with the surface of the substrate 1, it becomes smooth.
弁付き人工血管３は、図１３〜図１５に示すように、膨出体１０の外周面の膨大部形成面２０によって、半径外方向に向かってこぶ状に膨出した膨大部８が形成される。そして、図２１〜図２３に示すように、膨大部８の内部において上流側部分に、ポケット状の構造が形成されることにより、そのポケット片が弁葉９となる。３枚の弁葉９が膨らんでその下流側（開放側）の端部が互いに近づいた状態が弁の閉じた状態であり（図１５の仮想線部分、図２４（ｃ））、３枚の弁葉９がしぼんでその下流側の端部が互いに離れていき（図２４（ｂ））、膨大部８の壁面に近づいた状態が弁の全開した状態（図１５の実線部分、図２４（ａ））となる。 As shown in FIG. 13 to FIG. 15, the valved artificial blood vessel 3 is formed with a bulged portion 8 bulging in a radially outward direction by the bulged portion forming surface 20 on the outer peripheral surface of the bulging body 10. The And as shown in FIGS. 21-23, the pocket piece becomes the leaflet 9 by forming a pocket-shaped structure in the upstream part inside the enormous part 8. FIG. The state in which the three leaflets 9 swell and their downstream (open side) end portions approach each other is the closed state of the valve (the phantom line portion in FIG. 15, FIG. 24 (c)) The leaflets 9 are deflated and their downstream ends are separated from each other (FIG. 24B), and the state of approaching the wall surface of the enormous portion 8 is the fully opened state (the solid line portion in FIG. 15, FIG. a)).
また、弁葉９の厚みが０．３〜１．０ｍｍである。生体における弁葉９の厚みは約０．２ｍｍであるので、通常であれば弁葉形成部２２の厚みは生体と同じ０．２ｍｍとすればよいのであるが、厚み０．２ｍｍの弁葉９を有する弁付き人工血管３を体内へ移植すると、安定するまでの間血流によって０．２ｍｍよりも薄くなって破けてしまい、弁としての機能を損なってしまう。そこで、弁葉形成部２２の厚みを０．３〜１．０ｍｍとすることにより、移植後に弁葉９が薄くなっても最終的に約０．２ｍｍで落ち着くので、弁の働きを持続させることができる。 Further, the thickness of the leaflet 9 is 0.3 to 1.0 mm. Since the thickness of the leaflets 9 in the living body is about 0.2 mm, the thickness of the leaflet forming portion 22 is usually 0.2 mm, which is the same as that of the living body. When the artificial blood vessel 3 with a valve having the above is transplanted into the body, it becomes thinner than 0.2 mm due to blood flow until it is stabilized, and the function as a valve is impaired. Therefore, by setting the thickness of the leaflet forming portion 22 to 0.3 to 1.0 mm, even if the leaflet 9 becomes thin after transplantation, it finally settles at about 0.2 mm. Can do.
また、第１柱状体５がシリコーン樹脂製であるので、その周りに形成される組織体２、特に弁葉９が厚く形成される。また、基材１の表面粗さ（Ｒａ）が５０μｍ以下とされているので、基材１表面に形成される組織体２が厚く形成される。したがって、組織体２は自立して管形状を維持することができることから、人工血管３として生体と縫合する時に吻合部位が開口した状態で、吻合操作を行いやすい。 Moreover, since the 1st columnar body 5 is a product made from a silicone resin, the structure | tissue 2 formed around it, especially the leaflet 9 is formed thickly. Moreover, since the surface roughness (Ra) of the base material 1 is 50 μm or less, the tissue body 2 formed on the surface of the base material 1 is formed thick. Therefore, since the tissue body 2 can stand independently and maintain the tube shape, it is easy to perform an anastomosis operation in a state where the anastomosis site is opened when the artificial blood vessel 3 is sutured to a living body.
以上の説明のとおり、人工血管形成用基材１と組織体２との分離は、第１柱状体５及び第２柱状体７を膨出体１０から上下に分解して、組織体２の内腔より取り出した後、複数の膨出体１０を内腔から取り出すことにより、簡単に行うことができる。分解して取り出すことができるので、組織体２を傷つけないですむ。また、形成された弁付き人工血管３は、弁葉形成部２２で１つの完成した弁葉９を形成することができるので、切断作業を行わずとも弁葉９を完成することができる。 As described above, the separation of the artificial blood vessel forming substrate 1 and the tissue body 2 is performed by disassembling the first columnar body 5 and the second columnar body 7 from the bulging body 10 in the vertical direction. After removing from the cavity, the plurality of bulging bodies 10 can be easily removed from the lumen. Since it can be disassembled and taken out, the tissue 2 is not damaged. In addition, since the formed valve-provided artificial blood vessel 3 can form one complete leaflet 9 by the leaflet forming portion 22, the leaflet 9 can be completed without performing a cutting operation.
生産された人工血管形成用基材１を異種移植する場合には、移植後の拒絶反応を防ぐため、脱細胞処理、脱水処理、固定処理などの免疫源除去処理を施すのが好ましい。脱細胞処理としては、超音波処理や界面活性剤処理、コラゲナーゼなどの酵素処理によって細胞外マトリックスを溶出させて洗浄する等の方法があり、脱水処理の方法としては、メタノール、エタノール、イソプロピルアルコール等の水溶性有機溶媒で洗浄する方法があり、固定処理する方法としては、グルタアルデヒドやホルムアルデヒドなどのアルデヒド化合物で処理する方法がある。 In the case of xenotransplantation of the produced artificial blood vessel forming substrate 1, it is preferable to perform immunogen removal treatment such as decellularization treatment, dehydration treatment, and fixation treatment in order to prevent rejection after transplantation. Examples of decellularization include ultrasonic treatment, surfactant treatment, and enzyme treatment such as collagenase to elute and wash the extracellular matrix. Dehydration methods include methanol, ethanol, isopropyl alcohol, etc. There is a method of washing with a water-soluble organic solvent, and as a method of fixing, there is a method of treating with an aldehyde compound such as glutaraldehyde or formaldehyde.
なお、本発明は上記実施形態に限定されるものではなく、本発明の範囲内で上記実施形態に多くの修正及び変更を加え得ることは勿論である。例えば、上記実施形態では、第１柱状体５及び第２柱状体７の各中心部分に貫通孔１３を形成したが、図２６に示すように、第１柱状体５及び第２柱状体７の中心よりずれた位置に貫通孔１３を形成してもよい。また、第１柱状体５（又は第２柱状体７）から突出部５ａを突出させ、第２柱状体７（又は第１柱状体５）に陥没部７ａを設けてもよい。突出部５ａを陥没部７ａに挿入して嵌合させることにより、第１柱状体５及び第２柱状体７の軸と直交する方向へのずれを防止することができる。 In addition, this invention is not limited to the said embodiment, Of course, many corrections and changes can be added to the said embodiment within the scope of the present invention. For example, in the above embodiment, the through hole 13 is formed in each central portion of the first columnar body 5 and the second columnar body 7, but as shown in FIG. 26, the first columnar body 5 and the second columnar body 7 The through hole 13 may be formed at a position shifted from the center. Further, the protruding portion 5a may be protruded from the first columnar body 5 (or the second columnar body 7), and the depressed portion 7a may be provided in the second columnar body 7 (or the first columnar body 5). By inserting and fitting the protruding portion 5a into the depressed portion 7a, it is possible to prevent the first columnar body 5 and the second columnar body 7 from being displaced in a direction perpendicular to the axis.
また、図２６に示すように、固定手段１２の貫通軸２４は、軸部２５と、軸部２５の両端を固定するロック部とから構成してもよい。ロック部は、軸部２５の両端に形成された雄ネジと、ナット２７ａとから構成される。第１柱状体５及び第２柱状体７の貫通孔１３に軸部２５を挿通した後に、軸部２５の両端からナット２７ａで締め上げることにより、２つの案ット２７ａの間で第１柱状体５、膨出体１０及び第２柱状体７を一体的に固定することができる。 As shown in FIG. 26, the through shaft 24 of the fixing means 12 may include a shaft portion 25 and a lock portion that fixes both ends of the shaft portion 25. The lock portion is composed of male screws formed at both ends of the shaft portion 25 and nuts 27a. After the shaft portion 25 is inserted into the through-holes 13 of the first columnar body 5 and the second columnar body 7, the first columnar shape is formed between the two drafts 27 a by tightening with nuts 27 a from both ends of the shaft portion 25. The body 5, the bulging body 10 and the second columnar body 7 can be fixed integrally.
また、図２７に示すように、固定手段１２は、貫通軸２４の軸部２５の外周に刻設された雄ネジと、第１柱状体５及び／又は第２柱状体７の貫通孔１３の周面に形成された雌ネジとから構成してもよい。この構成によれば、上記ロック部２７が不要となり、部品点数を減らすことができる。すなわち、第２柱状体７の貫通孔１３の周面の一部又は全部に雌ネジを設け、雌ネジの形成されていない第１柱状体５側から貫通孔１３に軸部２５を挿入して、第２柱状体７の貫通孔１３においてネジ止めを行えば、軸台２６と第２柱状体７とで第１柱状体５及び膨出体１０を挟み込んで固定することができる。なお、第２柱状体７ではなく第１柱状体５に雌ネジを設ける構成としてもよいし、第１柱状体５及び第２柱状体７の両方に雌ネジを設ける構成としてもよい。 In addition, as shown in FIG. 27, the fixing means 12 includes a male screw engraved on the outer periphery of the shaft portion 25 of the through shaft 24 and the through holes 13 of the first columnar body 5 and / or the second columnar body 7. You may comprise from the internal thread formed in the surrounding surface. According to this configuration, the lock portion 27 is not necessary, and the number of parts can be reduced. That is, a female screw is provided on a part or all of the peripheral surface of the through hole 13 of the second columnar body 7, and the shaft portion 25 is inserted into the through hole 13 from the first columnar body 5 side where the female screw is not formed. If screwing is performed in the through-hole 13 of the second columnar body 7, the first columnar body 5 and the bulging body 10 can be sandwiched and fixed between the shaft 26 and the second columnar body 7. In addition, it is good also as a structure which provides a female screw in the 1st columnar body 5 instead of the 2nd columnar body 7, and it is good also as a structure which provides a female screw in both the 1st columnar body 5 and the 2nd columnar body 7. FIG.
また、図２８に示すように、固定手段１２は、第２柱状体７に形成された雄ネジと、該雄ネジに螺合するよう第１柱状体５に形成された雌ネジとを備える構成とすることができる。第２柱状体７の雄ネジを第１柱状体５の雌ネジに螺合することにより、第１柱状体５、第２柱状体７及び膨出体１０を一体的に固定することができる。なお、雄ネジを第１柱状体５に設け、雌ネジを第２柱状体７に設ける構成としてもよい。 As shown in FIG. 28, the fixing means 12 includes a male screw formed on the second columnar body 7 and a female screw formed on the first columnar body 5 so as to be screwed to the male screw. It can be. By screwing the male screw of the second columnar body 7 into the female screw of the first columnar body 5, the first columnar body 5, the second columnar body 7 and the bulging body 10 can be fixed integrally. In addition, it is good also as a structure which provides a male screw in the 1st columnar body 5, and provides a female screw in the 2nd columnar body 7. FIG.
また、固定手段１２は、第１柱状体及び第２柱状体のうちの一方に配置された磁性体と、第１柱状体及び第２柱状体のうちの他方に配置され磁性体に吸着する被磁性体とを備える構成とすることができる。例えば、図２９に示すように、第１柱状体５（又は第２柱状体７）に磁性体１２ａを設け、第２柱状体７（又は第１柱状体５）に被磁性体１２ｂ設けることにより、磁性体１２ａと被磁性体１２ｂとが吸着し、第１柱状体５、第２柱状体７及び膨出体１０を一体的に固定することができる。このとき、磁性体１２ａ及び被磁性体１２ｂをそれぞれ第１柱状体５及び第２柱状体７の端面に設けてもよいが、磁性体１２ａを第１柱状体５（又は第２柱状体７）から突出する突部５ｂの先端に設け、被磁性体１２ｂを第２柱状体７（又は第１柱状体５）に形成した嵌合凹部７ｂの底に設ける構成とすれば、第１柱状体５の突部５ｂを第２柱状体７の嵌合凹部７ｂに挿入することにより、その固定をより強固なものとすることができる。 The fixing means 12 includes a magnetic body disposed on one of the first columnar body and the second columnar body and an object to be attracted to the magnetic body disposed on the other of the first columnar body and the second columnar body. It can be set as the structure provided with a magnetic body. For example, as shown in FIG. 29, a magnetic body 12a is provided on the first columnar body 5 (or second columnar body 7), and a magnetic body 12b is provided on the second columnar body 7 (or first columnar body 5). The magnetic body 12a and the magnetic body 12b are adsorbed, and the first columnar body 5, the second columnar body 7, and the bulging body 10 can be fixed integrally. At this time, the magnetic body 12a and the magnetic body 12b may be provided on the end surfaces of the first columnar body 5 and the second columnar body 7, respectively. However, the magnetic body 12a is disposed on the first columnar body 5 (or the second columnar body 7). The first columnar body 5 is provided at the tip of the protrusion 5b protruding from the first columnar body 5 when the magnetic body 12b is disposed at the bottom of the fitting recess 7b formed in the second columnar body 7 (or the first columnar body 5). By inserting the protrusion 5b into the fitting recess 7b of the second columnar body 7, the fixing can be made stronger.
さらにまた、図３０に示すように、固定手段１２は、第１柱状体５（又は第２柱状体７）に配置された先端が折曲した係合爪５ｃと、第２柱状体７（第１柱状体５）に形成された係合穴７ｃとを備える構成とすることができる。係合穴７は止め構造７ｄを有しており、第１柱状体５の係合爪５ｃを第２柱状体７の係合穴７ｃに挿入した後、第１柱状体５を軸周りにＸからＹ方向に９０度回転させることにより、係合爪５ｃの先端の折曲部分が係合穴７ｃの止め構造７ｄにひっかかる。このような構造により第１柱状体５を第２柱状体７に係脱自在に係合することができる。なお、係合穴を第１柱状体５に設け、係合爪を第２柱状体７に設ける構成としてもよい。 Furthermore, as shown in FIG. 30, the fixing means 12 includes an engaging claw 5c having a bent tip disposed on the first columnar body 5 (or the second columnar body 7) and a second columnar body 7 (first columnar body 7). One columnar body 5) may be provided with an engagement hole 7c. The engagement hole 7 has a stop structure 7d. After the engagement claw 5c of the first columnar body 5 is inserted into the engagement hole 7c of the second columnar body 7, the first columnar body 5 is rotated around the axis X. , The bent portion at the tip of the engaging claw 5c is caught by the locking structure 7d of the engaging hole 7c. With such a structure, the first columnar body 5 can be detachably engaged with the second columnar body 7. The engagement hole may be provided in the first columnar body 5 and the engagement claw may be provided in the second columnar body 7.
また、図３０に示すように、第１柱状体５及び第２柱状体７の内部に設けられた薬剤収容用の空洞部３２と、空洞部３２の開口を開閉自在とする蓋３３と、空洞部３２から半径外方向に延び各柱状体５、７の外面へ開口する浸出路３４とを設ける構成としてもよい。空洞部３２の開口から薬剤を入れた後、蓋３３を閉めた状態で弁付き人工血管形成用基材１を生体組織材料が存在する環境下へ置くと、空洞部３２内の薬剤を浸出路３４を通して基材１の外部へ浸み出させることができる。浸出路３４の口径は０．５ｍｍ以下とすることが望ましい。０．５ｍｍ以下とすると、浸出路３４へ細胞が侵入しにくい。 Further, as shown in FIG. 30, a medicine containing cavity 32 provided inside the first columnar body 5 and the second columnar body 7, a lid 33 for opening and closing the opening of the cavity 32, and a cavity It is good also as a structure which provides the leaching path 34 extended in the radial outward direction from the part 32 and opened to the outer surface of each columnar body 5 and 7. FIG. After putting the medicine from the opening of the cavity portion 32 and placing the valved artificial blood vessel forming substrate 1 in an environment where the biological tissue material exists with the lid 33 closed, the medicine in the cavity portion 32 is leached out. 34 can be leached out of the substrate 1. The diameter of the brewing path 34 is preferably 0.5 mm or less. If the thickness is 0.5 mm or less, cells are unlikely to enter the leaching path 34.
薬剤の種類としては、組織体２の形成を促進させるもの、たとえば、内皮細胞増殖促進剤（血管新生因子ＨＦＧ、ＶＥＧＦ、ｂＦＧＦなど）が挙げられるが、これに限定されるものではない。 Examples of the drug include those that promote the formation of the tissue body 2, for example, endothelial cell proliferation promoters (angiogenic factors HFG, VEGF, bFGF, etc.), but are not limited thereto.
なお、上記の空洞部３２及び浸出路３４を備えた構造は、弁及び膨大部を有する血管に限定されるものではなく、弁又は膨大部を有しない血管を含む管状組織、膜状組織等の結合組織を形成するための基材にも適用することができる。すなわち、本発明は、基材を構成する構造体の内部に設けられた薬剤収容用の空洞部と、空洞部の開口を開閉自在とする蓋と、空洞部から構造体の外方へ延び、構造体の外面へ開口する浸出路とを設けた基材も提供することができる。形成された生体由来組織は、管状組織、膜状組織及び弁状組織を含む結合組織となる。管状組織としては、血管、リンパ管、気管、胆管、腸管、尿道管、尿管、卵管等が挙げられる。膜状組織としては、心膜、硬膜、角膜、皮膚、心膜等が挙げられ、表層を覆うあるいは膜状で機能する平面状の組織である。弁状組織としては、心臓弁、静脈弁等が挙げられる。 Note that the structure including the hollow portion 32 and the leaching path 34 is not limited to a valve and a blood vessel having an enormous portion, and includes a tubular tissue, a membrane tissue, or the like including a blood vessel having no valve or an enormous portion. The present invention can also be applied to a substrate for forming a connective tissue. That is, the present invention is a medicine accommodating cavity provided inside the structure constituting the substrate, a lid that can open and close the opening of the cavity, and the cavity extends outward from the structure, A base material provided with a leaching path that opens to the outer surface of the structure can also be provided. The formed biological tissue becomes a connective tissue including a tubular tissue, a membranous tissue, and a valve-like tissue. Examples of the tubular tissue include blood vessels, lymphatic vessels, trachea, bile ducts, intestinal tracts, urethral tubes, ureters, oviducts, and the like. Examples of the membranous tissue include pericardium, dura mater, cornea, skin, pericardium and the like, and are planar tissues that cover the surface layer or function in a membranous form. Examples of valve-like tissues include heart valves and venous valves.
また、上記実施形態では、凹部１５ａ、１５ｂを第１柱状体５と第２柱状体７に設けたが、いずれか一方に設けてもよい。また、図３１に示すように、係止手段１１を第１柱状体５側にずらすことにより、弁葉形成部２２を第１柱状体５及び第２柱状体７と、膨出体本体１７との間に形成してもよい。 Moreover, although the recessed parts 15a and 15b were provided in the 1st columnar body 5 and the 2nd columnar body 7 in the said embodiment, you may provide in any one. In addition, as shown in FIG. 31, by shifting the locking means 11 toward the first columnar body 5, the leaflet forming portion 22 is moved to the first columnar body 5 and the second columnar body 7, and the bulging body main body 17. You may form between.
また、図３２に示すように、１又は複数の膨出体本体１７の外面に接続される第３の柱状体３０を設けてもよい。第３の柱状体３０は、膨出体本体１７の外面に着脱可能に設けられるのがよい。例えば膨出体本体１７に形成した孔に雌ネジを切り、第３の柱状体３０の先端に雄ネジを形成することにより、ネジ止めによって着脱可能に設ければよい。第３の柱状体３０を膨出体本体１７の外面に設けることにより、第３の柱状体３０の外周面が膨大部８から分岐する血管内腔の形成面となる Further, as shown in FIG. 32, a third columnar body 30 connected to the outer surface of one or a plurality of bulging body bodies 17 may be provided. The third columnar body 30 is preferably detachably provided on the outer surface of the bulging body main body 17. For example, a female screw may be cut into a hole formed in the bulging body main body 17 and a male screw may be formed at the tip of the third columnar body 30 so as to be detachable by screwing. By providing the third columnar body 30 on the outer surface of the bulging body main body 17, the outer peripheral surface of the third columnar body 30 becomes the formation surface of the blood vessel lumen that branches from the enormous portion 8.
また、基材１の表面に凹凸や外郭部材を設けて、生体由来組織の機械的強度をさらに向上させてもよい。 Moreover, unevenness and an outline member may be provided on the surface of the base material 1 to further improve the mechanical strength of the living body-derived tissue.
１ 弁付き人工血管形成用基材
２ 組織体
３ 弁付き人工血管
４ 上流側管状部
５ 第１柱状体
６ 下流側管状部
７ 第２柱状体
８ 膨大部
９ 弁葉
１０ 膨出体
１１ 係止手段
１２ 固定手段
１３ 貫通孔
１５ａ、１５ｂ 凹部
１７ 膨出体本体
１８ 係止部
２０ 膨大部形成面
２２ 弁葉形成部
２３ 侵入孔
２４ 貫通軸
３０ 第３の柱状体
DESCRIPTION OF SYMBOLS 1 Substrate for artificial blood vessel formation with valve 2 Tissue 3 Artificial blood vessel with valve 4 Upstream tubular portion 5 First columnar body 6 Downstream tubular portion 7 Second columnar body 8 Enlarged portion 9 Valve leaf 10 Swelling body 11 Locking Means 12 Fixing means 13 Through-holes 15a, 15b Recess 17 Bump body 18 Locking portion 20 Enlarged portion forming surface 22 Leaf leaf forming portion 23 Intrusion hole 24 Through shaft 30 Third columnar body
Claims (15)
血管の上流側管状部を形成する第１柱状体と、血管の下流側管状部を形成する第２柱状体と、上流側管状部と下流側管状部の間にあって血管壁が半径外方向に膨出する膨大部、及びその内部において半径方向内側に突出して血流方向に開閉可能な弁葉を形成するための複数の膨出体と、前記膨出体を第１柱状体および／または第２柱状体に着脱自在に係止する係止手段とを備え、
前記係止手段は、前記第１柱状体及び第２柱状体の一方又は両方の軸方向端面に形成され軸方向に凹んだ凹部と、前記膨出体の本体から半径方向内側に張り出し前記凹部に係止することにより、前記膨出体が前記第１柱状体及び前記第２柱状体に対して半径方向、周方向及び軸方向に位置ずれするのを規制する係止部とを備え、
前記膨出体は、その本体の外周面が膨大部形成面となり、前記膨出体本体と第１柱状体及び／又は第２柱状体との間に設けられた隙間が弁葉形成部となることを特徴とする弁付き人工血管形成用基材。 A base material for forming a membrane-like tissue body on the surface thereof by placing it in an environment in which a biological tissue material exists, and peeling the tissue body to form a valved artificial blood vessel,
The first columnar body that forms the upstream tubular portion of the blood vessel, the second columnar body that forms the downstream tubular portion of the blood vessel, and the blood vessel wall swells radially outward between the upstream tubular portion and the downstream tubular portion. A plurality of bulging bodies for forming a protruding portion, a plurality of bulging bodies projecting radially inwardly within the bulging section and capable of opening and closing in a blood flow direction, and the bulging bodies as first columnar bodies and / or second Locking means for detachably locking to the columnar body,
The locking means includes a recess formed in one or both axial end surfaces of the first columnar body and the second columnar body and recessed in the axial direction, and projecting radially inward from the main body of the bulging body into the recess. A locking portion for restricting displacement of the bulging body in the radial direction, the circumferential direction, and the axial direction with respect to the first columnar body and the second columnar body by being locked;
As for the said bulging body, the outer peripheral surface of the main body turns into a huge part formation surface, and the clearance gap provided between the said bulging body main body and a 1st columnar body and / or a 2nd columnar body becomes a leaf-leaf formation part. A base material for forming an artificial blood vessel with a valve.
前記分離工程は、前記第１柱状体及び第２柱状体を前記膨出体から上下に分解して、前記組織体の内腔より取り出した後、複数の前記膨出体を前記内腔から取り出すことを特徴とする弁付き人工血管の生産方法。 An installation step of placing the artificial blood vessel forming substrate with a valve according to any one of claims 1 to 14 in an environment in which a living tissue material excluding a human body is present, and the valve covered with a tissue from the environment A step of taking out the artificial blood vessel forming base with attachment, and a separation step of taking out the artificial blood vessel forming base with valve from the tissue body,
In the separation step, the first columnar body and the second columnar body are disassembled vertically from the bulging body, taken out from the lumen of the tissue body, and then a plurality of the bulging bodies are taken out from the lumen. A method for producing a valved artificial blood vessel.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
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| JP2010257821A JP5658008B2 (en) | 2010-11-18 | 2010-11-18 | Artificial blood vessel forming substrate with valve, production method of artificial blood vessel with valve using the same, and artificial blood vessel with valve |
| EP11817453.1A EP2641565A4 (en) | 2010-11-18 | 2011-11-16 | Base material for forming lumen-shaped tissue with valve, method for producing lumen-shaped tissue with valve, and artificial blood vessel with valve |
| CN201180003418.2A CN102958468B (en) | 2010-11-18 | 2011-11-16 | Base material for forming lumen-shaped tissue with valve, method for producing lumen-shaped tissue with valve, and artificial blood vessel with valve |
| PCT/JP2011/076372 WO2012067137A1 (en) | 2010-11-18 | 2011-11-16 | Base material for forming lumen-shaped tissue with valve, method for producing lumen-shaped tissue with valve, and artificial blood vessel with valve |
| US13/390,480 US8685082B2 (en) | 2010-11-18 | 2011-11-16 | Base material for forming valved lumen shape tissue, method for producing valved lumen shape tissue, and valved artificial blood vessel |
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| JP2010257821A JP5658008B2 (en) | 2010-11-18 | 2010-11-18 | Artificial blood vessel forming substrate with valve, production method of artificial blood vessel with valve using the same, and artificial blood vessel with valve |
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| JP2007037764A (en) * | 2005-08-03 | 2007-02-15 | National Cardiovascular Center | Prosthetic valve |
| DK1864687T3 (en) * | 2006-06-09 | 2013-10-07 | Eidgenoess Tech Hochschule | Skeleton for artificial heart valves and vascular structures |
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