WO2001030274A1 - Valve cardiaque mecanique et procede de production - Google Patents

Valve cardiaque mecanique et procede de production Download PDF

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Publication number
WO2001030274A1
WO2001030274A1 PCT/JP2000/007265 JP0007265W WO0130274A1 WO 2001030274 A1 WO2001030274 A1 WO 2001030274A1 JP 0007265 W JP0007265 W JP 0007265W WO 0130274 A1 WO0130274 A1 WO 0130274A1
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WO
WIPO (PCT)
Prior art keywords
heart valve
base
leaflets
valve
substrate
Prior art date
Application number
PCT/JP2000/007265
Other languages
English (en)
French (fr)
Inventor
Shinichiro Morita
Saburo Nakamura
Shigeyuki Hirata
Toshiharu Shin'oka
Yasuharu Imai
Original Assignee
Gunze Limited
Tokyo Women's Medical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gunze Limited, Tokyo Women's Medical University filed Critical Gunze Limited
Priority to US10/111,244 priority Critical patent/US6875230B1/en
Priority to DE60022075T priority patent/DE60022075T8/de
Priority to AU79494/00A priority patent/AU7949400A/en
Priority to EP00969885A priority patent/EP1230901B1/en
Publication of WO2001030274A1 publication Critical patent/WO2001030274A1/ja

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Classifications

    • 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
    • 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
    • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A61F2/06—Blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/507—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/36—Materials or treatment for tissue regeneration for embolization or occlusion, e.g. vaso-occlusive compositions or devices

Definitions

  • the present invention relates to an artificial heart valve and a method for producing the same.
  • Valves do not work properly like mitral stenosis, mitral regurgitation (reflux), aortic stenosis, aortic valve insufficiency, tricuspid regurgitation, etc. If stenosis or backflow occurs, the valve needs to be replaced.
  • mitral stenosis mitral regurgitation (reflux)
  • aortic stenosis mitral regurgitation (reflux)
  • aortic valve insufficiency aortic valve insufficiency
  • tricuspid regurgitation etc.
  • stenosis or backflow the valve needs to be replaced.
  • the mechanical valve needs to keep the durable force and lifelong anticoagulant. Heterogeneous biological valves using animal valves do not need to continue to take anticoagulants, but may fail in 6-10 years.
  • the human frozen allogeneic valve provided by the cadaver has a long-term remote performance superior to that of a heterologous biological valve, and the power supply generally used in Europe and the United States where the use of cadaver tissue is progressing is not sufficient. 'is there.
  • An object of the present invention is to provide a practical bioabsorbable base material in which the entire heart valve is made of a bioabsorbable material.
  • FIG. 1 is a development view of an outer cylinder having a Valsalva sinus structure.
  • FIG. 2 shows the tricuspid valve
  • FIG. 3 shows a cross-sectional view of the artificial heart valve of the present invention.
  • FIG. 4 shows a plan view of the artificial heart valve of the present invention.
  • FIG. 5 shows a perspective view of the artificial heart valve of the present invention.
  • FIG. 6 shows a view in which the tricuspid valve 4 is integrally sewn to the Valsalva sinus 1 of the sheet-like base 2.
  • FIG. 7 is a cross-sectional photograph of the outer cylinder.
  • Figure 8 is a plan photograph of the outer cylinder.
  • FIG. 9 is a cross-sectional photograph of a cylindrical base material for manufacturing a leaflet.
  • FIG. 10 is a plan photograph of a cylindrical substrate for manufacturing a leaflet.
  • the present invention relates to the following artificial heart valve and a method for producing the same.
  • Item 1 An artificial heart valve having a sinus of Valsalva in a cylindrical base and a leaflet inside the base, wherein the base and the leaflets are made of a bioabsorbable polymer material. Prosthetic heart valve.
  • Item 2 The human heart valve according to Item 1, wherein a bioabsorbable polymer material containing a fiber structure made of a bioabsorbable polymer as a reinforcing material is used as a base and / or a leaflet material.
  • Item 3 The artificial heart valve according to Item 1, wherein the base and Z or the leaflets are porous.
  • Item 4 A human heart valve formed by seeding a living cell with the artificial heart valve according to any one of Items 1 to 3.
  • Item 5 A method for producing a prosthetic heart valve, comprising: forming a sinus of Valsalva on a base; and combining a valve leaflet with the base.
  • Item 6 The method according to Item 5, wherein the leaflets are combined with the substrate by adhesion.
  • Item 7 The method according to Item 5, wherein the composite leaf is attached to the base of the valve leaflet by suturing.
  • Item 8 The method according to Item 7, wherein the suture is performed using a bioabsorbable suture.
  • Item 9 The method according to Item 5, wherein the compounding of the leaflets to the substrate is performed by heat fusion.
  • Item 10 The method according to Item 5, wherein the complexation of the valve leaflets with the substrate is performed using a bioabsorbable polymer solution.
  • Item 11 The method according to Item 5, wherein a tubular base having a noresalva sinus is formed by molding, and the end of the tubular base is folded inward to form a leaflet by heat setting.
  • Bioabsorbable materials include polyglycolic acid, polylactic acid (D-form, L-form, and DL-form), polyprolactone, glycolic acid-lactic acid (D-form, L-form, and DL-form) copolymer, and dalicholic acid
  • the artificial heart valve of the present invention is made of a foam, a film, a non-woven fabric, or the like made of a bioabsorbable material. If strength is required, the woven fabric, knit, It is also possible to reinforce with a reinforcing material such as a nonwoven fabric.
  • the reinforcing member and the prosthetic heart valve body may use the same bioabsorbable material or different bioabsorbable materials.
  • the following method can be exemplified as a method for manufacturing a heart valve.
  • a substrate having a Valsalva sinus is obtained by a molding method in which a bioabsorbable polymer solution is poured into a mold for producing a substrate having a Valsalva sinus structure, followed by freezing and freeze-drying.
  • the mold may be flat or hollow cylindrical (donut-shaped).
  • the obtained sheet-shaped substrate can be formed into a cylindrical shape by sewing, heat fusion, or the like. Fabrication of a substrate reinforced with a reinforcing material is performed by fitting a woven fabric, knitted fabric, nonwoven fabric, etc.
  • a bioabsorbable polymer used as a reinforcing material to an outer mold for fabricating a substrate having a Valsalva sinus structure, fitting the mold from the inside, and filling the gap. It can be carried out by a molding method in which a bioabsorbable polymer solution is poured, frozen and freeze-dried. According to this method, the substrate becomes porous.
  • Cylindrical woven or knitted fabric or flat woven or knitted fabric in a Teflon test tube Is wound in a cylindrical shape, and the cylindrical shape is formed by fusing or suturing. Then, a bioabsorbable polymer solution serving as a base material is poured into the gap, frozen, and freeze-dried. By this method, a porous cylindrical substrate can be manufactured. Fold out one end of the cylindrical base material so that the inside overlaps (from two directions for bicuspid, from three directions for tricuspid) to obtain the leaflets (Fig. 2).
  • valve leaflet is inserted around the sinus of Valsalva of the cylindrical base body prepared above, and the non-folded portion of the leaflet and the periphery of the sinus of Valsalva are sutured with a bioabsorbable suture.
  • the prepared heart valve base material is sterilized with ethylene oxide gas and used for the following experiments.
  • Biological cells endothelial cells, fibroblasts, smooth muscle cells, etc. are collected from the femoral artery, mixed and cultured, and then seeded on an artificial heart valve to form endothelial cells.
  • the heart valve thus produced can be used for transplantation of human ⁇ animals into adults, especially infants or children.
  • the artificial heart valve which can replace a mechanical valve, a heterogeneous living-body valve, and a homogeneous valve can be provided. Also, since the whole is composed of a bioabsorbable polymer, it disappears after tissue regeneration and does not remain in the body as a foreign substance. Growth can be expected especially in children. In addition, if it is porous, it has excellent cell adhesion.
  • FIG. 1 is a development view of the cylindrical body.
  • Cylindrical woven fabric made of polydalicholate was placed in a Teflon test tube having a diameter of 18 mm. This is placed in a cylindrical mold with a diameter of 20 mm, and a dioxane solution (5%) of a copolymer (molar ratio: 50:50) composed of lactic acid-based prolactone is poured into the gap, frozen at -30 and frozen at 20 for 24 hours at 20 Lyophilized.
  • the leaflet taken out had a base material foam structure, and had a structure in which a fibrous reinforcement was incorporated in the core material (cross-sectional photograph 9 and plan photograph 10).
  • a sheet-like base 2 may be used, and the valsalva sinus 1 and the tricuspid valve 4 may be integrally sewn and then formed into a tubular shape as described above.
  • valve leaflets 4 are inserted into the cylinder having the valsalva sinus structure 1, and the periphery of each valsalva sinus 1 and the periphery of the top 5 of the tricuspid valve 4 are integrally sewn with polydalicholate suture, and the other end is cylindrical.
  • the artificial heart valve 3 of the present invention having the valve 6 was integrally sewn.
  • a femoral artery of about 2 cm in diameter was collected from a 20-day-old Dover lamb under general anesthesia while preserving the deep femoral artery.
  • the tissue collected under completely clean conditions was immersed in the cell culture solution, and washed using a phosphorylated saline in a clean bench.
  • the tissue was cut on a Petri dish using a scalpel according to a simple explant technique. Approximately 1-2 ram 2 fine fiber strands were evenly distributed on the dish.
  • the culture solution was added after the tissue had firmly adhered to the lower surface of the dish. At this time, care was taken so that the tissue piece did not come off the dish.
  • the culture medium used was Dulbecco, S Modified Eagles Media supplemented with 10% fetal bovine serum and 1% antibiotic solution (L-glutamine 29.2mg ml, penicillin G 1000u / ml and Streptomyci sulfate 10,000g ml). .
  • Sheep vascular wall cells After 7 days, cells begin to migrate from the tissue onto the dish, and after a week, a mixed colony of endothelial cells, fibroblasts and smooth muscle cells An explant was formed around the tissue piece. After a few more weeks, mix fine The vesicle became confluent on the dish. Performed immediately Passage with 0.25% trypsin, 75 C m 2 of but culture was started on culture flasks will generally be the flasks was obtained about 200 million cells becomes a confluent. Cell culture was performed in an environment of 5% C02 and 95% 02, and the culture was continued until a cell number of 10 ⁇ 10 6 was obtained. The culture medium was changed every 4-5 days. The doublling time of the cells was about 48 hours.
  • endothelial cells were separated and separated from the mixed cells using FACS according to the following procedure.
  • Dil-acethylated LDL fluorescent marker
  • D-Ac-LDL Biomedical Technologies
  • Endothelial cells are sorted as Dil-Ac-LDL positive or negative based on cell size and fluorescence. Endothelial cells were positive and were found in about 5-8% of the mixed culture. After separation, these were separately cultured and continued until the number of endothelial cells reached 2 million. The number of cells during the course was calculated according to the classic exclusion method using trypan blue.

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Transplantation (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Vascular Medicine (AREA)
  • Dermatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Cardiology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pulmonology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Manufacturing & Machinery (AREA)
  • Prostheses (AREA)
  • Materials For Medical Uses (AREA)

Description

人工心臓弁およびその作製方法
技術分野
本発明は、 人工心臓弁及びその作製方法に関する。
背景技術
僧帽弁狭窄症、 僧帽弁閉鎖不全症 （逆流症） 、 大動脈弁狭窄症、 大動脈弁閉鎖不 全症、 三尖弁閉鎖不全症等の心臓弁膜症のように、 弁が正常に働かず、 狭窄や逆流 力生じた場合、弁を交換する必要がある。現在手術に用いられる弁には (1)機械弁 (2) 異種生体弁 (3)同種弁の三種類がある。
機械弁は耐久性に優れる力、一生抗凝固剤を飲みつづける必要がある。 また動物 の弁を用いる異種生体弁は抗凝固剤を飲みつづける必要はないが、 6-10年で弁機能 不全をきたすことがある。一方、死体より提供されるヒト凍結同種弁は長期遠隔成 績が異種生体弁より優れ、死体組織の利用が進んでいる欧米では一般的に使用され ている力^ 供給が十分ではないという問題が'ある。
これに対して、 近年 培養 （Tissue Engineering) 技術を用いて生体の多くの組 織を再生させる試みが行われている。これは生体吸収性高分子からなる足場に組織 の細胞を播種し、培養することによって自己の を再生しょうとする試みである。 ~ 乙、、に皮膚 (,M.L.Cooper,L.F.Hansbrough,R.L.Spiel vogel et.al.:In vivo optimization o f dermal substitute employing cultured human fibroblasts on a biodegradable polygly colic acid or polyglactin mesh. Bioraaterials, 12:243-248,1991) や軟骨 （C.A.Vacanti， R. Langer et.al.:Synthetic polymers seeded with chondrocytes provide a templete fo r new cartilage formation. Plast.Reconstr.Surg.,88:753-759,199l) については多くの研 究例が報告されている。
また心臓弁についても組織培養技術による再生の試みが行われ、 弁葉構造の再生 に関して良好な研究成果が報告されている （T.Shinoka et.al.： Tissue-engineered hear t valve leaflets. Autologous valv leaflet replacement study ma lamb model. Circulati on, 94(suppl.II) :11- 164-11- 168, 1996. T.Shinokaet.al. ： Tissue-engineered heart valve le aflets. Does cell origin affect outocome? Circulation, 96(suppl.II):II-102-II-107,1996 )。 しかしながら心臓弁全体を生体吸収性材料にて作製する実用的な生体吸収性基材 は得られていない。
本発明は、心臓弁全体を生体吸収性材料にて作製する実用的な生体吸収性基材を 提供することを目的とする。
図面の簡単な説明
図 1は、 バルサルバ洞構造を有する外筒の展開図を示す。
図 2は、 三尖弁を示す。
図 3は、 本発明の人工心臓弁の断面図を示す。
図 4は、 本発明の人工心臓弁の平面図を示す。
図 5は、 本発明の人工心臓弁の斜視図を示す。
図 6は、 シート状の基体 2のバルサルバ洞 1に三尖弁 4を一体縫合した図を示す 図 7は、 外筒の断面写真である。
図 8は、 外筒の平面写真である。
図 9は、 弁尖製造用の円筒形基材の断面写真である。
図 1 0は、 弁尖製造用の円筒形基材の平面写真である。
発明の開示
本発明は、 以下の人工心臓弁及びその作製方法に関する。
項 1 . 筒状の基体にバルサルバ洞を有し、 かつ、 基体の内部に弁尖を備えてなる 人工心臓弁であつて、基体及び弁尖を生体吸収性高分子素材から構成したことを特 徴とする人工心臓弁。
項 2 . 生体吸収性高分子より成る繊維構造物を補強材として含む生体吸収性高分 子材料を基体及び 又は弁尖の素材として用いたことを特徴とする項 1記載の人 ェ心臓弁。
項 3 . 前記基体及び Z又は弁尖が多孔状である項 1に記載の人工心臓弁。
項 4. 項 1〜 3のいずれかに記載の人工心臓弁に生体細胞を播種して構成した人 ェ心臓弁。
項 5 . 基体にバルサルバ洞を成形する工程、 及び、 弁尖を基体に複合化する工程 を含む人工心臓弁の作製方法。
項 6 . 弁尖の基体への複合化を接着により行う項 5に記載の方法。
項 7 . 弁尖の基体への複合ィヒを縫合により行う項 5に記載の方法。 項 8 . 縫合を生体吸収性縫合糸を用いて行う項 7に記載の方法。
項 9 . 弁尖の基体への複合化を熱融着により行う項 5に記載の方法。
項 1 0 . 弁尖の基体への複合化を生体吸収性高分子溶液により行う項 5に記載の 方法。
項 1 1 . ノ レサルバ洞を有する筒状の基体をモールディング (molding)により形成 し、筒状基材の末端を内側に折り込み熱セッ卜することにより弁尖を形成する項 5 に記載の方法。
生体吸収性材料としては、 ポリグリコール酸、 ポリ乳酸 （D体， L体、 D L体） 、 ポリ力プロラクトン、 グリコール酸—乳酸 （D体， L体、 D L体） 共重合体、 ダリ コール酸一力プロラクトン共重合体、 乳酸 （D体， L体、 D L体） —力プロラクト ン共重合体、 ポリ （P—ジォキサノン）等の合成生体吸収性高分子やコラーゲン、 変性コラーゲン、 ゼラチン、 キチン、 キトサン等の天然高分子等が挙げられる。 本発明の人工心臓弁は、 生体吸収性材料からなる発泡体、 フィルム、 不織布等か らなり、 また、 強度が必要とされる場合には、 同じく生体吸収性高^からなる織 物、 編物、 不織布等の補強材によって補強することも可能である。
補強材と人工心臓弁本体は、 同一の生体吸収性材料を用いてもよく、異なる生体 吸収性材料を用いてもよい。
心臓弁の作製方法としては以下の方法が例示できる。
( 1 ) ゾ レサルバ洞の作製
バルサルバ洞構造を有する基体作製用の型に生体吸収性高分子溶液を流し込み、 凍結後凍結乾燥する成形法によってバルサルバ洞を有する基体を得る。該型は平面 状であっても、 中空円筒状 （ドーナツ状） であってもよい。 基体作製用の型が平面 状である場合、得られたシート状の基体は縫合、熱融着等により筒状に成形できる。 補強材によって補強された基体の作製は、バルサルバ洞構造を有する基体作製用 外型に強化材として用いる生体吸収性高分子からなる織物、編物、不織布等をはめ、 内側から型をはめ込み、 間隙に生体吸収性高分子溶液を流し込み、凍結後凍結乾燥 する成形法によって実施できる。 この方法によると、 基体は多孔状になる。
( 2 ) 弁尖 (内部弁)の作製
テフロン製試験管に円筒状の織物または編物、あるいは平面状の織物または編物 を円筒状に巻きつけ、融着あるいは縫合によって円筒状としたものを外型に入れ、 間隙に基材となる生体吸収性高分子溶液を流し込み、凍結後凍結乾燥する。 この方 法により、多孔状の円筒形基材を製造できる。取り出した円筒形基材の片側の末端 を内側が重なるように折り込み (二尖の場合は 2方向から、三尖の場合は三方から） 熱セットして、 弁尖を得る （図 2 ) 。
( 3 ) 複合化
上記で作製した筒状の基体のバルサルバ洞のあたりに弁尖を挿入し、弁尖の非折 り込み部分とバルサルバ洞の辺縁を生体吸収性縫合糸で縫合する。作製した心臓弁 基材はエチレンォキサイドガス滅菌して、 以下の実験に供する。
( 4 ) 細胞培養及び播種
大腿動脈より生体細胞 （内皮細胞、 線維芽細胞、 平滑筋細胞等） を採取し、 混合 培養を行った後、 人工心臓弁に播種し、 内皮細胞化させる。
( 5 ) 移植
こうして作製した心臓弁は、 ヒトゃ動物の、 成人、 特に乳幼児あるいは子供への 移植に使用することができる。
本発明によれば、 機械弁、 異種生体弁、 同種弁に代わる人工心臓弁を提供できる。 また、 全体を生体吸収性高分子で構成しているので、組織再生後に消失し、 異物 として体内に残存しない。特に小児においては成長が期待できる。 また、 多孔状で あれば、 細胞の接着性に優れる。
発明を実施するための最良の形態
以下、 本発明を実施例に基づきより詳細に説明する。
実施例 1
( 1 ) 外筒の作製
直径 20mmのバルサルバ洞構造 1を有する外筒用型に円筒状のポリダリコール酸 製の編物を挿入した。内側から内型をはめた後、間隙に乳酸力プロラクトンからな る共重合体 （モル比 50 : 50) のジォキサン溶液 （5 %) を流し込み、 -30 で凍結 ¾20でで2 4時間凍結乾燥した。乾燥後取り出した基体 2は、基材が発泡体構造で、 芯材に繊維状強化材が組み込まれた筒状の構造をしていた（断面写真図 7および平 面写真図 8 ) 。 図 1には該筒状体の展開図を示す。 ( 2 ) 弁尖の作製
直径 18mmのテフロン製試験管に円筒状のポリダリコール酸製の織物をはめた。 これを直径 20mmの円筒状型に入れ、 間隙に乳酸力プロラクトンからなる共重合体 (モル比 50 : 50) のジォキサン溶液 （5 %) を流し込み、 -30でで凍結後 20 で 2 4時間凍結乾燥した。取り出した弁尖は基材カ発泡体構造で、芯材に繊維状強化材 が組み込まれた構造をしていた (断面写真図 9および平面写真図 1 0)。 図 2に示す 三尖弁 4を作製する場合は、末端を三方から内側に折り込み、 中央部で縫合したの ち、 lOOt: 3時間真空下で熱セッ卜する。熱セッ卜が完了した後縫合糸を切断した。 尚、 複合化に際しては、 図 6に示すようにシート状の基体 2を用い、 上記と同様 にバルサルバ洞 1と三尖弁 4を一体縫合した後に筒状としてもよい。
( 3 ) 複合化
弁尖 4をバルサルバ洞構造 1を有する筒内に挿入し、各バルサルバ洞 1の周縁と 三尖弁 4の頂部 5の周縁とをポリダリコール酸縫合糸にて一体縫合し、更に他端を 円筒状に一体縫合して弁 6を有する本発明の人工心臓弁 3を得た。
( 4 ) 細胞の培養
A. 細胞単離、 細胞培養、 細胞数増大
生後 2 0日の Dover子羊より全身麻酔下に約 2 cmの大腿動脈を深部大腿動脈を 温存して採取した。完全清潔下に採取した組織を細胞培養液に浸漬し、 クリーンべ ンチ内でリン酸化生食を用いて洗浄した。次に、ぺトリディッシュ上で外科メスを 用いて単純な explant techniqueに準じて組織の裁断を行った。 約 1 - 2 ram2 大の 細糸纖片を均等にディッシュ上に 分配し、約 2 0分後、組織がディッシュ下面に 強固に接着した後に培養液を加えた。 この際、組織片がディッシュから剥がれない ように注意した。
培養液は Dulbecco、 S Modified Eagles Mediaに 10%牛胎児血清と 1 %の抗生物質 溶液 （L— glutamine 29.2mg ml 、 ペニシリン G 1000u/mlと Streptomyci 硫酸塩 10,000 g ml) を補填したものを使用した。
羊の血管壁細胞 （mixed cell) 〖お- 7日後に、 細胞が組織からディッシュ上に移 動し始め、 さらに一週間後には内皮細胞、線維芽細胞及び平滑筋細胞からなる混合 細胞のコロニーが explant組織片の周囲に形成された。 さらに 2 - 3週後に、 混合細 胞はディッシュ上でコンフルェン卜の状態になった。直ちに 0.25%トリプシンにで Passageを行い、 75 C m2の培養フラスコ上での培養を開始したが、 概ねこのフラス コが confluentになると約二百万個の細胞を得たことになる。 5 %C02、 95% 02の 環境下で細胞培養を行い、 10 X 10 6個の細胞数を得るまで培養を続けた。 培養液 は 4-5日毎に交換した。 細胞の doublling timeは約 4 8時間であつた。
B.細胞隔離、 内皮細 JW化
混合細胞がコンフルェントに達し、ある程度の細胞数が得られた段階で以下の手 順に従って、 FACS を用いて、 混合細胞から内皮細胞を選別分離した。 Biomedi cal Technologies 社の Dil-acethylated LDL(fluorescent marker) (以下 D-Ac-LDL)を混 合細胞培養液中に l g/mlの濃度で添加し、 2 4時間の incubationを行った。 この マーカーは内皮細胞、 マクロファージに特有な scavenger pathwayを通過して細胞 内に取り込まれる。 2 4時間後に tripsinizeを行い混合細胞細胞浮遊液を作成し、 セリレソ一夕一 (FACS machine: Bectin Dickenson t製, Mountainview, California) ¾r 使用してソートした。 細胞は細胞の大きさと蛍光発光に基づいて Dil-Ac-LDL陽性 と陰性に選別される。 内皮細胞は陽性で混合培養の約 5-8%程度認めた。 分離後こ れらを別々に培養し、 内皮細胞が二百万個になるまで継続した。 尚、 経過中の細胞 数の算定はトリパンブルーによる古典的な exclusion法に従った。
C 弁葉組織構築
心臓弁並びに弁尖基材に約二千万個の Dil-Ac-LDL陰性の myofibroblastを播種 (seedi ng)した。 濃縮細胞浮遊液のポリマー上への seeding直後は、 3 0— 6 0分間培養皿 上でクリーンベンチ内に放置し、 その後約 5 0 mlの培養液を添加した。 培養液は 基本的に毎日交換し、 7日後、 動物への移植一日前に内皮細胞の細胞浮遊液（約二 百万個） でさらなる seedingを行い、 この作業で単一層の内皮細胞化を図った。
D. 動物実験
上記で作製した心臓弁を子犬の心臓弁と置換したところ、抗凝固剤の使用無しに 良好な開存性を得、 培養心臓弁としての十分な機能を果たしていることを確認 した。

Claims

請求の範囲
1 . 筒状の基体にバルサルバ洞を有し、 かつ、 基体の内部に弁尖を備えてなる人 ェ心臓弁であつて、基体及び弁尖を生体吸収性高分子素材から構成したことを特徵 とする人工心臓弁。
2. 生体吸収性高分子より成る繊維構造物を補強材として含む生体吸収性高分子 材料を基体及び Z又は弁尖の素材として用いたことを特徴とする請求項 1記載の 人工心臟弁。
3. 前記基体及び Z又は弁尖が多孔状である請求項 1に記載の人工心臓弁。
4. 請求項 1〜 3のいずれかに記載の人工心臓弁に生体細胞を播種して構成した 人工心臓弁。
5 . 基体にバルサルバ洞を成形する工程、 及び、 弁尖を基体に複合化する工程を 含む人工心臓弁の作製方法。
6. 弁尖の基体への複合化を接着により行う請求項 5に記載の方法。
7. 弁尖の基体への複合化を縫合により行う請求項 5に記載の方法。
8. 縫合を生体吸収性縫合糸を用いて行う請求項 7に記載の方法。
9. 弁尖の基体への複合化を熱融着により行う請求項 5に記載の方法。
10. 弁尖の基体への複合化を生体吸収性高分子溶液により行う請求項 5に記載の 方法。
11. バルサルバ洞を有する筒状の基体をモールディングにより形成し、筒状基材 の末端を内側に折り込み熱セットすることにより弁尖を形成する請求項 5に記載 の方法。
PCT/JP2000/007265 1999-10-22 2000-10-19 Valve cardiaque mecanique et procede de production WO2001030274A1 (fr)

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AU79494/00A AU7949400A (en) 1999-10-22 2000-10-19 Mechanical heart valve and production method thereof
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WO2015189716A1 (en) 2014-06-09 2015-12-17 Ojaghihaghighi Seyedhossein Thrombosis resistant mechanical prosthetic heart valve

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EP1230901A4 (en) 2003-07-30
US6875230B1 (en) 2005-04-05
EP1230901B1 (en) 2005-08-17
AU7949400A (en) 2001-05-08
JP2001120582A (ja) 2001-05-08
DE60022075T8 (de) 2007-08-02
DE60022075T2 (de) 2006-06-29
DE60022075D1 (de) 2005-09-22
EP1230901A1 (en) 2002-08-14

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