JPH08198763A - Medical material integrated with cell capable of producing cell growth factor - Google Patents
Medical material integrated with cell capable of producing cell growth factorInfo
- Publication number
- JPH08198763A JPH08198763A JP7013864A JP1386495A JPH08198763A JP H08198763 A JPH08198763 A JP H08198763A JP 7013864 A JP7013864 A JP 7013864A JP 1386495 A JP1386495 A JP 1386495A JP H08198763 A JPH08198763 A JP H08198763A
- Authority
- JP
- Japan
- Prior art keywords
- cells
- artificial
- cell growth
- blood vessel
- growth factor
- Prior art date
- Legal status (The legal status 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 status listed.)
- Granted
Links
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は基質に細胞成長因子を産
生することのできる細胞、又は、細胞成長因子及び生体
組織細胞を付着、捕捉又は混在させた人工血管、心臓血
管壁修復材、人工腱、創傷治癒促進材に関し、特に生体
内に植え込まれた後、自然に治癒が促進されて希望の軟
組織が生体内で形成される細胞組込み型医療材料に関す
る。TECHNICAL FIELD The present invention relates to a cell capable of producing a cell growth factor on a substrate, or an artificial blood vessel having a cell growth factor and a biological tissue cell attached thereto, trapped or mixed therewith, a cardiovascular wall repair material, an artificial body. TECHNICAL FIELD The present invention relates to a tendon and a wound healing promoting material, and more particularly to a cell-integrated medical material in which healing is naturally promoted and desired soft tissue is formed in the living body after being implanted in the living body.
【０００２】[0002]
【０００３】人工血管、心臓血管壁修復材、人工腱、創
傷治癒促進材などの医療材料には柔軟性、強度、耐久性
などの力学的適合性、毒性、発癌性などに対する生物学
的安全性、生体組織との非関与性又は親和性などが求め
られている。これらに用いられる素材としては生体非吸
収性物質と生体吸収性物質とがある。生体非吸収性物質
としてはポリエステル、ポリウレタン、ポリビニールア
ルコール、ポリビニール系共重合体、ポリエーテルエス
テル、ナイロン、レーヨン、ポリプロピレン、ポリテト
ラフルオロエチレン、綿、絹などが、また、生体吸収性
物質としては、ポリグリコール酸、ポリ乳酸−ポリグリ
コール酸共重合体、生分解性（３−ヒドロキシブチレー
ト−４−ヒドロキシブチレート）ポリエステル共重合
体、ポリジオキサン、コラーゲン、ゼラチン、アルブミ
ン、キチン、キトサンが挙げられる。Medical materials such as artificial blood vessels, cardiovascular wall repair materials, artificial tendons, and wound healing promoting materials have mechanical compatibility such as flexibility, strength and durability, biological safety against toxicity and carcinogenicity. , Non-participation or affinity with living tissue is required. Materials used for these include non-bioabsorbable substances and bioabsorbable substances. Examples of non-bioabsorbable substances include polyester, polyurethane, polyvinyl alcohol, polyvinyl copolymers, polyetheresters, nylon, rayon, polypropylene, polytetrafluoroethylene, cotton, silk, etc. Is polyglycolic acid, polylactic acid-polyglycolic acid copolymer, biodegradable (3-hydroxybutyrate-4-hydroxybutyrate) polyester copolymer, polydioxane, collagen, gelatin, albumin, chitin, chitosan. Can be mentioned.
【０００４】これらのうちポリテトラフルオロエチレン
は生体組織との接着、粘着性が低いことから、癒着防止
膜や血栓を付着させないための人工血管に使用されてい
る。しかし、それと生体組織との縫合部においては細胞
との接着性が要求されるにもかかわらず細胞が接着でき
ないため、パンヌスと呼ばれる不要な膜が形成され、そ
れが人工血管表面より剥離されやすい等の不都合性が生
じている。Of these, polytetrafluoroethylene is used for artificial blood vessels for preventing adhesion of anti-adhesion membranes and thrombus because of its low adhesion and adhesion to living tissue. However, since the cells cannot adhere to each other at the sutured part between them and the biological tissue, even though the cells cannot adhere to each other, an unnecessary film called pannus is formed, which is easily peeled off from the artificial blood vessel surface. Inconvenience has occurred.
【０００５】前述の素材のうち、ポリテトラフルオロエ
チレン以外の素材は細胞との親和性、すなわち易接着性
を前提として人工臓器の設計が行われており、人工血
管、人工心臓壁、人工心膜、人工腹壁、人工胸壁、人工
腱などに多用されている。そして細胞との親和性を向上
させるため基質の構造を繊維状物で編んだり織ったり、
発泡させたり延伸させて無数の亀裂を生じさせるなどの
操作で多孔質にし、細胞の侵入を容易にさせている。し
かし、細胞の侵入には長時間を要する。Of the above-mentioned materials, the materials other than polytetrafluoroethylene are designed for artificial organs on the premise of affinity with cells, that is, easy adhesion. Artificial blood vessels, artificial heart walls, artificial pericardiums. It is widely used for artificial abdominal wall, artificial chest wall, artificial tendon, etc. And to improve the affinity with cells, weaving or weaving the structure of the substrate with fibrous material,
It is made porous by operations such as foaming and stretching to create innumerable cracks, which facilitates cell invasion. However, it takes a long time for cells to enter.
【０００６】例えば人工血管、血管修復材や人工心臓壁
の場合、宿主組織との吻合部付近には細胞の侵入はみら
れるものの、それより１〜２ｃｍ離れると、手術後数年
経過しても細胞の侵入はみられない。そのため、天然の
抗血栓性を有する内皮細胞の被覆はみられず、植え込み
後何年経過しても血栓が付着しやすいという不都合な状
態となっている。[0006] For example, in the case of artificial blood vessels, blood vessel repair materials and artificial heart walls, invasion of cells can be seen near the anastomosis with the host tissue, but if it is 1 to 2 cm away from it, it will be several years after the operation. No cell invasion is observed. Therefore, there is no coating of natural endothelial cells having antithrombogenicity, which is an inconvenient state in which thrombus is likely to adhere even if many years have elapsed after implantation.
【０００７】また、人工腱における研究としては、ポリ
エステルやポリテトラフルオロエチレンなどの繊維で作
られた布の中に化学処理を行った動物の腱を入れたもの
などが考案されているが、人工血管例と同じく細胞親和
性が悪いため、繊維と生体組織との一体化が得られてい
ない。ここに細胞組み込みという概念が要求されてい
る。Further, as research on artificial tendons, there has been devised one in which a chemically treated animal tendon is put in a cloth made of fibers such as polyester and polytetrafluoroethylene. As in the case of blood vessels, because of poor cell affinity, the integration of fibers and living tissue has not been obtained. The concept of cell integration is required here.
【０００８】この問題を解決するため、１９７９年にポ
リエステル製人工血管に内皮細胞を付着させた後に植え
込む方法が開発され、１９８０年代に細胞培養技術を駆
使して多くの基礎的研究が行われた。しかし細胞培養で
増殖させた内皮細胞は実際に生体に人工血管の一部とし
て植え込んでみると剥離しやすく、その生着率は２〜３
％であった。また細胞培養に２−４週間という準備期間
が必要であるため実際には利用しにくい技術であった。In order to solve this problem, in 1979, a method was developed in which endothelial cells were adhered to a polyester artificial blood vessel and then implanted, and in the 1980s, many basic studies were carried out using cell culture technology. . However, when endothelial cells grown in cell culture are actually implanted into a living body as part of an artificial blood vessel, they tend to exfoliate and their engraftment rate is 2-3.
%Met. In addition, since the preparation period of 2-4 weeks is required for cell culture, it is a technique that is difficult to use in practice.
【０００９】創傷治癒促進材などの考え方は従来存在し
なかった考え方であるが、実際に臨床面においては、そ
れを用いることで、この部に多量の毛細血管を誘導する
ことができたり、それにより栄養豊富な結合組織層を得
ることで多量の線維芽細胞が活発に活動できる場を作
り、癒着を促進させたり、あるいは治癒が遅延していた
傷を栄養豊富な結合組織細胞層を形成させることで治癒
を促進させるものであり、具体的には人工血管床、人工
基質、癒着促進材、人工真皮等が挙げられる。Though the idea of a wound healing promoting material has not existed in the past, it is possible to induce a large amount of capillaries in this area by actually using it. By providing a nutrient-rich connective tissue layer, a field where a large amount of fibroblasts can be actively activated is created, promoting adhesion or forming a nutrient-rich connective tissue cell layer in a wound in which healing is delayed. This promotes healing, and specific examples thereof include an artificial vascular bed, an artificial matrix, an adhesion promoting material, and an artificial dermis.
【００１０】このうち人工真皮の応用の一部とも言える
人工皮膚の研究は既に行われている。これによると、人
工的にコラーゲンのテンプレートを作成し、ここに線維
芽細胞を培養し散布したり、さらにまたその上に表皮細
胞を播く方法などが考えられており、臨床面でもすでに
使用されている。しかしながら、このような培養型人工
皮膚は作成するのに特殊な技術、設備が必要であり、一
般的ではないことに加えてこれを一人一人の患者に応じ
てオーダーメイドで作るのに２〜３週間の準備期間が必
要であるため、手術室で活力ある細胞を付着させた、即
座に作れるような人工皮膚、もしくはその基礎となる人
工真皮の開発、そしてさらに、細胞を活性化するための
システムを持つような基材の開発が望まれていた。Of these, research on artificial skin, which can be said to be a part of the application of artificial dermis, has already been conducted. According to this, a method of artificially creating a collagen template, culturing and spraying fibroblasts here, and further seeding epidermal cells on it is considered, and it has already been used clinically. There is. However, such a culture-type artificial skin requires special technology and equipment to make it, and it is not common, and it is 2-3 to make it custom-made according to each patient. Because of the need for a weekly preparation period, the development of an artificial skin that can be instantly made with active cells attached to the operating room, or the underlying artificial dermis, and a system to further activate the cells It has been desired to develop a base material having such properties.
【００１１】先に本発明者は、細胞の生着率の向上、お
よび準備期間をなくするという画期的な発明を完成し出
願した（特開平３−１９８８４６号公報参照）。この発
明は、人工基材壁内部に血管組織、結合組織、脂肪組
織、筋肉組織等の生体組織の細片及び／又は血管内皮細
胞、平滑筋細胞、線維芽細胞等の血管を構成する細胞を
付着、捕捉させたことを特徴とする人工血管に関するも
のである。そして、この発明によれば、自己の組織を細
切し、布製人工血管や血管修復材の繊維の間隙に捕捉さ
せておくと、手術中に約３０分間の操作で作成可能であ
った。この技術は多くの利点があり、臨床上も有用であ
る。The inventor of the present invention has completed and applied for an epoch-making invention for improving the cell engraftment rate and eliminating the preparation period (see Japanese Patent Laid-Open No. 3-198846). The present invention provides a piece of living tissue such as vascular tissue, connective tissue, adipose tissue, muscle tissue and / or cells constituting blood vessels such as vascular endothelial cells, smooth muscle cells, fibroblasts, etc. inside the artificial substrate wall. The present invention relates to an artificial blood vessel characterized by being attached and captured. Further, according to the present invention, when the own tissue is cut into small pieces and captured in the interstices between the fibers of the cloth artificial blood vessel and the blood vessel repair material, it can be created in about 30 minutes during the operation. This technique has many advantages and is clinically useful.
【００１２】しかし採取する組織が血管や筋肉、結合組
織であるため、これらを細切したり、あるいは酵素によ
って分離させることにより、細胞の活性度の低下は刻々
と経過する時間との兼ね合いで避けられないものであっ
た。また、これらの組織は年齢や病状、栄養状態などで
異なるため、それらより得られる細胞が必ずしも活性に
富むものとは限らなかった。[0012] However, since the tissues to be collected are blood vessels, muscles, and connective tissues, a decrease in cell activity is avoided by dividing them into small pieces or separating them with an enzyme in consideration of the time elapsed. I couldn't do it. Moreover, since these tissues differ according to age, medical condition, nutritional state, etc., the cells obtained from them are not always rich in activity.
【００１３】人工腱における研究としては、ポリエステ
ルやポリテトラフルオロエチレンなどの繊維で作られた
布の中に化学処理を行った動物の腱を入れたものなどが
考案されていが、人工血管例と同じく細胞親和性が悪い
ため、繊維と生体組織との一体化が得られていない。As a study on artificial tendons, there has been devised one in which a chemically treated animal tendon is placed in a cloth made of fibers such as polyester and polytetrafluoroethylene. Similarly, since the cell affinity is poor, the integration of fibers and living tissue has not been obtained.
【００１４】[0014]
【発明が解決しようとする課題】そこで、上記の欠点を
種々検討した結果、捕捉させる細胞として組織治癒を促
進させる細胞成長因子を産生することのできる細胞、又
は、細胞成長因子及び生体組織細胞との組み合わせを用
いることにより、積極的に細胞を活性化させ、さらに細
胞の特性を利用して治癒を促進させ、人工的に希望する
軟組織を生体内で形成させることによって上記の欠点を
解決しうることを見いだし、本発明を完成したもので、
本発明は希望する軟組織を生体内で形成させて治癒を促
進させる細胞組み込み型医療材料を提供することを目的
とする。Therefore, as a result of various studies on the above-mentioned drawbacks, cells capable of producing a cell growth factor which promotes tissue healing as cells to be trapped, or cell growth factors and biological tissue cells It is possible to solve the above-mentioned drawbacks by positively activating cells, further promoting healing by utilizing the characteristics of cells, and artificially forming desired soft tissue in vivo by using the combination of After finding out that, and completing the present invention,
It is an object of the present invention to provide a cell-incorporated medical material that promotes healing by forming desired soft tissue in vivo.
【００１５】[0015]
【課題を解決するための手段】本発明の要旨は基質に細
胞成長因子を産生することのできる細胞、又は、細胞成
長因子及び生体組織細胞、を付着、捕捉又は混在させた
ことを特徴とする医療材料である。即ち、本発明は、基
材に細胞成長因子を産生することのできる細胞、又は、
細胞成長因子及び生体組織細胞を付着、捕捉又は混在さ
せる。本発明の細胞成長因子とは、増殖を促進させる糖
蛋白であるが、単に細胞増殖を誘導するのみならず、細
胞の分化、機能発現などを規定する極めて多彩な役割を
はたし、生体の発生、形態形成等にも関与する生理活性
物質である。そしてさまざまな細胞から産生され、細胞
間において情報を交換するのに寄与している。例えば、
細胞が他の細胞に増殖を指示したり、細胞の誘導を促し
たりする。従って、本発明ではこのような因子を産生す
る細胞もしくは、そのような因子と生体組織細胞との組
み合わせによって、さらに増植が促進され、新しい器官
を急速に形成させるものであることから、先の発明にお
いて、単に人工血管壁に播種された細胞が単純に増殖し
て人工血管壁を形成するものとは基本的に異なるもので
ある。The gist of the present invention is characterized in that a cell capable of producing a cell growth factor, or a cell growth factor and a biological tissue cell are attached, captured or mixed in a substrate. It is a medical material. That is, the present invention is a cell capable of producing a cell growth factor on a substrate, or
Cell growth factors and living tissue cells are attached, captured or mixed. The cell growth factor of the present invention is a glycoprotein that promotes proliferation, but it not only induces cell proliferation but also plays an extremely diverse role in regulating cell differentiation, functional expression, etc. It is a physiologically active substance involved in development, morphogenesis, etc. It is produced by various cells and contributes to the exchange of information between cells. For example,
A cell directs other cells to proliferate or promotes induction of the cell. Therefore, in the present invention, cells that produce such factors, or a combination of such factors and living tissue cells, further promotes transplantation and rapidly forms a new organ. In the present invention, the cells basically seeded on the artificial blood vessel wall are basically different from those simply proliferating to form the artificial blood vessel wall.
【００１６】本発明について以下に詳細に説明する。本
発明における医療材料としては、例えば、人工血管、心
臓血管壁修復材、人工腱、創傷治癒促進材などであり、
また、これに使用する基質としては。従来よりこの種の
医療材料に使用されているものならば何れでもよく、そ
の具体例をあげるとポリエステル、ポリウレタン、ポリ
ビニールアルコール、ポリビニール系共重合体、ポリエ
ーテルエステル、ナイロン、レーヨン、ポリプロピレ
ン、ポリテトラフルオロエチレン、綿、絹などの生体非
吸収性物質や、ポリグリコール酸、ポリ乳酸−ポリグリ
コール酸共重合体、生分解性（３−ヒドロキシブチレー
ト−４−ヒドロキシブチレート）ポリエステル共重合
体、ポリジオキサン、コラーゲン、ゼラチン、アルブミ
ン、キチン、キトサンの如き生体吸収性物質である。The present invention will be described in detail below. Examples of the medical material in the present invention include artificial blood vessels, cardiovascular wall repair materials, artificial tendons, and wound healing promoting materials,
Also, as the substrate used for this. Any material may be used as long as it has been conventionally used in this kind of medical material, and specific examples thereof include polyester, polyurethane, polyvinyl alcohol, polyvinyl copolymer, polyether ester, nylon, rayon, polypropylene, Non-bioabsorbable substances such as polytetrafluoroethylene, cotton, silk, polyglycolic acid, polylactic acid-polyglycolic acid copolymer, biodegradable (3-hydroxybutyrate-4-hydroxybutyrate) polyester copolymer Bioabsorbable substances such as coalesced, polydioxane, collagen, gelatin, albumin, chitin, chitosan.
【００１７】基材の形態は、多孔質もしくは分散状のも
ので、多孔質の形状は管状、平板状等何れでもよく、多
孔質のチューブ、多孔質のシート、多孔質のスポンジで
あり、分散状のものとしては多孔質のスポンジを粉砕し
た分散状の基材、微細線維を分散状にした、もしくはそ
れを浮遊させた液状の基材等である。そして、これらの
基材は適用する医療材料の種類によって適宣選択するこ
とが望ましい。例えば、人工血管、人工腱、などの力学
的な強度が要求されるされる場合にはポリエーテルエス
テルやポリテトラフルオロエチレンなどの生体非吸収性
物質よりなる繊維を編んだり、織ったりして作成した布
を使用することが好ましく、永久的な力学的強度が要求
されない場合にはポリグリコール酸、ポリ乳酸−ポリグ
リコール酸共重合体等の生体吸収性物質を用いることが
好ましい。The base material may be porous or dispersed, and the shape of the porous material may be tubular, flat, or the like, and may be a porous tube, a porous sheet, a porous sponge, or a dispersed material. Examples of the material include a dispersed base material obtained by crushing a porous sponge, a liquid base material in which fine fibers are dispersed or suspended. It is desirable that these base materials are appropriately selected according to the type of medical material to be applied. For example, when mechanical strength is required for artificial blood vessels, artificial tendons, etc., create by knitting or weaving fibers made of non-bioabsorbable substances such as polyetherester and polytetrafluoroethylene. It is preferable to use the above-mentioned cloth, and when permanent mechanical strength is not required, it is preferable to use a bioabsorbable substance such as polyglycolic acid or polylactic acid-polyglycolic acid copolymer.
【００１８】本発明における軟組織医療材料において基
材内に接着、捕捉、又は混在させた細胞の濃度分布とし
ては少なすぎると生着率が低下するため、１ｃｍ2あた
り１０個以上もしくは１ｃｍ3あたり１００個以上の細
胞が接着、捕捉、又は混在させられていることが好まし
い。本発明において基材内に細胞を接着、捕捉、又は混
在させる手段は特に限定されるものではないが、たとえ
ば、人工血管の場合には、先に述べた特開平３−１９８
８４６号に記載の方法が適用される。即ち、円筒状の人
工血管の基材を組織細切片及び／又は細胞分散液が収容
されている塩ビバッグのような透明のバッグの中にい
れ、その一端を閉鎖し、他端より微孔を無数に有する人
工血管を挿入し、注射器などをつないで管の全体にわた
り、均一に壁の内外に圧力差をかけて、これによって基
材中に細胞や組織細切片を捕捉、又は混在させることが
できる。In the soft tissue medical material of the present invention, if the concentration distribution of the cells adhered, trapped or mixed in the substrate is too small, the engraftment rate decreases, so 10 or more per cm 2 or 100 per cm 3. It is preferable that one or more cells are attached, captured, or mixed. In the present invention, the means for adhering, trapping, or mixing the cells in the substrate is not particularly limited, but in the case of an artificial blood vessel, for example, the above-mentioned JP-A-3-198.
The method described in No. 846 is applied. That is, the base material of a cylindrical artificial blood vessel is put into a transparent bag such as a vinyl chloride bag containing a tissue slice and / or a cell dispersion liquid, one end of which is closed, and a micropore is formed from the other end. Inserting a myriad of artificial blood vessels, connecting syringes, etc., to apply a pressure difference evenly inside and outside the wall over the entire tube, which allows cells or tissue slices to be captured or mixed in the substrate. it can.
【００１９】本発明における医療材料においては、基質
に細胞成長因子を産生することのできる細胞、又は、細
胞成長因子及び生体組織細胞を付着、捕捉又は混在させ
た基材をそのまま医療材料として使用すること、又はそ
のような細胞を付着、捕捉又は混在させで得られた基材
を組織培養用医療材料として使用する。さらにまた、こ
のようにして作成したのち、一時的に凍結保存してお
き、解凍して使用することもできる。In the medical material of the present invention, cells capable of producing a cell growth factor on a substrate, or a substrate having cell growth factor and biological tissue cells attached, captured or mixed together is used as it is as a medical material. Or a substrate obtained by attaching, capturing or mixing such cells is used as a tissue culture medical material. Furthermore, after being created in this way, it can be temporarily frozen and stored, and then thawed and used.
【００２０】細胞成長因子を産生する細胞を多く含む組
織としては生体の中では骨髄、肝臓、脾臓、腎臓、膵
臓、大網、胎盤、子宮内膜、甲状腺、胸腺、副腎、卵
巣、睾丸、血液、皮膚、皮下組織等が挙げられる。例え
ば骨髄は高齢者においても多くの***、分化能の高い細
胞を含んでおり、またさらにこれらの細胞は多量の細胞
成長因子を産生するので好適である。したがって、骨髄
を使用することが最も好ましい。このような細胞を組み
込んだ医療材料はそれらの細胞の産生する細胞成長因子
により、又は組み込まれた細胞成長因子と細胞との働き
によって、組織治癒が促進されたり、またそれらの細胞
が置かれた環境によって新しい細胞が分化によって形成
され、さらに***増殖を繰り返して、新しい組織を創生
させることによって、生体親和性及び治癒性の高い人工
血管、心臓血管壁修復材、人工腱、創傷治癒促進材など
を植え込み後、体内において作らせることができる。Tissues containing a large amount of cells for producing cell growth factors include, in the living body, bone marrow, liver, spleen, kidney, pancreas, omentum, placenta, endometrium, thyroid, thymus, adrenal gland, ovary, testis, blood. , Skin, subcutaneous tissue and the like. For example, bone marrow is suitable because it contains many cells with high division and differentiation potential even in the elderly, and these cells produce a large amount of cell growth factor. Therefore, it is most preferred to use bone marrow. A medical material incorporating such cells promotes tissue healing by the cell growth factor produced by those cells or the action of the incorporated cell growth factor and the cells, or the cells are placed. New cells are formed by differentiation due to the environment, and by further dividing and proliferating to create new tissue, artificial blood vessels with high biocompatibility and high healing properties, cardiovascular wall repair materials, artificial tendons, wound healing promoting materials. After implanting, etc., it can be made in the body.
【００２１】これらのうち、骨髄細胞を用いて細胞組み
込み型医療材料として使用する試みは骨組織形成の研究
において行われた例がある。すなわち、ハイドロオキシ
アパタイトと骨髄細胞とを混在させて生体内に植え込む
と骨成分がハイドロオキシアパタイトの表面に付着、蓄
積して骨の新生がみられるというものである。しかし、
骨髄の細胞から産生される細胞成長因子を積極的に利用
することで目的とする人工臓器を体内で作成させようと
いう考え方は未だ考案されていなかった。[0021] Among these, there is an example in which an attempt to use bone marrow cells as a cell-incorporated medical material has been conducted in the study of bone tissue formation. That is, when a mixture of hydroxyapatite and bone marrow cells is implanted in a living body, bone components adhere to and accumulate on the surface of hydroxyapatite, and new bone is observed. But,
The idea of using the cell growth factor produced from the cells of bone marrow to create a target artificial organ in the body has not been devised yet.
【００２２】本発明においては、組織治癒を促進させる
細胞成長因子を産生することのできる細胞、又は、細胞
成長因子と生体組織細胞とを基質に付着、又は混在させ
ておき、生体内に埋め込むことにより、その細胞自身が
その場で生着して細胞成長因子を産生し続けて細胞増殖
を促進したり、細胞成長因子と細胞との共同作業の結
果、新たな細胞や毛細血管を基質内に誘導して治癒を促
進させたり、又はその基質を足場として、それの置かれ
た最も条件の良い環境に応じて活発な分化能をもつ細胞
が新しい細胞に分化してゆくことなどで、目的とした器
官や人工臓器を体内で形成させるものである。生体組織
細胞とは一般の生体組織を形成する線維芽細胞、平滑筋
細胞、内皮細胞、漿膜細胞、脂肪細胞、細網細胞、肥満
細胞等を意味する。これらの細胞が細胞成長因子ととも
に基質に付着、又は混在されると、細胞成長因子とそれ
らの細胞との共同作業の結果、新たな細胞や毛細血管を
基質内に誘導して治癒を促進させることが可能となる。In the present invention, cells capable of producing a cell growth factor that promotes tissue healing, or cell growth factors and living tissue cells are attached to a substrate or mixed together and embedded in a living body. This allows the cells themselves to engraft in situ and continue to produce cell growth factors to promote cell growth, or as a result of collaborative work between cell growth factors and cells, new cells or capillaries can be introduced into the matrix. By inducing and promoting healing, or using its substrate as a scaffold, cells with active differentiation potential according to the most favorable environment in which they are placed are differentiated into new cells. It is the one that causes the formation of such organs and artificial organs in the body. Living tissue cells mean fibroblasts, smooth muscle cells, endothelial cells, serosa cells, adipocytes, reticulum cells, mast cells and the like that form general living tissues. When these cells are attached to or mixed with the substrate together with the cell growth factor, as a result of the collaboration between the cell growth factor and those cells, new cells and capillaries are introduced into the substrate to promote healing. Is possible.
【００２３】従って、同一の細胞から置かれた立場によ
って性質のまったく異なる細胞が分化しうる。たとえ
ば、本発明における医療材料を創傷治癒促進材一つであ
る治癒促進型人工腹壁として使用した場合、その膜の表
面に出た細胞は漿膜細胞に分化し増殖して、その細胞の
もつ天然の抗癒着作用を表面にもたらし、その場で永久
に癒着を生じなくする。又一方、本発明における医療材
料を創傷治癒促進材一つである癒着促進材として使用し
た場合、その膜の表面に出た細胞は平滑筋細胞や線維芽
細胞に分化し増殖して細胞周囲に膠原線維や弾性線維を
産生し、周囲組織との癒着を促進するのに貢献する。そ
してこのような細胞の分化、***のための適切な指図が
細胞成長因子を産生する細胞によって細胞成長因子を用
いた刺激によって行なわれる。Therefore, cells having completely different properties can be differentiated depending on the position placed from the same cell. For example, when the medical material of the present invention is used as a healing-promoting artificial abdominal wall, which is one of the wound-healing promoters, the cells appearing on the surface of the membrane are differentiated into serosa cells and proliferate. It provides an anti-adhesion effect to the surface, which permanently eliminates adhesions in-situ. On the other hand, when the medical material of the present invention is used as an adhesion promoting material, which is one of wound healing promoting materials, cells appearing on the surface of the membrane are differentiated into smooth muscle cells and fibroblasts and proliferate around the cells. It produces collagen fibers and elastic fibers, and contributes to promoting adhesion with surrounding tissues. Appropriate instructions for differentiation and division of such cells are carried out by stimulation with cell growth factors by cells producing the cell growth factors.
【００２４】例えば、人工血管、心臓血管壁修復材にお
いては内面に出た細胞は細胞成長因子による刺激によっ
て内皮細胞へと分化し、この部位において***増殖し、
内面を覆って、内皮細胞のもつ天然の抗血栓性を全内表
面にもたらし、その場に血栓を形成させなくする。その
下層に置かれた細胞は平滑筋組織や線維芽細胞に分化
し、そこで増殖して、細胞周囲に膠原線維や弾性線維を
産生し、壁全体の強度と弾性および周囲組織との親和性
を獲得維持する。そしてさらに細胞成長因子を産生する
ことのできる細胞はその場で生着し、増植して、成長因
子などの細胞成長因子を産生し続ける事により細胞の侵
入を誘導し、細胞の増植を促進させて治癒促進、器官形
成促進などに貢献する。For example, in artificial blood vessels and cardiac vascular wall repair materials, the cells on the inner surface are differentiated into endothelial cells by stimulation with cell growth factors, and divide and proliferate at this site,
By covering the inner surface, the natural antithrombogenicity of endothelial cells is brought to the entire inner surface, and thrombus is not formed in situ. The cells placed underneath it differentiate into smooth muscle tissue and fibroblasts, which proliferate there to produce collagen and elastic fibers around the cells, which enhances the strength and elasticity of the entire wall and its affinity with surrounding tissues. Earn and maintain. Then, cells capable of producing cell growth factors are further engrafted on the spot, transplanted, and continue to produce cell growth factors such as growth factors to induce invasion of cells and to expand cells. It promotes healing and contributes to the promotion of healing and organ formation.
【００２５】人工腱においては、永久的に力学的強度が
要求される場に置かれるため、生体内でのマクロファー
ジなどの細胞や電解質、酵素などの攻撃に耐えて、決し
て劣化することのないようにポリエステル繊維の如き生
体内非吸収性物質により多孔性の紐状構造を作ることが
好ましい。この場合にこの基質に分化能の高い細胞を接
着、捕捉、又は混在させておくことにより、紐状構造の
外面において、人工腱が関節腔内に直接露出される部位
においては、表面近くに播かれた分化能の高い細胞は漿
膜細胞へと分化し、そこで増殖して人工腱の表面を覆い
つくす。その結果、人工腱は漿膜細胞のもつ天然の抗癒
着性を獲得し、関節内で自由に動くことができる。また
一方、紐状構造の内部や人工腱が骨に付着固定させられ
る部位における紐状構造の表面および内部においては、
そこに播かれた細胞が細胞成長因子による刺激によって
平滑筋細胞や線維芽細胞に分化し、そこで増殖して細胞
周囲に膠原線維や弾性線維を産生し、互いに癒着して人
工腱全体の強度と弾性を向上させるとともに、周囲組織
との親和性の向上に貢献する。Since the artificial tendon is permanently placed in a place where mechanical strength is required, it is resistant to attack by cells such as macrophages and electrolytes and enzymes in the living body and never deteriorates. In addition, it is preferable to form a porous string-like structure by a non-absorbable substance such as polyester fiber. In this case, by adhering, trapping, or mixing the cells having high differentiation potential with this matrix, the artificial tendon is seeded near the surface at the site where the artificial tendon is directly exposed in the joint cavity on the outer surface of the string-like structure. The cells with high differentiation potential differentiate into serosa cells, where they proliferate and cover the surface of the artificial tendon. As a result, the artificial tendon acquires the natural anti-adhesion properties of serosa cells and can move freely within the joint. On the other hand, on the surface and inside of the string-like structure in the part where the artificial tendon is attached and fixed to the bone inside the string-like structure,
The cells seeded there are differentiated into smooth muscle cells and fibroblasts by stimulation with cell growth factors, which proliferate there to produce collagen fibers and elastic fibers around the cells and adhere to each other to increase the strength of the entire artificial tendon. Improves elasticity and contributes to improvement of affinity with surrounding tissues.
【００２６】創傷治癒促進材という考え方は従来存在し
なかった考え方であるが、それを用いることで、その部
に多量の毛細血管を誘導することができたり、それによ
り栄養豊富な結合組織層を得ることで多量の線維芽細胞
が活発に活動できる場を提供させたり、癒着を促進させ
たり、あるいは治癒が遅延していた傷を栄養豊富な結合
組織細胞層を形成させることで治癒促進を図るものであ
る。その具体的な例としては人工血管床、人工基質、癒
着促進材、人工真皮層等が挙げられる。またさらにその
解釈を広げると、治癒性を促進させた人工心膜、人工漿
膜、人工横隔膜、人工腹壁、人工胸壁、癒着防止膜、人
工骨、人工内分泌、等も含まれる。人工血管床において
は、無数の毛細血管の新生を望む場合に使用される。こ
の場合も、人工血管床が永久的な力学的強度を要求され
る場合においては、ポリエステル繊維による多孔性基質
が望ましいが、力学的強度を要求されない場合は生体内
吸収性素材による多孔性の基材もしくは分散させた基
材、例えば、IV型コラーゲンのスポンジや液体に分散さ
れたコラーゲン線維などを用いるのが好ましく、これに
細胞成長因子を産生する細胞、又は、細胞成長因子と細
胞とを接着、捕捉、又は混在させておくことにより、こ
れらの細胞が内皮細胞へと分化し、***増殖し、あるい
は細胞成長因子の働きによって毛細血管新生を促し、さ
らに周囲からも毛細血管の侵入を誘導し、それらが互い
に集合して毛細血管網を形成する。そしてこれらが太い
宿主血管と連絡を持つことによって人工的に血管の豊富
な床を形成させることができる。そしてさらに細胞成長
因子を産生することのできる細胞はその場で生着し、増
植して、成長因子などの細胞成長因子を産生し続ける事
により細胞を誘導し、細胞の増植を促進させて治癒促
進、器官形成促進などに貢献する。癒着促進材、創傷治
癒促進材などにおいては、永久的に力学的強度は要求さ
れないため、生体内吸収性素材による多孔性の基材もし
くは分散させた基材を用い、これに細胞成長因子を産生
することのできる細胞、又は細胞成長因子と細胞とを接
着、捕捉、又は混在させておくことができる。この場合
の基材としてはＩ型コラーゲンやIV型コラーゲン、キチ
ン、キトサンなど、もしくは、これらの混合物を用いる
ことが好ましい。これにより細胞成長因子を産生する細
胞などの一部が細胞成長因子の働き及び環境という場の
与える影響によって線維芽細胞を増殖させ、それらが膠
原線維や弾性線維を作ることにより、周囲組織との親和
性を高めるとともに、一部の細胞は内皮細胞へと分化
し、これが増殖し、互いに集合して毛細血管網を形成
し、周囲の宿主血管との連絡がつくことにより栄養豊富
な結合組織が形成される。その結果、この部位に癒着を
促進させたり、あるいは創傷治癒を促進させることがで
きる。以下、実施例をもって、更に具体的に本発明につ
いて説明する。Although the idea of a wound healing promoting material has not existed in the past, by using it, it is possible to induce a large amount of capillaries in the part, thereby providing a connective tissue layer rich in nutrients. By providing a place where a large amount of fibroblasts can be actively activated, promoting adhesion, or promoting healing of wounds whose healing has been delayed by forming a nutrient-rich connective tissue cell layer. It is a thing. Specific examples thereof include an artificial vascular bed, an artificial matrix, an adhesion promoting material, an artificial dermis layer and the like. Further expanding its interpretation also includes artificial pericardium, artificial serosa, artificial diaphragm, artificial abdominal wall, artificial chest wall, anti-adhesion membrane, artificial bone, artificial endocrine, etc., which promote healing. In artificial blood vessel beds, it is used when it is desired to create a myriad of capillaries. Also in this case, when the artificial vascular bed is required to have permanent mechanical strength, a porous substrate made of polyester fiber is preferable, but when mechanical strength is not required, a porous group made of a bioabsorbable material is used. It is preferable to use a material or a dispersed base material, for example, a type IV collagen sponge or a collagen fiber dispersed in a liquid, to which cells that produce cell growth factors or cell growth factors and cells are adhered. , These cells are differentiated into endothelial cells and proliferate, or by the action of cell growth factors, angiogenesis is promoted and the invasion of capillaries is also induced from the surroundings. , They aggregate together to form a capillary network. And since these have contact with thick host blood vessels, they can artificially form a bed rich in blood vessels. Further, cells capable of producing cell growth factors are engrafted on the spot, transplanted, and continue to produce cell growth factors such as growth factors to induce the cells to promote cell transplantation. Contributes to healing and organ formation. For adhesion promoters, wound healing promoters, etc., since mechanical strength is not required permanently, a porous base material or a dispersed base material made of a bioabsorbable material is used to produce a cell growth factor. Cells that can be used, or cell growth factors and cells can be adhered, captured, or mixed. In this case, it is preferable to use type I collagen, type IV collagen, chitin, chitosan, etc., or a mixture thereof as the base material. This causes some of the cells that produce cell growth factors to proliferate fibroblasts due to the effects of the environment of the function of cell growth factors and the environment, and by making them collagen and elastic fibers, As well as increasing the affinity, some cells differentiate into endothelial cells, which proliferate, aggregate with each other to form a capillary network, and connect with surrounding host blood vessels to form nutrient-rich connective tissue. It is formed. As a result, adhesion can be promoted to this site or wound healing can be promoted. Hereinafter, the present invention will be described more specifically with reference to Examples.
【００２７】[0027]
【実施例及び比較例】実施例を示すに当たり、細胞成長
因子を産生することのできる細胞を持つ組織の代表とし
て骨髄組織を、生体細胞の代表として皮下組織より採取
した線維芽細胞を、そして細胞成長因子の代表として線
維芽細胞成長因子（ＦＧＦ）を用いて以下に実例を記
す。 実施例１ ポリエステル布製人工血管（内径８ｍｍ，長さ６ｃｍ、
有孔性：１８００ｃｃ／ｃｍ2、１２０ｍｍＨｇ）の一
端に三方括栓をつなぎ、これを介して骨髄細胞浮遊液を
シリンジにて人工血管内に圧注入した。人工血管の他端
は鉗子で止め、外側を塩ビのバックで覆い、人工血管壁
を通過した骨髄細胞浮遊液を受け、これをコネクティブ
チューブを介してシリンジ内にもどし、再度、人工血管
内に圧注入を繰り返すことで骨髄細胞を人工血管壁に接
着、捕捉させた。この操作は約２０分間で終了した。次
にこのようにして作成した人工血管断面を光学顕微鏡で
検査したところ、この手段によってポリエステルの繊維
間隙に高密度に骨髄細胞が集まっていることが確認でき
た。また免疫組織学的検査により、この骨髄細胞が集ま
っている部位に多量のＦＧＦ等の成長因子が検出され
た。EXAMPLES AND COMPARATIVE EXAMPLES In showing examples, bone marrow tissue is representative of tissues having cells capable of producing cell growth factors, fibroblasts collected from subcutaneous tissues as representative of living cells, and cells. An example is given below using fibroblast growth factor (FGF) as a representative growth factor. Example 1 Artificial blood vessel made of polyester cloth (inner diameter 8 mm, length 6 cm,
Porosity: 1800 cc / cm 2 , 120 mmHg) was connected to one end of a three-way closure plug, and the bone marrow cell suspension was pressure-injected into the artificial blood vessel with a syringe therethrough. Stop the other end of the artificial blood vessel with forceps, cover the outside with a vinyl chloride bag, receive the bone marrow cell suspension that has passed through the wall of the artificial blood vessel, return it to the syringe via the connective tube, and insert it again into the artificial blood vessel. The bone marrow cells were adhered to and trapped on the artificial blood vessel wall by repeating pressure injection. This operation was completed in about 20 minutes. Next, when the cross section of the artificial blood vessel thus created was examined by an optical microscope, it was confirmed that bone marrow cells were densely gathered in the polyester fiber gaps by this means. In addition, by immunohistological examination, a large amount of growth factors such as FGF were detected at the site where the bone marrow cells were collected.
【００２８】実施例２ フィブリル長９０ミクロンの延伸ポリテトラフルオロエ
チレン製人工血管、内径６ｍｍ、長さ６ｃｍを用い、実
施例１と同様の操作によって骨髄細胞を人工血管壁に接
着、捕捉させた。次にこのようにして作成した人工血管
を光学顕微鏡で断面を検査したところ、この手段によっ
て延伸されたポリテトラフルオロエチレンの繊維間隙に
高密度に骨髄細胞が集まっていることが確認できた。ま
た免疫組織学的検査により、この部位に多量のＦＧＦ等
の成長因子が検出された。 実施例３ ポリエステル布製人工血管（内径８ｍｍ，長さ６ｃｍ、
有孔性：１８００ｃｃ／ｃｍ2、１２０ｍｍＨｇ）の内
面に、牛アキレス腱より得たファイバーコラーゲン分散
液をしみ込ませた後凍結乾燥し、ヘキサメチレンジイソ
シアネイトにより架橋処理して不溶化し、多孔性の膜を
得た。次に実施例１と同様の手法を用いて、この管状物
の壁内部に骨髄細胞を捕捉させた。このようにして作成
した膜を実施例１と同様の手法で検査したところ実施例
１と同様の結果が得られた。Example 2 An artificial blood vessel made of expanded polytetrafluoroethylene having a fibril length of 90 microns, an inner diameter of 6 mm and a length of 6 cm was used, and the bone marrow cells were adhered to and trapped on the artificial blood vessel wall by the same operation as in Example 1. Next, when the cross section of the artificial blood vessel thus produced was inspected by an optical microscope, it was confirmed that bone marrow cells were densely gathered in the fiber gap of polytetrafluoroethylene stretched by this means. In addition, a large amount of growth factors such as FGF were detected at this site by immunohistological examination. Example 3 Artificial blood vessel made of polyester cloth (inner diameter 8 mm, length 6 cm,
Porosity: 1800 cc / cm 2 , 120 mmHg) The inner surface was impregnated with a fiber collagen dispersion obtained from bovine Achilles tendon, lyophilized, and crosslinked with hexamethylene diisocyanate to insolubilize it to form a porous membrane. Got Next, using the same method as in Example 1, bone marrow cells were captured inside the wall of this tubular material. When the film thus formed was inspected by the same method as in Example 1, the same result as in Example 1 was obtained.
【００２９】実施例４ 実施例１で使用したポリエステル布製人工血管（内径８
ｍｍ，長さ６ｃｍ、有孔性：１８００ｃｃ／ｃｍ2、１
２０ｍｍＨｇ）の内腔面に生分解性ポリエステル共重合
体（３−ヒドロキシブチレートと４−ヒドロキシブチレ
ートの共重合体）をクロロフォルムで溶解して塗布し、
凍結乾燥することにより多孔性の生分解膜をポリエステ
ル布製人工血管繊維間隙に形成させた。次にこの人工血
管を用いて実施例１と同様の方法で細胞を人工血管壁に
捕捉させた。光学顕微鏡による検査では、この手段によ
って高密度に骨髄細胞が集まっていることが確認でき
た。また免疫組織学的検査により、この部位に多量のＦ
ＧＦ等の成長因子が検出された。 実施例５ 実施例３と同様の方法により牛アキレス腱より得たファ
イバーコラーゲン分散液を絡ませた多孔性の基材を得
た。次に線維芽細胞成長因子（ＦＧＦ）溶液（１０ＣＣ
に１０マイクログラム溶解したもの）にそれを浸し、Ｆ
ＧＦをコラーゲンに吸着させた。次に実施例１と同様の
方法により皮下組織より採取した線維芽細胞をこの基材
の壁内部に捕捉させた。この操作により、基材に線維芽
細胞成長因子と組織細胞からなる人工血管を作成するこ
とができた。Example 4 The polyester cloth artificial blood vessel used in Example 1 (inner diameter 8
mm, length 6 cm, porosity: 1800 cc / cm 2 , 1
20 mmHg), the biodegradable polyester copolymer (copolymer of 3-hydroxybutyrate and 4-hydroxybutyrate) is dissolved in chloroform and applied on the inner surface of
By freeze-drying, a porous biodegradable membrane was formed in the interstices of the polyester cloth artificial blood vessel fibers. Next, using this artificial blood vessel, cells were trapped on the artificial blood vessel wall in the same manner as in Example 1. Examination with an optical microscope confirmed that bone marrow cells were concentrated at high density by this means. Also, immunohistological examination revealed that a large amount of F
Growth factors such as GF were detected. Example 5 By the same method as in Example 3, a porous substrate in which a fiber collagen dispersion obtained from bovine Achilles tendon was entangled was obtained. Next, a fibroblast growth factor (FGF) solution (10 CC
Dip it in 10 micrograms)
GF was adsorbed on collagen. Next, by the same method as in Example 1, fibroblasts collected from the subcutaneous tissue were trapped inside the wall of this base material. By this operation, an artificial blood vessel composed of fibroblast growth factor and tissue cells could be created on the substrate.
【００３０】実施例６ 実施例１と同様の方法により、骨髄細胞をポリエステル
の繊維間隙に集めた人工血管を得た。つぎにこれを組織
培養装置によって２週間これを培養したところ、ポリエ
ステル繊維間隙にさらに高密度に骨髄細胞、線維芽細
胞、内皮細胞等が増殖し、繊維間隙を完全に占めつくし
ており、このままで人工血管としての植え込みができる
状態となっていた。 実施例７ 実施例２と同様の方法により、骨髄細胞をフィブリル長
９０ミクロンの延伸ポリテトラフルオロエチレン製人工
血管の繊維間隙に集めた人工血管を得た。つぎにこれを
組織培養装置によって２週間培養したところ、ポリテト
ラフルオロエチレンの繊維間隙にさらに高密度に骨髄細
胞、線維芽細胞、内皮細胞等が増殖し、繊維間隙を完全
に占めつくしており、このままで人工血管としての植え
込みができる状態となっていた。Example 6 By the same method as in Example 1, an artificial blood vessel in which bone marrow cells were collected in polyester fiber interstices was obtained. Next, when this was cultured for 2 weeks with a tissue culture device, the bone marrow cells, fibroblasts, endothelial cells, etc. proliferated in the polyester fiber gap at a higher density and completely occupied the fiber gap. It was ready for implantation as an artificial blood vessel. Example 7 By the same method as in Example 2, an artificial blood vessel was obtained in which bone marrow cells were collected in the fiber gap of the expanded polytetrafluoroethylene artificial blood vessel having a fibril length of 90 μm. Next, when this was cultured for 2 weeks using a tissue culture device, bone marrow cells, fibroblasts, endothelial cells, etc. proliferated in the fiber gap of polytetrafluoroethylene at a higher density and completely occupied the fiber gap. It was ready for implantation as an artificial blood vessel.
【００３１】実施例８ 実施例１と同様の方法により、骨髄細胞をポリエステル
の繊維間隙に集めた人工血管を得た。つぎにこれを犬の
背部皮下組織内に挿入し、１週間生体内組織培養をした
ところ、ポリエステルの繊維間隙にさらに高密度に骨髄
細胞、線維芽細胞、内皮細胞等が増殖し、繊維間隙を完
全に占めつくしており、さらに周囲組織より無数の毛細
血管がポリエステルの繊維間隙に侵入しており、このま
までハイブリッド型人工血管としての植え込みができる
状態となっていた。 実施例９ 実施例２と同様の方法により、骨髄細胞をポリテトラフ
ルオロエチレンの繊維間隙に集めた人工血管を得た。つ
ぎにこれを犬の背部皮下組織内に挿入し、１週間生体内
組織培養をしたところ、実施例８と同様の結果が得られ
た。 実施例１０ 実施例１と同様の方法により、組織培養技術を用いて細
胞組込み型人工血管を得た。次にこれを生体組織冷凍保
存システムを用いて３カ月間冷凍保存し、その後解凍し
て細胞活性を検討したところ、人工血管内の細胞は生き
続けており、細胞増殖の確認によって、この型の細胞組
込み型人工血管が冷凍により保存しておくことが可能で
あることが示された。Example 8 By the same method as in Example 1, an artificial blood vessel in which bone marrow cells were collected in polyester fiber gaps was obtained. Next, this was inserted into the dorsal subcutaneous tissue of the dog and subjected to in-vivo tissue culture for 1 week. As a result, bone marrow cells, fibroblasts, endothelial cells, etc. proliferated at higher density in the polyester fiber gap, and It was completely occupied, and innumerable capillaries penetrated from the surrounding tissues into the fiber interstices of polyester, and it was ready for implantation as a hybrid artificial blood vessel. Example 9 By the same method as in Example 2, an artificial blood vessel in which bone marrow cells were collected in the fiber gap of polytetrafluoroethylene was obtained. Next, this was inserted into the dorsal subcutaneous tissue of a dog and in-vivo tissue culture was carried out for 1 week, and the same results as in Example 8 were obtained. Example 10 By the same method as in Example 1, a cell-incorporated artificial blood vessel was obtained using the tissue culture technique. Next, this was cryopreserved for 3 months using a biological tissue cryopreservation system, and then thawed and the cell activity was examined. As a result, cells in the artificial blood vessel remained alive, and by confirmation of cell proliferation, this type of It was shown that the cell-incorporated artificial blood vessel can be preserved by freezing.
【００３２】実施例１１ 実施例１と同様の方法により、骨髄細胞をポリエステル
の繊維間隙に集めた人工血管を得た。次にこのようにし
て作成した人工血管を成犬の胸部下行大動脈に植え込ん
だところ、植え込み直後、内面は新鮮なフィブリン層で
覆われていたが、骨髄細胞は流れ去ることなくその場に
とどまっており、植え込み後３週間で人工血管内面はす
べて一層の連続した内皮細胞に覆われていた。内皮細胞
下には平滑筋細胞および線維芽細胞の多重層がみられ、
毛細血管も多数認められた。このようにして形成された
新しい器官の内部の所々に骨髄細胞が生着し、異所性の
造血現象がおきていることが判明した。また免疫組織学
的検査により、この部位に多量のＦＧＦ等の成長因子が
検出された。このことより、骨髄組織特有の細胞成長因
子が産生され続けて、この部分での治癒を促進させてい
たと考えられた。外膜側には無数のマクロファージ、線
維芽細胞、膠原線維が認められ、周囲組織との親和性は
良好であった。このような新しい血管壁の完成は人工血
管と生体血管との吻合部付近も人工血管中央部も等しく
認められた。 実施例１２ 実施例２と同様の方法により、骨髄細胞をポリテトラフ
ルオロエチレンの繊維間隙に集めた人工血管を得た。次
にこのようにして作成した人工血管を成犬の胸部下行大
動脈に植え込んだところ、実施例１１と同様の結果が得
られた。Example 11 By the same method as in Example 1, an artificial blood vessel in which bone marrow cells were collected in polyester fiber gaps was obtained. Next, when the artificial blood vessel created in this way was implanted into the descending thoracic aorta of an adult dog, immediately after implantation, the inner surface was covered with a fresh fibrin layer, but the bone marrow cells remained there without flowing away. However, three weeks after the implantation, the inner surface of the artificial blood vessel was entirely covered with one continuous layer of endothelial cells. There are multiple layers of smooth muscle cells and fibroblasts under the endothelial cells,
Many capillaries were also recognized. It was revealed that bone marrow cells were engrafted in various places inside the new organ thus formed, and an ectopic hematopoietic phenomenon occurred. In addition, a large amount of growth factors such as FGF were detected at this site by immunohistological examination. From this, it was considered that the cell growth factor peculiar to bone marrow tissue was continuously produced to promote healing in this part. Innumerable macrophages, fibroblasts, and collagen fibers were observed on the adventitia side, and had good affinity with surrounding tissues. The completion of such a new blood vessel wall was recognized equally in the vicinity of the anastomosis between the artificial blood vessel and the living blood vessel and in the central portion of the artificial blood vessel. Example 12 By the same method as in Example 2, an artificial blood vessel in which bone marrow cells were collected in the fiber gap of polytetrafluoroethylene was obtained. Next, when the artificial blood vessel thus created was implanted into the descending thoracic aorta of an adult dog, the same results as in Example 11 were obtained.
【００３３】実施例１３ 実施例３と同様の方法により、骨髄細胞をポリエステル
の繊維間隙に集めた人工血管を得た。次にこのようにし
て作成した人工血管を成犬の胸部下行大動脈に植え込ん
だところ、実施例１１と同様の結果が得られた。 実施例１４ 実施例４と同様の方法により、骨髄細胞をポリエステル
の繊維間隙に集めた人工血管を得た。次にこのようにし
て作成した人工血管を成犬の胸部下行大動脈に植え込ん
だところ、実施例１１と同様の結果が得られた。 実施例１５ 実施例５と同様の方法により基材に線維芽細胞成長因子
と組織細胞からなる人工血管を得た。次にこのようにし
て作成した人工血管を成犬の胸部下行大動脈に植え込ん
だところ、植え込み直後、内面は新鮮なフィブリン層で
覆われていたが、植え込み後３週間で人工血管内面はす
べて一層の連続した内皮細胞に覆われていた。内皮細胞
下には平滑筋細胞および線維芽細胞の多重層がみられ、
毛細血管も多数認められた。外膜側には無数のマクロフ
ァージ、線維芽細胞、膠原線維が認められ、周囲組織と
の親和性は良好であった。このような新しい血管壁の完
成は人工血管と生体血管との吻合部付近も人工血管中央
部も等しく認められた。Example 13 By the same method as in Example 3, an artificial blood vessel in which bone marrow cells were collected in polyester fiber gaps was obtained. Next, when the artificial blood vessel thus created was implanted into the descending thoracic aorta of an adult dog, the same results as in Example 11 were obtained. Example 14 By the same method as in Example 4, an artificial blood vessel in which bone marrow cells were collected in polyester fiber gaps was obtained. Next, when the artificial blood vessel thus created was implanted into the descending thoracic aorta of an adult dog, the same results as in Example 11 were obtained. Example 15 By the same method as in Example 5, an artificial blood vessel composed of fibroblast growth factor and tissue cells was obtained as a substrate. Next, when the artificial blood vessel created in this way was implanted into the descending thoracic aorta of an adult dog, the inner surface was covered with a fresh fibrin layer immediately after implantation, but three weeks after the implantation, the inner surface of the artificial blood vessel was completely covered. It was covered with continuous endothelial cells. There are multiple layers of smooth muscle cells and fibroblasts under the endothelial cells,
Many capillaries were also recognized. Innumerable macrophages, fibroblasts, and collagen fibers were observed on the adventitia side, and had good affinity with surrounding tissues. The completion of such a new blood vessel wall was recognized equally in the vicinity of the anastomosis between the artificial blood vessel and the living blood vessel and in the central portion of the artificial blood vessel.
【００３４】実施例１６ 実施例６と同様の方法により、骨髄細胞をポリエステル
の繊維間隙に集めた人工血管を得た。次にこのようにし
て作成した人工血管を成犬の胸部下行大動脈に植え込ん
だところ、実施例１１と同様の結果が得られた。 実施例１７ 実施例７と同様の方法により、骨髄細胞をポリテトラフ
ルオロエチレンの繊維間隙に集めた人工血管を得た。次
にこのようにして作成した人工血管を成犬の胸部下行大
動脈に植え込んだところ、実施例１１と同様の結果が得
られた。 実施例１８ 実施例１と同様の方法により、骨髄細胞をポリエステル
の繊維間隙に集めた人工血管を得た。次にこの人工血管
を長軸方向に切り開き、骨髄細胞の播種された膜状物を
得た。このようにして作成した膜を成犬の右心室肺動脈
の右室流出路部分に心臓壁および肺動脈の一部への人工
心臓壁、血管修復材用パッチとして植え込んだ。植え込
み直後、内面は新鮮なフィブリン層に覆われたが、骨髄
細胞は流れ去ることなくその場にとどまっており、植え
込み３週間ではパッチ材内面は完全に内皮細胞によって
覆われていた。パッチ材壁内部には無数の線維芽細胞、
マクロファージ、および赤芽球、毛細血管などが認めら
れた。外膜側には多数の線維芽細胞、毛細血管が集まっ
てきており、周囲組織との親和性は極めて良好であっ
た。このようにして形成された新しい器官の内部の所々
に骨髄細胞が生着し、異所性の造血現象がおきているこ
とが判明した。また免疫組織学的検査により、この部位
に多量のＦＧＦ等の成長因子が検出された。このことよ
り、骨髄組織特有の細胞成長因子が産生され続けて、こ
の部分での治癒を促進させていたと考えられた。Example 16 By the same method as in Example 6, an artificial blood vessel in which bone marrow cells were collected in polyester fiber spaces was obtained. Next, when the artificial blood vessel thus created was implanted into the descending thoracic aorta of an adult dog, the same results as in Example 11 were obtained. Example 17 By the same method as in Example 7, an artificial blood vessel in which bone marrow cells were collected in the fiber gap of polytetrafluoroethylene was obtained. Next, when the artificial blood vessel thus created was implanted into the descending thoracic aorta of an adult dog, the same results as in Example 11 were obtained. Example 18 By the same method as in Example 1, an artificial blood vessel in which bone marrow cells were collected in the fiber interstices of polyester was obtained. Next, the artificial blood vessel was cut open in the longitudinal direction to obtain a membranous material in which bone marrow cells were seeded. The membrane thus prepared was implanted in the right ventricular outflow tract of the right ventricular pulmonary artery of an adult dog as a heart wall, an artificial heart wall to part of the pulmonary artery, and a patch for a vascular repair material. Immediately after the implantation, the inner surface was covered with a fresh fibrin layer, but the bone marrow cells remained in place without flowing away, and the inner surface of the patch material was completely covered with endothelial cells at 3 weeks after the implantation. Countless fibroblasts inside the patch wall,
Macrophages, erythroblasts, capillaries, etc. were observed. A large number of fibroblasts and capillaries gathered on the adventitia side, and the affinity with surrounding tissues was extremely good. It was revealed that bone marrow cells were engrafted in various places inside the new organ thus formed, and an ectopic hematopoietic phenomenon occurred. In addition, a large amount of growth factors such as FGF were detected at this site by immunohistological examination. From this, it was considered that the cell growth factor peculiar to bone marrow tissue was continuously produced to promote healing in this part.
【００３５】実施例１９ 実施例７と同様の方法により、骨髄細胞をフィブリル長
９０ミクロンの延伸ポリテトラフルオロエチレン製人工
血管の繊維間隙に集めた人工血管を得た。次にこの人工
血管を長軸方向に切り開き、骨髄細胞の播種された膜状
物を得た。このようにして作成した膜を成犬の右心室肺
動脈の右室流出路部分に心臓壁および肺動脈の一部への
人工心臓壁、血管修復材用パッチとして植え込んだとこ
ろ、実施例１８と同様の結果が得られた。 実施例２０ 実施例１０と同様の方法により、冷凍保存した人工血管
をえた。次にこれを解凍後、人工血管として成犬の胸部
下行大動脈に植え込んだところ、実施例１１と同様の結
果が得られた。Example 19 By the same method as in Example 7, an artificial blood vessel was obtained in which bone marrow cells were collected in the fiber gap of the expanded polytetrafluoroethylene artificial blood vessel having a fibril length of 90 μm. Next, the artificial blood vessel was cut open in the longitudinal direction to obtain a membranous material in which bone marrow cells were seeded. The membrane thus prepared was implanted in the right ventricular outflow tract portion of the right ventricular pulmonary artery of an adult dog as a heart wall, an artificial heart wall to part of the pulmonary artery, and a patch for a vascular repair material. Results were obtained. Example 20 By the same method as in Example 10, an artificial blood vessel cryopreserved was obtained. Next, this was thawed and then implanted as an artificial blood vessel into the descending thoracic aorta of an adult dog, and the same results as in Example 11 were obtained.
【００３６】実施例２１ ポリエステル布製人工血管内径６ｍｍ，長さ１０ｃｍ，
有孔性８００ｃｃ／ｃｍ2，Ｈ2Ｏ１２０ｍｍＨｇの一端
を三方活栓につなぎ、これを介して骨髄浮遊液をシリン
ジにて人工血管内に圧注入した。そして実施例１と同様
の方法で、骨髄細胞の捕捉された人工血管を得た。次に
このようにして作成した人工血管を筒状のまま紐状にし
て人工腱として使用した。動物実験として、成犬膝関節
部の前十字靭帯を切除し、これに代わって作成した人工
腱を植え込んだところ、植え込み直後人工腱の関節腔内
に露出した部分の表面は薄いフィブリン層に覆われた
が、骨髄細胞は人工腱のポリエステル繊維間隙にとどま
っていた。植え込み３週間でこの部分の表面は漿膜細胞
によって覆われていた。そして内部においては無数の線
維芽細胞、マクロファージおよび赤芽球、毛細血管など
が認められ、人工腱の器質化が進行していた。一方、人
工腱の関節腔内に露出していない部分においてはその内
部外部とともに無数の線維芽細胞、マクロファージ、毛
細血管などが入り込み器質化は完成していた。そして周
囲組織との親和性は極めて良好であった。このようにし
て形成された新しい器官の内部の所々に骨髄細胞が生着
し、異所性の造血現象がおきていることが判明した。ま
た免疫組織学的検査により、この部位に多量のＦＧＦ等
の成長因子が検出された。このことより、骨髄組織特有
の細胞成長因子が産生され続けて、この部分での治癒を
促進させていたと考えられた。Example 21 Polyester cloth artificial blood vessel Inner diameter 6 mm, length 10 cm,
One end of porous 800 cc / cm 2 , H 2 O 120 mmHg was connected to a three-way stopcock, and the bone marrow suspension was pressure-injected into the artificial blood vessel with a syringe therethrough. Then, in the same manner as in Example 1, an artificial blood vessel in which bone marrow cells were captured was obtained. Next, the artificial blood vessel thus created was used as an artificial tendon by making a tubular shape with a tubular shape. As an animal experiment, the anterior cruciate ligament of the adult knee joint was excised, and an artificial tendon created in place of this was implanted. Immediately after implantation, the surface of the exposed part of the artificial tendon in the joint cavity was covered with a thin fibrin layer. However, the bone marrow cells remained in the polyester fiber interstices of the artificial tendon. Three weeks after implantation, the surface of this part was covered with serosa cells. A myriad of fibroblasts, macrophages, erythroblasts, capillaries, etc. were found inside, and the organization of the artificial tendon was progressing. On the other hand, in the part of the artificial tendon that is not exposed in the joint cavity, numerous fibroblasts, macrophages, capillaries, etc. entered inside and outside of the joint, and the organization was completed. And the affinity with surrounding tissues was extremely good. It was revealed that bone marrow cells were engrafted in various places inside the new organ thus formed, and an ectopic hematopoietic phenomenon occurred. In addition, a large amount of growth factors such as FGF were detected at this site by immunohistological examination. From this, it was considered that the cell growth factor peculiar to bone marrow tissue was continuously produced to promote healing in this part.
【００３７】実施例２２ 牛アキレス腱より得たファイバーコラーゲン分散液を凍
結乾燥したあと、ヘキサメチレンジイソシアネイトによ
り架橋処理して不溶化し、多孔性の膜を得た。次にこれ
を丸めて管状物を作った。次に実施例１と同様の手法を
用いて、この管状物の壁内部に骨髄細胞を捕捉させた。
次にこの管状物を元どおりに開くことによって骨髄細胞
の播種された癒着促進膜を得た。このようにして作成し
た膜を成犬の膜壁縫合不全部位に、に組織治癒促進型癒
着促進膜として植え込んだ。植え込み直後、内面は薄い
フィブリン層に覆われたが、骨髄細胞はその場にとどま
っており、植え込み３週間では癒着促進膜内面は完全に
漿膜細胞に覆われていて、腹壁の筋肉や筋膜との間に丈
夫な結合組織層を形成していた。癒着促進膜内部には無
数の線維芽細胞、マクロファージ、および赤芽球、毛細
血管などが認められた。このようにして形成された新し
い器官の内部の所々に骨髄細胞が生着し、異所性の造血
現象がおきていることが判明した。このことより、骨髄
組織特有の細胞成長因子が産生され続けて、この部分で
の治癒を促進させていたと考えられた。また、コラーゲ
ン膜は既に吸収されていた。外膜側には多量の線維芽細
胞、毛細血管が集まってきており、周囲組織との親和性
は極めて良好であった。Example 22 A fiber collagen dispersion obtained from bovine Achilles tendon was freeze-dried and then crosslinked with hexamethylene diisocyanate to insolubilize it to obtain a porous film. Then, this was rolled into a tubular product. Next, using the same method as in Example 1, bone marrow cells were captured inside the wall of this tubular material.
Then, the tubular product was opened again to obtain an adhesion promoting membrane seeded with bone marrow cells. The thus-prepared membrane was implanted as a tissue-healing-promoting adhesion-promoting membrane in an adult dog's membrane wall suture failure site. Immediately after implantation, the inner surface was covered with a thin fibrin layer, but bone marrow cells remained in place, and the adhesion promoting membrane inner surface was completely covered with serosa cells 3 weeks after implantation, and the abdominal wall muscle and fascia were Had formed a tough connective tissue layer between. A myriad of fibroblasts, macrophages, erythroblasts, capillaries, etc. were found inside the adhesion promoting membrane. It was revealed that bone marrow cells were engrafted in various places inside the new organ thus formed, and an ectopic hematopoietic phenomenon occurred. From this, it was considered that the cell growth factor peculiar to bone marrow tissue was continuously produced to promote healing in this part. Also, the collagen membrane had already been absorbed. A large amount of fibroblasts and capillaries were collected on the adventitia side, and the affinity with surrounding tissues was extremely good.
【００３８】実施例２３ 牛真皮より得たアテロコラーゲン分散液を凍結乾燥し、
これをポリエポキシ化合物（ＥＸ−８１０，ナガセ化成
工業Ｋ．Ｋ．大阪）で架橋処理して不溶化し、多孔性の
スポンジ状基材を得た。次に注射器内に骨髄細胞浮遊液
を入れて、作成した基材の中に圧注入し、骨髄細胞を捕
捉させる事により、細胞組み込み型人工基質を得た。次
に動物実験として、成犬の右肺上葉を切除し、この欠損
した部分に作成した人工基質を創傷治癒促進材として植
え込んだところ、植え込み３週間で、この部分に線維芽
細胞が無数に遊走し増殖し、毛細血管が多量に侵入して
新しい結合組織を形成していた。そして周囲組織とは軽
度に癒着しており、異物反応や炎症反応等もみられず、
自然な基質として肺の欠けた部分を埋めていた。このよ
うにして形成された新しい結合組織の内部の所々に骨髄
細胞が生着し、異所性の造血現象がおきていることが判
明した。また免疫組織学的検査により、この部位に多量
のＦＧＦ等の成長因子が検出された。このことより、骨
髄組織特有の細胞成長因子を産生し続けて、この部分で
の治癒を促進させていたと考えられた。Example 23 An atelocollagen dispersion obtained from bovine dermis was freeze-dried,
This was crosslinked with a polyepoxy compound (EX-810, Nagase Kasei KK Osaka) to insolubilize it to obtain a porous sponge-like substrate. Next, the bone marrow cell suspension was placed in a syringe and pressure-injected into the prepared base material to capture the bone marrow cells to obtain a cell-embedded artificial substrate. Next, as an animal experiment, the upper lobe of the right lung of an adult dog was excised, and an artificial substrate created in this defective portion was implanted as a wound healing promoting material, and in three weeks after implantation, a large number of fibroblasts were found in this portion. It migrated and proliferated, and a large amount of capillaries invaded to form new connective tissue. And it is mildly adherent to the surrounding tissues, and no foreign body reaction or inflammatory reaction is seen,
It filled the missing part of the lung as a natural matrix. It was found that bone marrow cells were engrafted in the new connective tissue thus formed, and ectopic hematopoietic phenomenon occurred. In addition, a large amount of growth factors such as FGF were detected at this site by immunohistological examination. From this, it was considered that the cell growth factor specific to bone marrow tissue was continuously produced to promote the healing in this part.
【００３９】実施例２４ 実施例２３と同様の方法により細胞組み込み型人工基質
を得た。次にこれを生体組織冷凍保存システムを用いて
３カ月間冷凍保存し、その後解凍して細胞活性を検討し
たところ、人工基質内の細胞は生き続けており、細胞増
殖の確認によって、この型の細胞組込み型人工基質が冷
凍により保存しておくことが可能であることが示され
た。 実施例２５ 実施例２４と同様の方法により、冷凍保存した人工基質
を得た。次にこれを解凍後、人工真皮層として成犬の背
部皮膚欠損部に植え込んだところ、毛細血管の豊富な結
合組織層を得た。そしてこの層は皮膚移植用の基礎層と
して有用であった。Example 24 By the same method as in Example 23, a cell-incorporated artificial substrate was obtained. Next, this was cryopreserved using a biological tissue cryopreservation system for 3 months, and then thawed and examined for cell activity. As a result, cells in the artificial matrix remained alive, and by confirmation of cell proliferation, It was shown that the cell-incorporated artificial substrate can be preserved by freezing. Example 25 By the same method as in Example 24, an artificial substrate stored in a frozen state was obtained. Next, this was thawed, and then implanted as an artificial dermis layer in the dorsal skin defect of an adult dog to obtain a connective tissue layer rich in capillaries. This layer was then useful as a base layer for skin grafts.
【００４０】[0040]
【発明の効果】本発明の医療材料は従来品に比し、きわ
めて組織治癒性、宿主細胞親和性、栄養血管誘導性に富
み、優れた人工血管、心臓血管壁修復材、人工腱、創傷
治癒促進材等を提供することができる。EFFECTS OF THE INVENTION The medical material of the present invention is extremely rich in tissue healing, host cell affinity, and inducing feeding blood vessels, as compared with conventional products, and is an excellent artificial blood vessel, cardiovascular wall repair material, artificial tendon, wound healing. Accelerators and the like can be provided.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ａ６１Ｋ 38/22 ＡＤＮ Ａ６１Ｌ 27/00 Ｃ Ｑ Ｕ ─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 6 Identification code Internal reference number FI Technical display location A61K 38/22 ADN A61L 27/00 C Q U
Claims (3)
きる細胞、又は、細胞成長因子及び生体組織細胞、を付
着、捕捉又は混在させたことを特徴とする医療材料。1. A medical material characterized in that cells capable of producing a cell growth factor, or a cell growth factor and a biological tissue cell are attached, captured or mixed in a substrate.
臓、腎臓、膵臓、大網、胎盤、子宮内膜、甲状腺、胸
腺、副腎、卵巣、睾丸、血液、皮膚、皮下組織等より採
取される細胞である請求項１に記載の医療材料。2. Cell growth factor-producing cells are collected from bone marrow, liver, spleen, kidney, pancreas, omentum, placenta, endometrium, thyroid, thymus, adrenal gland, ovary, testis, blood, skin, subcutaneous tissue, etc. The medical material according to claim 1, which is a cell.
創傷治癒促進材などである請求項１及び請求項２のいず
れかに記載の医療材料。3. An artificial blood vessel, a cardiovascular wall repair material, an artificial tendon,
The medical material according to claim 1, which is a wound healing promoting material or the like.
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| JP01386495A JP4277939B2 (en) | 1995-01-31 | 1995-01-31 | Cell growth factor-producing cell-embedded medical material |
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|---|---|---|---|
| JP01386495A JP4277939B2 (en) | 1995-01-31 | 1995-01-31 | Cell growth factor-producing cell-embedded medical material |
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| JPH08198763A true JPH08198763A (en) | 1996-08-06 |
| JP4277939B2 JP4277939B2 (en) | 2009-06-10 |
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ID=11845125
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Cited By (3)
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|---|---|---|---|---|
| WO2003013588A1 (en) * | 2001-08-08 | 2003-02-20 | Kaken Pharmaceutical Co., Ltd. | Kidney regeneration material comprising cells and cell growth factor |
| WO2004082694A1 (en) * | 2003-03-20 | 2004-09-30 | Cosmotec Co. Ltd. | Cell therapy material and intravascular therapy method |
| JP2006130007A (en) * | 2004-11-04 | 2006-05-25 | Japan Science & Technology Agency | Hybrid complex and manufacturing method thereof, and medical material using the same |
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| WO2003013588A1 (en) * | 2001-08-08 | 2003-02-20 | Kaken Pharmaceutical Co., Ltd. | Kidney regeneration material comprising cells and cell growth factor |
| WO2004082694A1 (en) * | 2003-03-20 | 2004-09-30 | Cosmotec Co. Ltd. | Cell therapy material and intravascular therapy method |
| JP2006130007A (en) * | 2004-11-04 | 2006-05-25 | Japan Science & Technology Agency | Hybrid complex and manufacturing method thereof, and medical material using the same |
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| Publication number | Publication date |
|---|---|
| JP4277939B2 (en) | 2009-06-10 |
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