JPH11319068A - Base material for artificial skin and production thereof - Google Patents

Base material for artificial skin and production thereof

Info

Publication number
JPH11319068A
JPH11319068A JP10129048A JP12904898A JPH11319068A JP H11319068 A JPH11319068 A JP H11319068A JP 10129048 A JP10129048 A JP 10129048A JP 12904898 A JP12904898 A JP 12904898A JP H11319068 A JPH11319068 A JP H11319068A
Authority
JP
Japan
Prior art keywords
support
sponge
extracellular matrix
base material
matrix component
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.)
Pending
Application number
JP10129048A
Other languages
Japanese (ja)
Inventor
Takamitsu Kuroyanagi
能光 黒柳
Akihisa Sugiyama
章寿 杉山
Hiroaki Yanagawa
博昭 柳川
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Menicon Co Ltd
Original Assignee
Menicon Co Ltd
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 Menicon Co Ltd filed Critical Menicon Co Ltd
Priority to JP10129048A priority Critical patent/JPH11319068A/en
Publication of JPH11319068A publication Critical patent/JPH11319068A/en
Pending legal-status Critical Current

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Classifications

    • 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
    • A61L27/60—Materials for use in artificial skin

Abstract

PROBLEM TO BE SOLVED: To impart strength while facilitating handling by constituting a base material of a support and a sponge formed from an extracellular matrix component. SOLUTION: A base material for an artificial skin consists of a support 2 and a sponge (like substance) 1 formed from an extracellular matrix component. The combined form of the sponge 1 and the support 2 is set so that the sponge 1 is pref. brought into contact with at least the single surface of the support 2 and more pref. brought into contact with both surfaces thereof. The base material is produced by placing the support 2 on a prepared extracellular matrix component soln. and further adding the soln. to the surface of the support if necessary and gelling the soln. to lyophilize the same and crosslinking the extracellular matrix component layer if necessary. Herein, as the extracellular matrix component, collagen, gelatin, hyaluroinic acid or a mixture of them are used. As the support 2, a knitted fabric, a fabric or a nonwoven fabric made of a synthetic polymer such as nylon or polyester or a natural polymer such as silk or cotton is used and, pref., the knitted fabric or the fabric is used.

Description

【発明の詳細な説明】DETAILED DESCRIPTION OF THE INVENTION

【０００１】[0001]

【発明の属する技術分野】本発明は支持体と細胞外基質
成分から作製されたスポンジからなる人工皮膚用基材お
よびその製法に関する。さらに詳しくは培養皮膚用基材
または創傷被覆材として用いられる前記基材およびその
製法に関する。The present invention relates to an artificial skin substrate comprising a support and a sponge prepared from an extracellular matrix component, and a method for producing the same. More particularly, the present invention relates to the above-mentioned substrate used as a substrate for cultured skin or a wound dressing and a method for producing the same.

【０００２】[0002]

【従来の技術】アテロコラーゲンなどの細胞外基質を用
いて作製したスポンジ状マトリックスを培養皮膚の基材
として皮膚欠損創へ適用するなど（黒柳能光、熱傷、
「細胞組み込み型人工皮膚」第２３巻、第１号、１９９
７年３月、９〜２７頁参照）、細胞外基質からなる培養
皮膚用基材および創傷被覆材が従来から使用されてい
る。しかしながら、前記基材は脆弱で強度が低いため、
ピンセットなどで前記基材をつまむと自重で落下した
り、創面に適用する際に欠損するなど扱いづらく、また
従来行なわれている移植皮膚片の固定で使用するステー
プル（ホッチキス）で前記基材を止めるとくずれるた
め、前記基材を創面に固定することはできず、非常に使
いにくいものであった。また、前記基材の上にガーゼま
たは被覆材をそえて皮膚欠損創面まで運び適用する試み
がなされているが、前記のガーゼや被覆材はそえている
だけなので、適用した基材は創面に固定されず、ずれて
しまうなどの問題があった。2. Description of the Related Art A sponge-like matrix prepared using an extracellular matrix such as atelocollagen is applied to a skin defect wound as a base material for cultured skin (Kuroyanagi Nomitsu, burns,
"Cell-Incorporated Artificial Skin", Vol. 23, No. 1, 199
(See March 9 pp. 9-27), a substrate for cultured skin and a wound dressing comprising an extracellular matrix have been used in the past. However, because the substrate is brittle and has low strength,
When the base material is pinched with tweezers or the like, it falls under its own weight, or is difficult to handle when it is applied to a wound surface, and is difficult to handle. Further, the base material is stapled (stapled) used for fixing a transplant skin piece conventionally performed. Since the base material collapses when stopped, the base material could not be fixed to the wound surface, and was very difficult to use. Attempts have been made to carry gauze or a coating material on the base material and carry it to the wound surface of the skin defect, but since the gauze or coating material is only provided, the applied base material is fixed to the wound surface. However, there was a problem that it was shifted.

【０００３】また、とくに前記基材を培養皮膚用基材と
して用いたときには、細胞培養の際に用いた血清を適用
前に除く洗浄操作、凍結保存後に解凍して適用する際に
は凍結保存液を除く洗浄操作などを行なう必要がある
が、基材が脆弱であるが故に破損することが多かった。[0003] In particular, when the above-mentioned substrate is used as a substrate for cultured skin, a washing operation for removing serum used in cell culture before application, and a cryopreservation solution for application after thawing after frozen storage. Although it is necessary to perform a cleaning operation, etc., except for the above, the base material is often broken due to its fragility.

【０００４】[0004]

【発明が解決しようとする課題】本発明者らはこのよう
な状況に鑑み、前記問題点を改善すべく鋭意研究を重ね
た結果、支持体と細胞外基質成分から作製されたスポン
ジを組み合せることにより、強度が付与され取扱いやす
くなった基材が提供されることを見出し、本発明を完成
するに至った。In view of such circumstances, the present inventors have conducted intensive studies to improve the above-mentioned problems, and as a result, have combined a support and a sponge made from an extracellular matrix component. As a result, the inventors have found that a base material having strength and being easy to handle is provided, and the present invention has been completed.

【０００５】[0005]

【課題を解決するための手段】すなわち、本発明は支持
体と細胞外基質成分から作製されたスポンジからなる人
工皮膚用基材（請求項１）に関する。That is, the present invention relates to a substrate for artificial skin comprising a support and a sponge prepared from an extracellular matrix component (Claim 1).

【０００６】また、本発明は支持体と細胞外基質成分か
ら作製されたスポンジを組み合せることからなる請求項
１記載の基材の製法（請求項６）に関する。[0006] The present invention also relates to a method for producing a substrate according to claim 1 comprising combining a support and a sponge produced from an extracellular matrix component (claim 6).

【０００７】前記基材は、好ましくは、支持体と前記ス
ポンジが組み合された請求項１記載の基材（請求項
２）、細胞外基質がコラーゲン、ゼラチン、ヒアルロン
酸またはそれらの混合物である請求項１記載の基材（請
求項３）、支持体が合成高分子製または天然高分子製の
編物または織布、または不織布である請求項１記載の基
材（請求項４）および培養皮膚用基材または創傷被覆材
である請求項１記載の基材（請求項５）である。[0007] Preferably, the base material is a base material according to claim 1 wherein the support and the sponge are combined (claim 2), and the extracellular matrix is collagen, gelatin, hyaluronic acid or a mixture thereof. The substrate (Claim 4) according to claim 1, wherein the support is a knitted or woven fabric or a nonwoven fabric made of a synthetic polymer or a natural polymer, and the cultured skin. The substrate according to claim 1, which is a substrate for use or a wound dressing (claim 5).

【０００８】[0008]

【発明の実施の形態】本発明における「細胞外基質成
分」とは、主に動植物からの分離・精製手法によりえら
れるものであって、かつ生体内で消化（分解・吸収）さ
れるものを意味し、具体的にはコラーゲン、ゼラチン、
ヒアルロン酸、ポリグリコール酸、コンドロイチン硫
酸、アルギン酸、アガロースおよびそれらの混合物など
を含む。また創傷被覆材および培養皮膚用基材では創傷
面周辺の線維芽細胞の活性化を促し、創傷治癒を促進す
ることからコラーゲンが好ましい。とくに培養皮膚用基
材では、さらに容易に細胞を接着させるためにコラーゲ
ンまたはコラーゲンとゼラチン混合物が好ましい。表皮
細胞、線維芽細胞の移動を促進するばあいには、ヒアル
ロン酸またはヒアルロン酸をコラーゲンおよび／または
コラーゲンとゼラチン混合物に混合することが好まし
い。前記混合物の組成と混合比は用途により適宜選択し
うる。BEST MODE FOR CARRYING OUT THE INVENTION The term “extracellular matrix component” in the present invention refers to those obtained mainly by separation and purification from animals and plants and those which are digested (decomposed and absorbed) in vivo. Means, specifically, collagen, gelatin,
Including hyaluronic acid, polyglycolic acid, chondroitin sulfate, alginic acid, agarose and mixtures thereof. In the wound dressing and the substrate for cultured skin, collagen is preferred because it promotes activation of fibroblasts around the wound surface and promotes wound healing. In particular, in the case of a substrate for cultured skin, collagen or a mixture of collagen and gelatin is preferred in order to allow cells to adhere more easily. When the migration of epidermal cells and fibroblasts is promoted, it is preferable to mix hyaluronic acid or hyaluronic acid with collagen and / or collagen and gelatin mixtures. The composition and mixing ratio of the mixture can be appropriately selected depending on the application.

【０００９】前記の分離・精製手法としては、当業者が
通常用いる、動植物組織から酵素処理して抽出するなど
の手法があげられる。[0009] Examples of the above-mentioned separation / purification techniques include techniques commonly used by those skilled in the art, such as enzyme treatment and extraction from animal and plant tissues.

【００１０】本発明における「細胞外基質成分から作製
されたスポンジ」とは、前記細胞外基質成分から作製
し、スポンジ状の多孔構造を有するものであればどんな
ものでもよい。培養皮膚用基材としては、細胞ができる
だけ均一にスポンジ全体に浸透し、接着できるようにす
るためには、空孔の径が１０〜５００μｍであることが
好ましく、３０〜３００μｍ程度であることがより好ま
しい。The "sponge prepared from the extracellular matrix component" in the present invention may be any sponge prepared from the extracellular matrix component and having a sponge-like porous structure. As a substrate for cultured skin, the diameter of the pores is preferably 10 to 500 μm, and preferably about 30 to 300 μm, in order to allow the cells to penetrate and adhere to the entire sponge as uniformly as possible. More preferred.

【００１１】創傷被覆材としては、創面からの浸出液を
充分に吸収し留置できる空孔を有することが望ましく、
そのためには、空孔の径が１０μｍ〜３ｍｍであること
が好ましく、５０〜１０００μｍ程度であることがより
好ましい。空孔の径が３ｍｍを超えると基材が脆弱とな
り、基材の分解も急速に起こりうるので、強度と分解速
度との関係で空孔の大きさを調整する。It is desirable that the wound dressing has a hole capable of sufficiently absorbing and retaining the exudate from the wound surface.
For this purpose, the diameter of the pores is preferably from 10 μm to 3 mm, and more preferably from about 50 to 1000 μm. If the diameter of the pores exceeds 3 mm, the base material becomes brittle and the decomposition of the base material can occur rapidly. Therefore, the size of the pores is adjusted in relation to the strength and the decomposition speed.

【００１２】前記スポンジの作製方法としては、たとえ
ば、前記細胞外基質成分を適当な溶媒（たとえば水）に
溶解し、ゲル化したのちに凍結乾燥し、要すれば架橋を
行なう方法、適当な溶媒（たとえば水）に架橋剤を加
え、成型したのちに、洗浄乾燥する方法などがあげられ
る。The sponge may be prepared, for example, by dissolving the extracellular matrix component in a suitable solvent (eg, water), gelling, freeze-drying, and, if necessary, crosslinking. (For example, water), a method of adding a cross-linking agent, molding, washing and drying.

【００１３】以下に細胞外基質成分から作製されたスポ
ンジがコラーゲンスポンジであるばあいについて、作製
手順を具体的に説明する。[0013] The procedure for preparing a sponge prepared from an extracellular matrix component when it is a collagen sponge will be specifically described below.

【００１４】コラーゲンスポンジは、酸可溶性コラーゲ
ンを用いるばあい、酸性に調製したコラーゲン溶液をホ
モジナイザーを用いてホモジナイズすることにより充分
に気泡を含ませたものを容器に流し込み、アンモニアガ
ス雰囲気中に静置してゲル化させたのち凍結乾燥を行な
い、ついで紫外線照射または架橋剤によって分子間架橋
を導入することにより作製することができる。In the case of using an acid-soluble collagen, the collagen sponge is homogenized using an homogenizer with an acidicly prepared collagen solution, poured into a container containing sufficient air bubbles, and allowed to stand in an ammonia gas atmosphere. After gelling, freeze-drying is carried out, and then intermolecular cross-linking is induced by ultraviolet irradiation or a cross-linking agent.

【００１５】前記コラーゲン溶液は、ウシ真皮などから
えられたコラーゲンから調製して、ｐＨを好ましくは２
〜４に調整し、濃度が０．２〜３ｗ／ｖ％、好ましくは
０．５〜２ｗ／ｖ％とすることによりえられる。ゲル化
はアンモニアなどのガス雰囲気下で必要に応じて数分〜
２時間程度行ない、水洗し、こののち、凍結乾燥を行な
う。The collagen solution is prepared from collagen obtained from bovine dermis and the like, and the pH is preferably adjusted to 2 or less.
To 4 and a concentration of 0.2 to 3 w / v%, preferably 0.5 to 2 w / v%. Gelation takes several minutes under gas atmosphere such as ammonia if necessary.
Perform for about 2 hours, wash with water, and then freeze-dry.

【００１６】架橋に用いる紫外線（ＵＶ）の主波長は２
５０〜２７０ｎｍのものが好ましく、紫外線量は５００
〜１２０００ｍＷｓｅｃ／ｃｍ2、好ましくは１０００
〜５０００ｍＷｓｅｃ／ｃｍ2の線量を照射するとよ
い。本発明に用いられる架橋剤の例としてはたとえば、
グルタルアルデヒド、エチレングリコールジグリシジル
エーテル、ポリグリセロールポリグリシジルエーテル、
グリセロールポリグリシジルエーテル、ヘキサメチレン
ジイソシアネートなどがあげられる。The main wavelength of ultraviolet light (UV) used for crosslinking is 2
It is preferably 50 to 270 nm, and the amount of ultraviolet rays is 500
１12000 mWsec / cm 2 , preferably 1000
It is preferable to irradiate a dose of ５5000 mWsec / cm 2 . Examples of the crosslinking agent used in the present invention include, for example,
Glutaraldehyde, ethylene glycol diglycidyl ether, polyglycerol polyglycidyl ether,
Glycerol polyglycidyl ether, hexamethylene diisocyanate and the like can be mentioned.

【００１７】前記スポンジの厚さは、用途により適宜選
択すればよいが、熱傷などによる皮膚欠損に適用するば
あいには、表皮層および真皮層に至る欠損創を被覆する
必要があるため、好ましくは０．５〜３ｍｍ、より好ま
しくは１〜２ｍｍ、深い褥瘡に適用するばあいには好ま
しくは１〜３０ｍｍである。The thickness of the sponge may be appropriately selected depending on the application. However, when the sponge is applied to a skin defect caused by a burn or the like, it is necessary to cover the defect wound leading to the epidermis layer and the dermis layer. Is 0.5 to 3 mm, more preferably 1 to 2 mm, and preferably 1 to 30 mm when applied to deep pressure sores.

【００１８】前記スポンジの形状および大きさは適宜選
択すればよいが薄板状、板状、棒状、紡錘状、両側凸レ
ンズ状、球状などがあげられる。The shape and size of the sponge may be appropriately selected, and examples thereof include a thin plate, a plate, a bar, a spindle, a double-sided convex lens, and a sphere.

【００１９】本発明における「支持体」とは、生体内で
消化されない（非吸収性）構造物を意味し、たとえば、
ナイロン、ポリエステルまたはシリコンなどの合成高分
子、絹、木綿または麻などの天然高分子からできている
編物または織布、または不織布などが包含されるが、好
ましくは前記編物または織布である。前記編物または織
布とは、当該人工皮膚用基材の強度を増して、基材が消
化される状態においても組織と癒着しにくい程度の目を
持つ編物または織布を意味するが、前記基準を満たす編
物または織布、または不織布であれば、本発明に用いる
ことができる。このことから、メッシュの大きさとして
は、３ 1/2〜４００メッシュでよい。好ましくは、細胞
を通過させ難い２００〜４００メッシュ、さらに好まし
くは、体液を通過、蒸散させ難く創面に体液を温存させ
うる閉鎖包帯法（オクルーシブ）の状態に近い２５０〜
４００メッシュである。前記メッシュとは、Ｔｙｌｅｒ
（テイラー）により定義されたものを意味する。The term "support" in the present invention means a structure that is not digested (non-absorbable) in a living body.
A knitted or woven fabric made of a synthetic polymer such as nylon, polyester or silicone, or a natural polymer such as silk, cotton or hemp, or a nonwoven fabric is included, but the knitted or woven fabric is preferable. The knit or woven cloth means a knit or woven cloth having an eye that increases the strength of the artificial skin base material and does not easily adhere to tissue even in a state where the base material is digested. Any knitted or woven fabric or nonwoven fabric satisfying the above can be used in the present invention. Therefore, the mesh size may be 3 1/2-400 mesh. Preferably, it is 200 to 400 mesh, which is difficult for cells to pass through, and more preferably, it is 250 to 400 mesh, which is close to a closed bandage method (occlusive) in which it is difficult to pass and evaporate bodily fluids and preserve body fluids on the wound surface.
400 mesh. The mesh is a Tyler
(Taylor).

【００２０】前記不織布とは短繊維とからみ合わせ、層
化させた布状物を意味し、たとえば、和紙のような形態
のものをいう。The non-woven fabric means a layered cloth intertwined with short fibers, for example, in the form of Japanese paper.

【００２１】前記支持体の厚みは、用途により適宜選択
すればよいが、充分に基材を支持する強度を与え、取扱
いやすくするためには、好ましくは０．０１〜１ｍｍで
ある。The thickness of the support may be appropriately selected depending on the application, but is preferably 0.01 to 1 mm in order to sufficiently provide strength for supporting the substrate and facilitate handling.

【００２２】本発明の基材とは、支持体と細胞外基質成
分から作製されたスポンジ（状物質）からなるものを意
味する。前記スポンジと前記支持体との組み合せの形態
は、好ましくは前記支持体の少なくとも片面で前記スポ
ンジが接触している形態であり、適用した際支持体が動
かず、皮膚欠損創面へのせ、その上にガーゼをのせてと
めたばあい、上方（前記創面からより遠方）のスポンジ
がクッションのような役割を果すので、より好ましくは
前記支持体の両面に前記スポンジが接触している形態
（サンドイッチ状の形態）である（図１および２参
照）。本発明の基材の形状および大きさは、適用するも
のにしたがい適宜選択すればよい。The substrate of the present invention means a substrate comprising a support and a sponge (state substance) prepared from an extracellular matrix component. The form of the combination of the sponge and the support is preferably a form in which the sponge is in contact with at least one surface of the support, and when applied, the support does not move, and is placed on the skin defect wound surface. When the gauze is put on the sponge, the sponge above (farther from the wound surface) plays a role of a cushion, so it is more preferable that the sponge is in contact with both surfaces of the support (sandwich type). (See FIGS. 1 and 2). The shape and size of the substrate of the present invention may be appropriately selected according to the application.

【００２３】本発明の基材の作製方法としては、前記の
ように調製した細胞外基質成分溶液上に支持体をのせ、
要すればさらにその上に前記溶液を加えたのち、ゲル化
し、凍結乾燥を行ない、要すれば架橋を行なう方法など
をあげることができる。As a method for producing the substrate of the present invention, a support is placed on the extracellular matrix component solution prepared as described above,
If necessary, the solution may be further added, gelled, freeze-dried, and, if necessary, crosslinked.

【００２４】本発明にしたがった前記基材の製法は、好
ましくは、細胞外基質成分からなる液体を支持体と前記
支持体の少なくとも片面で接触させて凍結乾燥すること
によって支持体と細胞外基質成分から作製されたスポン
ジを組み合わせることからなり、より好ましくは、細胞
外基質成分溶液上に支持体をのせてゲル化および凍結乾
燥を行なうことによって支持体と細胞外基質成分から作
製されたスポンジを組み合わせることからなり、とくに
好ましくは、細胞外基質成分溶液上に支持体をのせ、そ
の上に前記溶液を加えたのちに、ゲル化および凍結乾燥
を行なうことによって支持体と細胞外基質成分から作製
されたスポンジを組み合わせることからなる。前記細胞
外基質成分溶液とは、細胞外基質成分と、前記細胞外基
質成分を溶解する溶媒からなり、好ましくは、細胞外基
質成分水溶液を意味する。In the method for producing the substrate according to the present invention, preferably, the liquid comprising the extracellular matrix component is brought into contact with the support on at least one side of the support and freeze-dried, whereby the support and the extracellular matrix are lyophilized. The sponge made from the support and the extracellular matrix component is more preferably obtained by placing the support on an extracellular matrix component solution and performing gelation and freeze-drying. It is particularly preferable to prepare the support from the support and the extracellular matrix component by placing the support on the extracellular matrix component solution, adding the solution thereon, and then performing gelation and freeze-drying. Consists of combining the sponges obtained. The extracellular matrix component solution is composed of an extracellular matrix component and a solvent that dissolves the extracellular matrix component, and preferably means an extracellular matrix component aqueous solution.

【００２５】本発明の基材は人工皮膚以外のいかなる用
途にも用いられうるが、人工皮膚用、好ましくは培養皮
膚用基材または創傷被覆材として用いられる。Although the substrate of the present invention can be used for any purpose other than artificial skin, it is used as a substrate for artificial skin, preferably as a substrate for cultured skin or a wound dressing.

【００２６】以下に本発明を実施例をあげてさらに詳細
に説明するが、本発明はもとよりこの実施例に限定され
るものではない。Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

【００２７】[0027]

【実施例】比較例１ コラーゲンスポンジの作製（従来技術） １ｇの粉末コラーゲン（（株）高研製）をｐＨ３の塩酸
酸性水溶液１００ｍｌに溶解した。えられたコラーゲン
溶液６０ｍｌをホモジナイザー（（株）日本精機製作所
製）で１分間ホモジナイズして充分に気泡を含ませたの
ち、１９ｃｍ×１０ｃｍ、高さ２．５ｃｍのポリスチレ
ン製の容器（商品名：スチロール角型ケースＮＯ．１
５、（株）サンプラテック製）に入れ、水平を維持して
アンモニアガスの雰囲気下にて中和し（２５℃、１２０
分）ゲル化させた。えられたコラーゲンゲルを約−８０
℃で凍結したのち、真空凍結乾燥機（ラブコンコ社製）
に移して−３０℃より段階的に室温まで昇温し、３０時
間かけて凍結乾燥しコラーゲンスポンジをえた。えられ
たコラーゲンスポンジに紫外線（３６００ｍＷ／ｃｍ2
ＵＶ、１５分）を表裏に照射して架橋した。えられた架
橋コラーゲンスポンジの形状は約１８×９．５×０．１
８ｃｍであった。EXAMPLES Comparative Example 1 Production of Collagen Sponge (Prior Art) 1 g of powdered collagen (manufactured by Koken Co., Ltd.) was dissolved in 100 ml of a hydrochloric acid aqueous solution of pH 3 (pH 3). 60 ml of the obtained collagen solution is homogenized with a homogenizer (manufactured by Nippon Seiki Seisakusho) for 1 minute to sufficiently contain air bubbles, and then a polystyrene container of 19 cm × 10 cm and 2.5 cm in height (trade name: Styrol square case No.1
5, manufactured by Sunplatetech Co., Ltd.) and neutralized in an atmosphere of ammonia gas while maintaining the level (25 ° C., 120
Min) Gelled. About -80 of the obtained collagen gel
After freezing at ℃, vacuum freeze dryer (manufactured by Labconco)
The mixture was gradually heated from -30 ° C to room temperature, and freeze-dried for 30 hours to obtain a collagen sponge. UV light (3600 mW / cm 2) is applied to the obtained collagen sponge.
UV, 15 minutes) to irradiate front and back to crosslink. The shape of the obtained cross-linked collagen sponge is about 18 × 9.5 × 0.1
It was 8 cm.

【００２８】また、ダルベッコ変法イーグル最小必須培
地（ギブコ社製）溶液５０ｍｌを前記架橋コラーゲンス
ポンジに加えたばあいの前記スポンジの引裂き強度は、
約０．２ニュートン／ｍｍであり、取扱いはガーゼを添
えて扱わなければならず非常に脆弱で取扱いが困難であ
った。なお、引裂き強度はインストロン万能材料試験機
（モデル４３０１、インストロン社製）を用いて、２×
３ｃｍの長方形試験片の短辺中央にて長辺に平行に２ｃ
ｍの長さの切り込みを入れ、この両端を引張ることで求
めた。When 50 ml of Dulbecco's modified Eagle minimum essential medium (manufactured by Gibco) solution is added to the crosslinked collagen sponge, the sponge has a tear strength of:
It was about 0.2 Newton / mm, and it had to be handled with gauze, and was very fragile and difficult to handle. The tear strength was measured using an Instron universal material tester (Model 4301, manufactured by Instron).
2c parallel to the long side at the center of the short side of a rectangular test piece of 3cm
An incision with a length of m was made, and this was obtained by pulling both ends.

【００２９】実施例１ コラーゲンスポンジと支持体からなる基材の作製 １ｇの粉末コラーゲン（（株）高研製）をｐＨ３の塩酸
酸性水溶液１００ｍｌに溶解した。えられたコラーゲン
溶液の６０ｍｌをホモジナイザー（（株）日本精機製作
所製）で１分間ホモジナイズして充分に気泡を含ませた
のち、このコラーゲン溶液の３０ｍｌを１９ｃｍ×１０
ｃｍ、高さ２．５ｃｍのポリスチレン製の容器（商品
名：スチロール角型ケースＮＯ．１５、（株）サンプラ
テック製）に入れ、水平を維持し、前記容器と同形状の
３００メッシュのナイロン製織布を前記コラーゲン溶液
の上に静かにのせた。さらに残りのコラーゲン溶液３０
ｍｌを前記ナイロン製織布の上に静かに注入した。コラ
ーゲン溶液＋ナイロン製織布＋コラーゲン溶液が入った
容器の水平を保ち、アンモニアガスの雰囲気下で中和し
（２５℃、１２０分）ゲル化させた。えられたコラーゲ
ンゲルについて比較例１と同様に凍結乾燥を行ない、コ
ラーゲンスポンジをえた。えられたコラーゲンスポンジ
に紫外線（３６００ｍＷ／ｃｍ2 ＵＶ、１５分）を表裏
に照射し架橋してえられた架橋コラーゲンスポンジの形
状は約１８×９．５×０．１９ｃｍであった（図３
（ａ）〜（ｄ）および図４（ａ）〜（ｄ）参照）。Example 1 Preparation of a Substrate Consisting of a Collagen Sponge and a Support 1 g of powdered collagen (manufactured by Koken Co., Ltd.) was dissolved in 100 ml of a hydrochloric acid aqueous solution of pH3. After 60 ml of the obtained collagen solution was homogenized with a homogenizer (manufactured by Nippon Seiki Seisakusho) for 1 minute to sufficiently generate air bubbles, 30 ml of the collagen solution was 19 cm × 10 3.
cm, 2.5 cm in height, placed in a polystyrene container (trade name: Styrol square case No. 15, manufactured by Sunplate Tech Co., Ltd.), kept horizontal, and woven with 300 mesh nylon having the same shape as the container. A cloth was gently placed on the collagen solution. In addition, the remaining collagen solution 30
ml was poured gently onto the nylon woven fabric. The container containing the collagen solution + nylon woven fabric + collagen solution was kept horizontal and neutralized in an atmosphere of ammonia gas (25 ° C., 120 minutes) to gel. The obtained collagen gel was freeze-dried in the same manner as in Comparative Example 1 to obtain a collagen sponge. The shape of the cross-linked collagen sponge obtained by irradiating the obtained collagen sponge with ultraviolet rays (3600 mW / cm 2 UV, 15 minutes) from front to back and cross-linking was about 18 × 9.5 × 0.19 cm (FIG. 3).
(A) to (d) and FIGS. 4 (a) to (d)).

【００３０】また、ダルベッコ変法イーグル最小必須培
地（ギブコ製）溶液５０ｍｌを前記架橋コラーゲンスポ
ンジに加えたばあいの前記スポンジは引裂き強度試験が
困難なほどの強度を有しており、ガーゼなどを添えるこ
となく、そのまま困難なく取扱うことができた。なお、
引裂き強度試験は比較例１と同様に行なった。When 50 ml of Dulbecco's modified Eagle minimum essential medium (manufactured by Gibco) solution is added to the crosslinked collagen sponge, the sponge has such a strength that a tear strength test is difficult, and gauze or the like is added. Without any difficulties. In addition,
The tear strength test was performed in the same manner as in Comparative Example 1.

【００３１】試験例１ 実施例１と同様にしてえられた基材の一方のスポンジ上
に１０％牛胎児血清（以下、ＦＢＳ）含有ダルベッコ変
法イーグル最小必須培地（以下、ＤＭＥＭ＋１０％ＦＢ
Ｓ、ギブコ社製）中に懸濁した培養ウサギ線維芽細胞を
１×１０4細胞／ｃｍ2の密度で播種したのちＣＯ2 ５
％、３５℃のインキュベーター中で７日間培養し、培養
真皮を作製した。培地を除去し、これを凍結保存液（１
０％グリセロール含有ＤＭＥＭ＋１０％ＦＢＳ）に入れ
−１５２℃の冷凍庫内で保存した。３カ月間凍結保存し
たのち、解凍して凍結保存液を除去し、ハンクス液３０
ｍｌで２回洗浄して動物実験に使用した。ウサギの背部
に直径７ｃｍの円を描き前層皮膚を切除した。切除後、
皮膚欠損創の直径は９ｃｍと広がった。この皮膚欠損創
に解凍した前記基材（同種培養真皮）を直径９ｃｍに切
って適用し創周辺をナイロン６．０縫合糸（協和時計工
業（株）製）により縫合し、その上にバイオクルーシブ
（ポリウレタンフィルム製創傷被覆材）を適用し、さら
に直径９ｃｍの滅菌パットをのせて、前記と同様に創周
辺と縫合固定し伸縮性包帯で圧迫固定した。１週間後
に、包帯交換を行ない創面を観察して、再度、新しい基
材を適用し、さらに２週間（３週目）に創面を観察し
た。Test Example 1 Dulbecco's modified Eagle minimum essential medium (hereinafter, DMEM + 10% FB) containing 10% fetal bovine serum (hereinafter, FBS) was placed on one sponge of the substrate obtained in the same manner as in Example 1.
S, manufactured by Gibco Co.) and seeded at a density of 1 × 10 4 cells / cm 2 on CO 2 5
% In a 35 ° C. incubator for 7 days to prepare a cultured dermis. The medium was removed, and this was stored in the cryopreservation solution (1).
(DMEM containing 0% glycerol + 10% FBS) and stored in a freezer at -152 ° C. After cryopreservation for 3 months, thaw to remove the cryopreservation solution,
Washed twice with ml and used for animal experiments. A 7 cm diameter circle was drawn on the back of the rabbit, and the anterior layer skin was excised. After resection,
The diameter of the skin defect wound increased to 9 cm. The base material (same culture cultured dermis) thawed on the skin defect wound is cut to a diameter of 9 cm and applied, and the wound periphery is sutured with a nylon 6.0 suture (manufactured by Kyowa Watch Industry Co., Ltd.). Shiv (a wound dressing made of polyurethane film) was applied, and a sterile pad having a diameter of 9 cm was further placed thereon. One week later, the dressing was changed to observe the wound surface, a new base material was applied again, and the wound surface was observed for another two weeks (the third week).

【００３２】コラーゲンスポンジ内にはナイロンメッシ
ュが組み込まれているため解凍後の洗浄操作は非常に容
易であり、また移植操作が容易であった。とくに創周辺
との縫合固定が可能であった。３週目において良好な肉
芽組織が形成され、創周辺からの表皮化も観察された。
新生組織はナイロンメッシュに食い込んでおらず容易に
創面からナイロンメッシュを除去することができた。The washing operation after thawing was very easy because the nylon mesh was incorporated in the collagen sponge, and the transplanting operation was easy. In particular, suture fixation around the wound was possible. At 3 weeks, good granulation tissue was formed, and epidermis around the wound was also observed.
The new tissue did not bite into the nylon mesh, and the nylon mesh could be easily removed from the wound surface.

【００３３】[0033]

【発明の効果】本発明によれば、支持体と細胞外基質成
分から作製されたスポンジを組み合せることにより、こ
れらからなる基材の強度が向上され取扱いやすくなった
人工皮膚用基材を提供することが可能となる。さらに、
本発明の基材のスポンジ上に細胞を播種することにより
培養皮膚が大量に生産でき、凍結保存が可能で、要時解
凍し使用できる。えられた培養皮膚は解凍後の凍結保存
液を除去するための洗浄操作性、輸送性および移植操作
性が向上されており、また創面をオクルーシブに近い状
態にできるので、創面の組織修復が促進されることにな
り、適当な時期に新生組織に悪影響を与えることなく創
面から支持体を除去することができる。本発明の基材
は、培養皮膚用基材と同様、創傷被覆材としても好適に
用いられる。According to the present invention, by combining a support and a sponge prepared from an extracellular matrix component, there is provided an artificial skin substrate in which the strength of the substrate made of these materials is improved and handling becomes easier. It is possible to do. further,
By seeding cells on a sponge of the substrate of the present invention, cultured skin can be produced in large quantities, can be cryopreserved, and can be thawed and used when necessary. The obtained cultured skin has improved washing operability to remove the cryopreservation solution after thawing, transportability and transplantation operability, and the wound surface can be made to be almost inclusive, promoting tissue repair of the wound surface Thus, the support can be removed from the wound surface at a suitable time without adversely affecting the neoplastic tissue. The base material of the present invention is suitably used as a wound dressing material, like the base material for cultured skin.

【図面の簡単な説明】[Brief description of the drawings]

【図１】本発明の基材の一実施例の説明図であって、ス
ポンジとスポンジの間に支持体がはさまった状態で支持
体とスポンジが組み合されている基材の断面図を示す図
である。FIG. 1 is an explanatory view of an embodiment of a base material of the present invention, showing a cross-sectional view of a base material in which a support and a sponge are combined in a state where the support is sandwiched between sponges. FIG.

【図２】本発明の基材の別の一実施例の説明図であっ
て、支持体の片面でスポンジが接触している状態で支持
体とスポンジが組み合されている基材の断面を示す図で
ある。FIG. 2 is an explanatory view of another embodiment of the base material of the present invention, and shows a cross section of the base material in which the sponge is combined with the support in a state where the sponge is in contact with one side of the support. FIG.

【図３】本発明の基材の一作製手順（前半）を示す説明
図である。FIG. 3 is an explanatory view showing one manufacturing procedure (first half) of the base material of the present invention.

【図４】本発明の基材の一作製手順（後半）を示す説明
図である。FIG. 4 is an explanatory view showing one production procedure (second half) of the base material of the present invention.

【符号の説明】[Explanation of symbols]

１ スポンジ ２ 支持体 ３ コラーゲン溶液 ４ コラーゲンゲル １１ コラーゲンスポンジ １２ 架橋コラーゲンスポンジ ２１ ナイロンメッシュ Reference Signs List 1 sponge 2 support 3 collagen solution 4 collagen gel 11 collagen sponge 12 cross-linked collagen sponge 21 nylon mesh

Claims (6)

【特許請求の範囲】[Claims] 【請求項１】 支持体と細胞外基質成分から作製された
スポンジからなる人工皮膚用基材。1. An artificial skin substrate comprising a support and a sponge prepared from an extracellular matrix component. 【請求項２】 支持体と前記スポンジが組み合された請
求項１記載の基材。2. The substrate according to claim 1, wherein the support and the sponge are combined. 【請求項３】 細胞外基質がコラーゲン、ゼラチン、ヒ
アルロン酸またはそれらの混合物である請求項１記載の
基材。3. The substrate according to claim 1, wherein the extracellular matrix is collagen, gelatin, hyaluronic acid or a mixture thereof. 【請求項４】 支持体が合成高分子製または天然高分子
製の編物または織布、または不織布である請求項１記載
の基材。4. The substrate according to claim 1, wherein the support is a knitted or woven fabric or a nonwoven fabric made of a synthetic polymer or a natural polymer. 【請求項５】 培養皮膚用基材または創傷被覆材である
請求項１記載の基材。5. The substrate according to claim 1, which is a substrate for cultured skin or a wound dressing. 【請求項６】 支持体と細胞外基質成分から作製された
スポンジを組み合せることからなる請求項１記載の基材
の製法。6. The method for producing a substrate according to claim 1, comprising combining a support and a sponge produced from an extracellular matrix component.
JP10129048A 1998-05-12 1998-05-12 Base material for artificial skin and production thereof Pending JPH11319068A (en)

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JPH11319068A true JPH11319068A (en) 1999-11-24

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