JPS6158196B2 - - Google Patents
Info
- Publication number
- JPS6158196B2 JPS6158196B2 JP59047931A JP4793184A JPS6158196B2 JP S6158196 B2 JPS6158196 B2 JP S6158196B2 JP 59047931 A JP59047931 A JP 59047931A JP 4793184 A JP4793184 A JP 4793184A JP S6158196 B2 JPS6158196 B2 JP S6158196B2
- Authority
- JP
- Japan
- Prior art keywords
- collagen
- layer
- heparin
- fibronectin
- antithrombotic
- 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.)
- Expired
Links
- 239000000463 material Substances 0.000 claims description 43
- 102000008186 Collagen Human genes 0.000 claims description 34
- 108010035532 Collagen Proteins 0.000 claims description 34
- 229920001436 collagen Polymers 0.000 claims description 34
- 230000002785 anti-thrombosis Effects 0.000 claims description 29
- 229920000669 heparin Polymers 0.000 claims description 21
- 229960002897 heparin Drugs 0.000 claims description 21
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 15
- 239000003146 anticoagulant agent Substances 0.000 claims description 14
- 102000016359 Fibronectins Human genes 0.000 claims description 13
- 108010067306 Fibronectins Proteins 0.000 claims description 13
- 238000000034 method Methods 0.000 description 15
- 239000002861 polymer material Substances 0.000 description 13
- 210000004369 blood Anatomy 0.000 description 11
- 239000008280 blood Substances 0.000 description 11
- 239000002473 artificial blood Substances 0.000 description 10
- 210000004204 blood vessel Anatomy 0.000 description 10
- 208000028659 discharge Diseases 0.000 description 9
- -1 for example Substances 0.000 description 8
- 239000002131 composite material Substances 0.000 description 7
- 239000002504 physiological saline solution Substances 0.000 description 7
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 6
- 208000007536 Thrombosis Diseases 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229920005601 base polymer Polymers 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000004698 Polyethylene Substances 0.000 description 3
- 239000004743 Polypropylene Substances 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 239000012567 medical material Substances 0.000 description 3
- 229920000728 polyester Polymers 0.000 description 3
- 229920000573 polyethylene Polymers 0.000 description 3
- 229920001155 polypropylene Polymers 0.000 description 3
- 239000004814 polyurethane Substances 0.000 description 3
- 238000005086 pumping Methods 0.000 description 3
- 230000002792 vascular Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 102000004506 Blood Proteins Human genes 0.000 description 2
- 108010017384 Blood Proteins Proteins 0.000 description 2
- 229920001287 Chondroitin sulfate Polymers 0.000 description 2
- 102000009123 Fibrin Human genes 0.000 description 2
- 108010073385 Fibrin Proteins 0.000 description 2
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 2
- 229920002683 Glycosaminoglycan Polymers 0.000 description 2
- 239000004677 Nylon Substances 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000021164 cell adhesion Effects 0.000 description 2
- 229940059329 chondroitin sulfate Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229950003499 fibrin Drugs 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 229920001778 nylon Polymers 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 230000010287 polarization Effects 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920002635 polyurethane Polymers 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229920002379 silicone rubber Polymers 0.000 description 2
- 239000004945 silicone rubber Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 230000000379 polymerizing effect Effects 0.000 description 1
- 229920003225 polyurethane elastomer Polymers 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 235000004252 protein component Nutrition 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000005297 pyrex Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Description
【発明の詳細な説明】
本発明は新規な抗血栓性材料、さらに詳しくい
えば、人工血管や血管カテーテルなどに使用され
る、抗血栓性及び生体適合性に優れた医療用高分
子材料に関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel antithrombotic material, and more specifically, to a medical polymer material with excellent antithrombotic properties and biocompatibility used in artificial blood vessels, vascular catheters, etc. It is.
近年、医療用材料として多くの高分子材料が用
いられるようになつたが、これを直接血液と接触
する個所に用いる医療用材料、例えば人工血管、
血管カテーテル、人工腎臓用チユーブ、人工心
肺、血液バイパスチユーブ、人工心臓ポンピング
チエンバー、バルーンポンピング用材料などとし
て使用する場合、抗血栓性はもちろんのこと、生
体適合性や弾性、耐久性、湿潤強靭性などの力学
的強度に優れていることが必要である。 In recent years, many polymer materials have come into use as medical materials, and medical materials that use them in areas that come into direct contact with blood, such as artificial blood vessels,
When used as vascular catheters, artificial kidney tubes, heart-lung machines, blood bypass tubes, artificial heart pumping chambers, balloon pumping materials, etc., they have not only antithrombotic properties, but also biocompatibility, elasticity, durability, and wet strength. It is necessary to have excellent mechanical strength such as strength.
現在、医療用材料として用いられている高分子
材料の中で、例えばナイロン、ポリエステル、ポ
リエチレン、ポリプロピレン、ポリウレタンなど
は抗血栓性をもたず、これを直接血液と接触する
個所で使用する場合、血液が凝固して血栓が生じ
るため、これらの高分子材料に抗血栓性をもたせ
る工夫がなされてきた。 Among the polymer materials currently used as medical materials, for example, nylon, polyester, polyethylene, polypropylene, and polyurethane do not have antithrombotic properties, and when used in areas that come into direct contact with blood, Since blood coagulates and thrombi occur, efforts have been made to provide these polymeric materials with antithrombotic properties.
従来、前記の高分子材料に抗血栓性をもたせる
方法として、材料自体を血栓を生じにくいものと
する方法、例えばヘパリンのような天然の抗凝血
剤を材料に混合したり、あるいは化学結合させる
方法、さらには生体適合性の優れたコラーゲンを
材料表面にコーテイングする方法などが知られて
いる。 Conventionally, methods for imparting antithrombotic properties to the above-mentioned polymeric materials include methods of making the material itself less likely to cause blood clots, such as mixing a natural anticoagulant such as heparin into the material or chemically bonding it to the material. Other known methods include coating the material surface with collagen, which has excellent biocompatibility.
前記の方法の中で、材料自体を血栓が生じにく
いものにする方法の例としては、ある種のポリウ
レタン系化合物を疎水性と親水性の部分が交互に
表面にでる構造をもたせたもの、あるいはヒドロ
ゲル又は親水性ポリマーを基材ポリマーに結合さ
せたものがある。しかしながら、これらの高分子
材料はかなり高い抗血栓性を示すものの、まだ実
用に供するには不十分であつて満足しうるものは
得られていない。 Among the above methods, examples of methods to make the material itself less likely to cause blood clots include using a certain type of polyurethane compound with a structure in which hydrophobic and hydrophilic parts alternately appear on the surface; Some include hydrogels or hydrophilic polymers attached to a base polymer. However, although these polymeric materials exhibit fairly high antithrombotic properties, they are still insufficient for practical use, and no satisfactory material has yet been obtained.
また、ヘパリンのような天然抗凝血剤を材料に
化学結合させる方法の例としては、基材ポリマー
に第三級アミノ基をもつビニル化合物をグラフト
重合させたのち、グラフト化されたポリマー中の
アミノ基を第四級化し、次いでヘパリン化する方
法が知られている。しかしながら、このようにし
てヘパリン化した高分子材料は、基材ポリマーが
本来有する望ましい力学的強度が低下し、実用に
際して必要な強度や耐久性が得られなくなるとい
う欠点がある。 In addition, as an example of a method for chemically bonding a natural anticoagulant such as heparin to a material, after graft polymerizing a vinyl compound having a tertiary amino group to a base polymer, Methods are known in which amino groups are quaternized and then heparinized. However, the polymeric material heparinized in this manner has the disadvantage that the desirable mechanical strength originally inherent in the base polymer is reduced, making it impossible to obtain the strength and durability required for practical use.
さらに、コラーゲンを材料表面にコーテイング
する方法の例として、ポリエチレン、ポリプロピ
レン、ポリエステルなどの表面を、例えばクロム
酸混液処理やアルカリ処理などの極性化処理によ
つて親水化したのち、コラーゲンを塗布し、次い
で放射線を照射して該コラーゲンをコーテイング
する方法（特公昭46−37433号公報）、あるいはシ
リコンゴム素材の表面を、プラズマグロー放電処
理や化学的処理などの極性化処理によつて親水化
したのち、前記と同様にしてコラーゲンをコーテ
イングする方法（特公昭49−4559号公報）が提案
されている。しかしながら、このようにしてコラ
ーゲンをコーテイングした高分子材料は、基材ポ
リマーが本来有する望ましい力学的強度は低下し
ないものの、抗血栓性については必ずしも満足し
うるものではない。 Furthermore, as an example of a method of coating a material surface with collagen, the surface of polyethylene, polypropylene, polyester, etc. is made hydrophilic by polarization treatment such as chromic acid mixture treatment or alkali treatment, and then collagen is applied. Next, the collagen is coated by irradiation with radiation (Japanese Patent Publication No. 46-37433), or the surface of the silicone rubber material is made hydrophilic by polarization treatment such as plasma glow discharge treatment or chemical treatment. , a method of coating collagen in the same manner as above (Japanese Patent Publication No. 49-4559) has been proposed. However, although the polymer material coated with collagen in this manner does not reduce the desirable mechanical strength inherent to the base polymer, it is not necessarily satisfactory in terms of antithrombotic properties.
本発明者らは、このような事情に鑑み、従来の
抗血栓性高分子材料のもつ欠点を改良し、優れた
抗血栓性と生体適合性を有し、かつ力学的強度の
良好な高分子材料を得るために研究を重ねてき
た。その結果、先に、プラズマグロー放電処理に
より活性化された高分子材料の表面にムコ多糖を
結合させたものが、抗血栓性材料として従来のも
のに比較して優れていることを見出した。 In view of these circumstances, the present inventors have improved the drawbacks of conventional antithrombotic polymer materials, and developed a polymer that has excellent antithrombotic properties, biocompatibility, and good mechanical strength. Research has been carried out to obtain the materials. As a result, we have previously found that a polymer material in which mucopolysaccharide is bonded to the surface of a polymer material activated by plasma glow discharge treatment is superior to conventional materials as an antithrombotic material.
しかしながら、この抗血栓性材料は、従来の抗
血栓性材料のもつ欠点がかなり改良されているも
のの、抗血栓性に関しては必ずしも満足しうるも
のではなかつた。 However, although this antithrombotic material has considerably improved the drawbacks of conventional antithrombotic materials, its antithrombotic properties are not necessarily satisfactory.
したがつて、本発明者らは、より優れた抗血栓
性材料を提供すべく、さらに鋭意研究を進めてき
た結果、高分子材料の表面に設けられたコラーゲ
ン層の上に、さらに細胞接着タンパク質として知
られているフイブロネクチン層を介してヘパリン
層を設けて成るものが、高分子材料のもつ力学的
強度を失わずに、優れた抗血栓性及び生体適合性
を有することを見出し、この知見に基づいて本発
明を完成するに至つた。 Therefore, the present inventors have carried out further intensive research in order to provide an even better antithrombotic material. As a result, the inventors have further conducted cell adhesion protein on the collagen layer provided on the surface of the polymeric material. Based on this finding, we discovered that a material consisting of a heparin layer interposed between a fibronectin layer, known as fibronectin, has excellent antithrombotic properties and biocompatibility without losing the mechanical strength of polymeric materials. Based on this, the present invention has been completed.
すなわち、本発明は、高分子材料の表面にコラ
ーゲン層を設け、さらのその上にフイブロネクチ
ン層を介してヘパリン層を設けて成る抗血栓性材
料を提供するものである。 That is, the present invention provides an antithrombotic material comprising a collagen layer provided on the surface of a polymeric material, and further a heparin layer provided thereon via a fibronectin layer.
本発明において用いる高分子材料としては、例
えばナイロン、ポリエステル、ポリエチレン、ポ
リプロピレン、ポリウレタン、シリコンゴムなど
の機械的性能の優れた高分子化合物が好ましく挙
げられる。 Preferred examples of the polymer material used in the present invention include polymer compounds with excellent mechanical performance, such as nylon, polyester, polyethylene, polypropylene, polyurethane, and silicone rubber.
本発明の抗血栓性材料においては、前記高分子
材料の表面に、まずコラーゲン層を設ける。この
コラーゲン層を設ける方法としては、例えば0.1
〜１重量％濃度のコラーゲン水溶液を該高分子材
料の表面に塗布する方法、該高分子材料を前記コ
ラーゲン水溶液に浸せきする方法、あるいは容器
状のものやチユーブ状のものの内面にコラーゲン
層を設ける場合は、該コラーゲン水溶液をそれら
に注入、排出する方法などが用いられる。 In the antithrombotic material of the present invention, a collagen layer is first provided on the surface of the polymer material. As a method for providing this collagen layer, for example, 0.1
A method in which an aqueous collagen solution with a concentration of ~1% by weight is applied to the surface of the polymer material, a method in which the polymer material is immersed in the aqueous collagen solution, or a collagen layer is provided on the inner surface of a container or tube. A method of injecting and discharging the collagen aqueous solution is used.
高分子材料として高有孔性のものを用いる場
合、漏血のない状態にするために、コラーゲン層
をグルタルアルデヒドで架橋することが好まし
い。このグルタルアルデヒドによる架橋処理は、
例えば0.05〜0.25％（Ｖ／Ｖ）のグルタルアルデ
ヒドを含有した生理食塩水溶液を用いて、コラー
ゲン層を設けた高分子材料を前記と同様に処理す
ることにより行われる。 When using a highly porous polymeric material, it is preferable to crosslink the collagen layer with glutaraldehyde in order to prevent blood leakage. This crosslinking treatment with glutaraldehyde is
For example, the polymer material provided with the collagen layer is treated in the same manner as described above using a physiological saline solution containing 0.05 to 0.25% (V/V) glutaraldehyde.
また、コラーゲン層をより強固に高分子材料の
表面に付着させるために、必要に応じ予め該高分
子材料の表面をプラズマグロー放電処理によつて
活性化しておいてもよい。このプラズマグロー放
電処理は、高分子材料の表面を常法に従つて清浄
にしたのち、プラズマグロー放電発生装置により
発生するプラズマを該高分子材料の表面に均一に
当てることによつて行われる。 Furthermore, in order to more firmly adhere the collagen layer to the surface of the polymeric material, the surface of the polymeric material may be activated in advance by plasma glow discharge treatment, if necessary. This plasma glow discharge treatment is performed by cleaning the surface of the polymeric material according to a conventional method and then uniformly applying plasma generated by a plasma glow discharge generator to the surface of the polymeric material.
このようにして、コラーゲン層を設けた高分子
材料はかなりの抗血栓性を有するものの、まだ十
分ではなく、本発明においては、さらにその上に
フイブロネクチン層を介してヘパリン層を設け
る。 Although the polymer material provided with the collagen layer has considerable antithrombotic properties, it is still insufficient, and in the present invention, a heparin layer is further provided thereon via a fibronectin layer.
フイブロネクチンは細胞接着タンパク質として
知られており、血液中に存在する。このものの分
子構造については、まだ明確には解明されていな
いが、コラーゲン、特に熱変性したゼラチンに結
合するドメインとヘパリンに結合するドメインと
を有しているため、このフイブロネクチンの層を
介することにより、ヘパリン層とコラーゲン層は
比較的強固に結合する。 Fibronectin is known as a cell adhesion protein and is present in blood. Although the molecular structure of this substance has not yet been clearly elucidated, it has a domain that binds to collagen, especially heat-denatured gelatin, and a domain that binds to heparin. , the heparin layer and collagen layer are relatively tightly bonded.
また、ヘパリンはムコ多糖類であつて、優れた
抗血栓性及び生体適合性を有している。 Further, heparin is a mucopolysaccharide and has excellent antithrombotic properties and biocompatibility.
前記のようにしてコラーゲン層を設けた高分子
材料に、さらにフイブロネクチン層を介してヘパ
リン層を設ける方法としては、例えば0.2〜２重
量％濃度のフイブロネクチンを含む生理食塩水溶
液を用いて該高分子材料を処理したのち、0.5〜
５重量％濃度のヘパリンを含む生理食塩水溶液で
処理する方法が用いられる。これらの水溶液によ
る処理は、前記のコラーゲン水溶液による処理の
場合と同様にして行われる。 A method for further providing a heparin layer via a fibronectin layer on a polymeric material provided with a collagen layer as described above is, for example, by using a physiological saline solution containing fibronectin at a concentration of 0.2 to 2% by weight. After processing, 0.5~
A method of treatment with a physiological saline solution containing heparin at a concentration of 5% by weight is used. The treatment with these aqueous solutions is carried out in the same manner as the treatment with the collagen aqueous solution described above.
このようにして、コラーゲン−フイブロネクチ
ン−ヘパリン複合層を設けた高分子材料は、コラ
ーゲン単独層、コンドロイチン硫酸単独層、ある
いはコラーゲン−コンドロイチン硫酸複合層を設
けた高分子材料に比べて優れた抗血栓性を有して
おり、例えば犬の静脈を利用するin vivo（生体
内）の実験において、血栓の形成はほとんど認め
られなかつた。 In this way, a polymeric material provided with a collagen-fibronectin-heparin composite layer has superior antithrombotic properties compared to a polymeric material provided with a single collagen layer, a single chondroitin sulfate layer, or a collagen-chondroitin sulfate composite layer. For example, in in vivo experiments using dog veins, almost no thrombus formation was observed.
本発明の抗血栓性材料は、優れた抗血栓性と生
体適合性を有し、かつ機械的性能が良好であつ
て、直接血液と接触する個所に用いられる各種医
料用機器の材料、例えば人工血管、血管カテーテ
ル、人工腎臓用チユーブ、人工心肺、血液バイパ
スチユーブ、人工心臓ポンピングチエンバー、バ
ルーンポンピング用などの材料として極めて価値
あるものである。 The antithrombotic material of the present invention has excellent antithrombotic properties and biocompatibility, and has good mechanical performance, and can be used as a material for various medical devices used in areas that come into direct contact with blood, such as It is extremely valuable as a material for artificial blood vessels, vascular catheters, artificial kidney tubes, heart-lung machines, blood bypass tubes, artificial heart pumping chambers, balloon pumps, etc.
また、フイブロネクチン自体が血漿タンパク質
成分であるため、本発明材料を生体内で長期間使
用する場合、徐々にヘパリンがはずれて生体内の
細胞や血漿タンパク質がフイブロネクチンと結合
して、器質化する（生体と同じ組織になる）こと
が期待できる。 Furthermore, since fibronectin itself is a plasma protein component, when the material of the present invention is used in vivo for a long period of time, heparin gradually comes off, and in vivo cells and plasma proteins combine with fibronectin and become organized (in vivo). It is expected that the organization will become the same organization as the
次に実施例によつて本発明をさらに詳細に説明
する。 Next, the present invention will be explained in more detail with reference to Examples.
実施例 １
高分子材料としてポリエステル繊維（デユポン
社製、ダクロン）から成る高有孔性（2000c.c.／
min／cm2）ダブル・ヴエロア型人工血管（ミード
ツクス社製）を用いプラズマグロー放電処理を行
つた。Example 1 Highly porous (2000 c.c./
min/cm 2 ) Plasma glow discharge treatment was performed using a double velois type artificial blood vessel (manufactured by Meedox).
このプラズマグロー放電処理は、試料の内面の
みを有効に処理するために、内径が試料の外径よ
りも１mm程度太い、長さ25cmのパイレックスのガ
ラス製反応管を用いて行つた。 In order to effectively treat only the inner surface of the sample, this plasma glow discharge treatment was carried out using a 25 cm long Pyrex glass reaction tube with an inner diameter approximately 1 mm thicker than the outer diameter of the sample.
一方、豚皮膚をペプシン処理により可溶化後、
塩化ナトリウムによる逐次分別によるコラーゲン
（2.5M NaCl沈殿成分）を得、これを酢酸水溶液
（0.2N）に溶解したのち、水に対して透析を繰返
して、0.4重量％のコラーゲン水溶液を調製し
た。 On the other hand, after solubilizing pig skin by pepsin treatment,
Collagen (2.5M NaCl precipitated component) was obtained by sequential fractionation with sodium chloride, and after dissolving it in an acetic acid aqueous solution (0.2N), dialysis against water was repeated to prepare a 0.4% by weight collagen aqueous solution.
このコラーゲン水溶液中に、前記のプラズマグ
ロー放電処理した人工血管を室温で１時間浸せき
したのち、さらに0.2％（Ｖ／Ｖ）グルタルアル
デヒドを含有した生理食塩水溶液中に浸せき処理
して、該人工血管表面にグルタルアルデヒドで架
橋されたコラーゲン層を設けた。 The artificial blood vessel treated with plasma glow discharge was immersed in this aqueous collagen solution for 1 hour at room temperature, and then further immersed in a physiological saline solution containing 0.2% (V/V) glutaraldehyde. A collagen layer crosslinked with glutaraldehyde was provided on the surface.
次に、前記のコラーゲン処理した人工血管を40
℃の精製水に１時間浸したのち、豚の血液からア
フイニテイークロマトグラフイーにより調製した
フイブロネクチン溶液（濃度５mg／ml）中に、中
性条件下で浸せきした。次いで過剰のフイブロネ
クチンを生理食塩水で洗い流したのち、10mg／ml
濃度のヘパリン（シグマ社製）を含む生理食塩水
溶液中に中性条件下で４時間浸せき後、過剰のヘ
パリンを生理食塩水で除去した。 Next, the collagen-treated artificial blood vessel was
After being immersed in purified water at ℃ for 1 hour, it was immersed under neutral conditions in a fibronectin solution (concentration 5 mg/ml) prepared from pig blood by affinity chromatography. Then, after washing away excess fibronectin with physiological saline, 10 mg/ml
After 4 hours of immersion in a physiological saline solution containing concentrated heparin (manufactured by Sigma) under neutral conditions, excess heparin was removed with physiological saline.
このようにして、人工血管の表面に設けられた
コラーゲン層の上に、さらにフイブロネクチン層
を介してヘパリン層を設けて成る抗血栓性材料が
得られた。 In this way, an antithrombotic material was obtained in which a heparin layer was further provided on the collagen layer provided on the surface of the artificial blood vessel with a fibronectin layer interposed therebetween.
なお、コラーゲン層をグルタルアルデヒドで架
橋処理したことにより、このものはほとんど漏血
のない状態となつた。 In addition, by crosslinking the collagen layer with glutaraldehyde, this product became almost free of blood leakage.
実施例 ２
高分子材料として、ポリエステル繊維（デユポ
ン社製、ダクロン）から成る高有孔性（2000c.c.／
min／cm2）ダブル・ヴエロア・フアブリツク型パ
ツチ（ミードツクス社製）を用い、プラズマグロ
ー放電処理しないこと以外は、実施例１と全く同
様にして該パツチ表面上にコラーゲン−フイブロ
ネクチン−ヘパリン複合層を設けてなる抗血栓性
材料を作成した。Example 2 Highly porous (2000 c.c./
min/cm 2 ) A collagen-fibronectin-heparin composite layer was formed on the surface of the patch in exactly the same manner as in Example 1, except that a double velor fabric type patch (manufactured by Meadox) was not treated with plasma glow discharge. An antithrombotic material was prepared.
参考例
実施例１で得られたコラーゲン−フイブロネク
チン−ヘパリン複合層を設けた人工血管、及び実
施例２で得られたコラーゲン−フイブロネクチン
−ヘパリン複合層を設けたパツチにおける抗血栓
性を次のようにして調べた。Reference Example The antithrombotic properties of the artificial blood vessel provided with the collagen-fibronectin-heparin composite layer obtained in Example 1 and the patch provided with the collagen-fibronectin-heparin composite layer obtained in Example 2 were evaluated as follows. I looked it up.
in vivo（生体内）実験
実施例１で得られたコラーゲン−フイブロネク
チン−ヘパリン複合層を設けた人工血管を犬の腹
部大静脈に置換して40分後に取り出し、表面を観
察した結果、血栓の付着はほとんど認められなか
つた。In vivo experiment The artificial blood vessel provided with the collagen-fibronectin-heparin composite layer obtained in Example 1 was replaced in the abdominal vena cava of a dog and removed after 40 minutes, and the surface observation revealed that thrombus was attached. was hardly recognized.
なお、コラーゲン層のみを設けた人工血管の抗
血栓性についても同様に調べたところ、フイブリ
ン網形成を伴う赤色血栓が認められた。 When the antithrombotic properties of an artificial blood vessel provided with only a collagen layer were similarly investigated, red blood clots accompanied by fibrin network formation were observed.
in vitro（生体外）実験
実施例２で得られたコラーゲン−フイブロネク
チン−ヘパリン複合層を設けたパッチを、クエン
酸ナトリウム水溶液を加えた豚の血液中に、37℃
で１時間浸せきしたのち、取り出して表面を観察
した結果、フイブリン網の形成はなく、赤血球の
凝集塊もほとんど認められなかつた。In vitro experiment The patch provided with the collagen-fibronectin-heparin composite layer obtained in Example 2 was placed in pig blood containing an aqueous sodium citrate solution at 37°C.
After soaking in water for 1 hour, the sample was taken out and the surface was observed. As a result, no fibrin network was formed and almost no red blood cell aggregates were observed.
なお、コラーゲン層のみを設けたパツチの抗血
栓性についても同様に調べたところ、赤血球の凝
集塊が認められた。 In addition, when the antithrombotic properties of a patch provided with only a collagen layer were examined in the same manner, aggregates of red blood cells were observed.
Claims (1)
らにその上にフイブロネクチン層を介してヘパリ
ン層を設けて成る抗血栓性材料。1. An antithrombotic material comprising a collagen layer on the surface of a polymeric material and a heparin layer on top of the collagen layer via a fibronectin layer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59047931A JPS60190966A (en) | 1984-03-13 | 1984-03-13 | Anti-thrombotic material |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59047931A JPS60190966A (en) | 1984-03-13 | 1984-03-13 | Anti-thrombotic material |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS60190966A JPS60190966A (en) | 1985-09-28 |
| JPS6158196B2 true JPS6158196B2 (en) | 1986-12-10 |
Family
ID=12789112
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP59047931A Granted JPS60190966A (en) | 1984-03-13 | 1984-03-13 | Anti-thrombotic material |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS60190966A (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5037377A (en) * | 1984-11-28 | 1991-08-06 | Medtronic, Inc. | Means for improving biocompatibility of implants, particularly of vascular grafts |
| US4743252A (en) * | 1986-01-13 | 1988-05-10 | Corvita Corporation | Composite grafts |
| DE3778195D1 (en) * | 1986-04-07 | 1992-05-21 | Agency Ind Science Techn | ANTITHROMOGENIC MATERIAL. |
| JP2692722B2 (en) * | 1992-10-06 | 1997-12-17 | 株式会社東洋電機工業所 | Submersible pump with drill cutter |
| WO1995010989A1 (en) * | 1993-10-19 | 1995-04-27 | Scimed Life Systems, Inc. | Intravascular stent pump |
| WO1998024385A1 (en) * | 1996-12-06 | 1998-06-11 | Tapic International Co., Ltd. | Artificial blood vessel |
-
1984
- 1984-03-13 JP JP59047931A patent/JPS60190966A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS60190966A (en) | 1985-09-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5028597A (en) | Antithrombogenic materials | |
| US5578073A (en) | Thromboresistant surface treatment for biomaterials | |
| JP4383851B2 (en) | Polysaccharide biomaterial and use thereof | |
| US5098977A (en) | Methods and compositions for providing articles having improved biocompatability characteristics | |
| JP2561309B2 (en) | Medical material and manufacturing method thereof | |
| JP2001500408A (en) | EPTFE small diameter vascular grafts with significant patency enhancement via a surface coating containing covalent heparin | |
| DE3639561C2 (en) | ||
| JPH03254752A (en) | Artificial blood vessel coated with polysaccharide or its derivative and manufacture of said artificial blood vessel | |
| WO1992009312A1 (en) | Implant material | |
| EP0366564A2 (en) | Antithrombic medical material, artificial internal organ, and method for production of antithrombic medical material | |
| US5098960A (en) | Methods and compositions for providing articles having improved biocompatibility characteristics | |
| EP0781089B1 (en) | Thromboresistant surface treatment for biomaterials | |
| Sipehia et al. | Enhanced albumin binding to polypropylene beads via anhydrous ammonia gaseous plasma | |
| WO1996008149A9 (en) | Thromboresistant surface treatment for biomaterials | |
| JPS6158196B2 (en) | ||
| JPS6344383B2 (en) | ||
| US5017670A (en) | Methods and compositions for providing articles having improved biocompatibility characteristics | |
| JPH07184989A (en) | High polymer material having compatibility with blood for medical treatment and medical treating material | |
| CA1299937C (en) | Antithrombogenic material | |
| JPS61263448A (en) | Blood vessel prosthesis | |
| Wilson | Hemocompatible polymers: preparation and properties | |
| JP3687995B2 (en) | Artificial blood vessel and manufacturing method thereof | |
| EP0282091A2 (en) | Medical device with heparin slow-release | |
| CN114306758A (en) | Long-acting anticoagulant coating, preparation method and application thereof | |
| JPS6158195B2 (en) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EXPY | Cancellation because of completion of term |