JP6578592B2 - Gel material for artificial blood vessel and method for producing the same - Google Patents
Gel material for artificial blood vessel and method for producing the same Download PDFInfo
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- JP6578592B2 JP6578592B2 JP2015095248A JP2015095248A JP6578592B2 JP 6578592 B2 JP6578592 B2 JP 6578592B2 JP 2015095248 A JP2015095248 A JP 2015095248A JP 2015095248 A JP2015095248 A JP 2015095248A JP 6578592 B2 JP6578592 B2 JP 6578592B2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/507—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/26—Mixtures of macromolecular compounds
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- 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
- A61L27/52—Hydrogels or hydrocolloids
Description
本発明は、人工血管用ゲル材料及びその製造方法に関する。 The present invention relates to an artificial blood vessel gel material and a method for producing the same.
人工血管の研究は古くから行われ、様々な種類の材料が開発されている。初期の人工血管は、ダクロンやテフロン等の合成繊維によって織られた布製人工血管であったが、長期の使用によって血小板や白血球が付着して人工血管が閉塞してしまうという問題があり、内径約５ｍｍ以下といった小口径の人工血管としては使用困難なものであった。 Artificial blood vessels have been studied for a long time, and various types of materials have been developed. Early artificial blood vessels were cloth artificial blood vessels woven with synthetic fibers such as Dacron and Teflon. However, there is a problem that platelets and white blood cells adhere due to long-term use, and the artificial blood vessels are blocked. It was difficult to use as an artificial blood vessel having a small diameter of 5 mm or less.
そこで、小口径の人工血管として、人工材料による管状構造の内側表面に内皮細胞を増殖させて、血栓形成等を防止し、閉塞を回避するハイブリッド型の人工血管の開発が試みられるようになってきた（特許文献１）。 Therefore, as a small-diameter artificial blood vessel, it has been attempted to develop a hybrid type artificial blood vessel that proliferates endothelial cells on the inner surface of a tubular structure made of an artificial material, prevents thrombus formation, and avoids blockage. (Patent Document 1).
特許文献２は、ジアセトンアクリルアミド共重合変性ＰＶＡに水溶性ヒドラジン化合物を反応させて得られる含水ゲルの製造方法を開示している。しかしながら、この方法では、水溶性ヒドラジンはジアセトンアクリルアミドの架橋剤として使用しており、得られるゲルには生体適合性を有する化合物を化学的に結合させるカルボニル基が残されていないか、少ないため、人工血管として使用する場合に生体適合性が小さいという問題があった。 Patent Document 2 discloses a method for producing a water-containing gel obtained by reacting a water-soluble hydrazine compound with diacetone acrylamide copolymer-modified PVA. However, in this method, water-soluble hydrazine is used as a cross-linking agent for diacetone acrylamide, and the resulting gel has no or few carbonyl groups for chemically binding biocompatible compounds. When used as an artificial blood vessel, there is a problem that biocompatibility is small.
ハイブリッド型の人工血管であっても、その力学的性質は、生体の血管と近似していることが望まれる。 Even in the case of a hybrid type artificial blood vessel, it is desirable that the mechanical properties thereof approximate those of a living blood vessel.
そこで、本発明の目的は、内側表面に内皮細胞を増殖させたハイブリッド型の人工血管であって力学的性質が生体の血管と近似した人工血管を、形成可能である人工材料を提供することにある。 Accordingly, an object of the present invention is to provide an artificial material capable of forming a hybrid artificial blood vessel in which endothelial cells are grown on the inner surface and having mechanical properties similar to those of a living body. is there.
本発明者は、鋭意研究の結果、特定の化学修飾がなされたＰＶＡ（ポリビニルアルコール）の高分子が、未修飾のＰＶＡ（ポリビニルアルコール）の高分子と混合して、ゲルを形成可能であること、得られたゲルが人工血管に適した力学的性質を備えていること、得られたゲルが上記特定の化学修飾部位を介して、生体適合性分子を共有結合可能であることを見いだして、本発明に到達した。 As a result of diligent research, the present inventor is able to form a gel by mixing a polymer of PVA (polyvinyl alcohol) having a specific chemical modification with a polymer of unmodified PVA (polyvinyl alcohol). And finding that the obtained gel has mechanical properties suitable for an artificial blood vessel, and that the obtained gel can covalently bind a biocompatible molecule via the specific chemical modification site. The present invention has been reached.
したがって、本発明は次の（１）以下を含む。
（１）
酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物、及びケン化度９８モル％以上の未変性ポリビニルアルコールを含む溶液を、冷却して、ゲルを形成する工程、
を含む、生体適合修飾性ゲルを製造する方法。
（２）
酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物、及びケン化度９８モル％以上の未変性ポリビニルアルコールを含む溶液を、冷却して、ゲルを形成する工程、
ゲルに、Ｈ2Ｎ−ＮＨ−ＣＯ−基を有する生体適合性分子を反応させて、結合する工程、
を含む、生体適合性ゲルを製造する方法。
（３）
生体適合性ゲルが、人工血管用ゲルである、（２）に記載の方法。
（４）
溶液を、冷却して、ゲルを形成する工程が、
溶液を、加熱した後に、冷却して、ゲルを形成する工程
である、（１）〜（３）のいずれかに記載の方法。
（５）
冷却が、−５℃〜−８０℃の温度で、１〜７２時間の冷却である、（１）〜（４）のいずれかに記載の方法。
（６）
加熱が、６０℃〜１８０℃の温度で、０．５〜５時間の加熱である、（４）〜（５）のいずれかに記載の方法。
（７）
溶液の溶媒が、ＤＭＳＯを含む水である、（１）〜（６）のいずれかに記載の方法。
（８）
酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物とケン化度９８モル％以上の未変性ポリビニルアルコールの質量の和が、溶液の質量に対して、１〜３０質量％の範囲にある、（１）〜（７）のいずれかに記載の方法。
（９）
酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物とケン化度９８モル％以上の未変性ポリビニルアルコールの質量比（酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物：ケン化度９８モル％以上の未変性ポリビニルアルコール）が、１０：０．０１〜０．０１：１０の範囲にある、（１）〜（８）のいずれかに記載の方法。
（１０）
酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物中のジアセトンアクリルアミド単位含有量が、０．１モル％〜１５モル％の範囲にある、（１）〜（９）のいずれかに記載の方法。
（１１）
溶媒がＤＭＳＯ／水＝８０／２０であるゲルのヤング率［ＭＰａ］が、０．０１〜０．１５の範囲にある、（１）〜（１０）のいずれかに記載の方法。
Accordingly, the present invention includes the following (1) and below.
(1)
A step of cooling a solution containing a saponified vinyl acetate-diacetone acrylamide copolymer and an unmodified polyvinyl alcohol having a saponification degree of 98 mol% or more to form a gel;
A method for producing a biocompatible modifying gel comprising:
(2)
A step of cooling a solution containing a saponified vinyl acetate-diacetone acrylamide copolymer and an unmodified polyvinyl alcohol having a saponification degree of 98 mol% or more to form a gel;
Reacting a gel with a biocompatible molecule having an H 2 N—NH—CO— group,
A method for producing a biocompatible gel comprising:
(3)
The method according to (2), wherein the biocompatible gel is an artificial blood vessel gel.
(4)
The step of cooling the solution to form a gel comprises
The method according to any one of (1) to (3), wherein the solution is a step of cooling and forming a gel after heating.
(5)
The method according to any one of (1) to (4), wherein the cooling is performed at a temperature of -5 ° C to -80 ° C for 1 to 72 hours.
(6)
The method according to any one of (4) to (5), wherein the heating is performed at a temperature of 60 ° C to 180 ° C for 0.5 to 5 hours.
(7)
The method according to any one of (1) to (6), wherein the solvent of the solution is water containing DMSO.
(8)
The sum of the masses of the saponified vinyl acetate-diacetone acrylamide copolymer and the unmodified polyvinyl alcohol having a saponification degree of 98 mol% or more is in the range of 1 to 30 mass% with respect to the mass of the solution (1 ) To (7).
(9)
Mass ratio of saponified product of vinyl acetate-diacetone acrylamide copolymer to unmodified polyvinyl alcohol having a saponification degree of 98 mol% or more (saponification product of vinyl acetate-diacetone acrylamide copolymer: saponification degree of 98 mol% or more) The method according to any one of (1) to (8), wherein (unmodified polyvinyl alcohol) is in the range of 10: 0.01 to 0.01: 10.
(10)
The method according to any one of (1) to (9), wherein the diacetone acrylamide unit content in the saponified product of vinyl acetate-diacetone acrylamide copolymer is in the range of 0.1 mol% to 15 mol%. .
(11)
The method according to any one of (1) to (10), wherein the solvent has a Young's modulus [MPa] of DMSO / water = 80/20 in the range of 0.01 to 0.15.
（２１）
酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物、及びケン化度９８モル％以上の未変性ポリビニルアルコールを含む溶液からなる、生体適合修飾性ゲル材料組成物。
（２２）
酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物とケン化度９８モル％以上の未変性ポリビニルアルコールの質量の和が、溶液の質量に対して、１〜３０質量％の範囲にある、（２１）に記載の生体適合修飾性ゲル材料組成物。
（２３）
酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物とケン化度９８モル％以上の未変性ポリビニルアルコールの質量比（酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物：ケン化度９８モル％以上の未変性ポリビニルアルコール）が、１０：０．０１〜０．０１：１０の範囲にある、（２１）〜（２２）のいずれかに記載の生体適合修飾性ゲル材料組成物。
（２４）
酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物中のジアセトンアクリルアミド単位含有量が、０．１モル％〜１５モル％の範囲にある、（２１）〜（２３）のいずれかに記載の生体適合修飾性ゲル材料組成物。
（２５）
（２１）〜（２４）のいずれかに記載の生体適合修飾性ゲル材料組成物がゲル化されてなる、生体適合修飾性ゲル。
（２６）
溶媒がＤＭＳＯ／水＝８０／２０であるゲルのヤング率［ＭＰａ］が、０．０１〜０．１５の範囲にある、（２５）に記載の生体適合修飾性ゲル。
（２７）
（２５）〜（２６）のいずれかに記載の生体適合修飾性ゲルへ、Ｈ2Ｎ−ＮＨ−ＣＯ−基を有する生体適合性分子が反応して、結合されてなる、生体適合性ゲル。
（２８）
（２７）に記載の生体適合性ゲルを使用して製造された、人工血管。
(21)
A biocompatible modifying gel material composition comprising a saponified product of vinyl acetate-diacetone acrylamide copolymer and a solution containing unmodified polyvinyl alcohol having a saponification degree of 98 mol% or more.
(22)
The sum of the masses of the saponified vinyl acetate-diacetone acrylamide copolymer and the unmodified polyvinyl alcohol having a saponification degree of 98 mol% or more is in the range of 1 to 30 mass% with respect to the mass of the solution (21 The biocompatible modifying gel material composition as described in 1).
(23)
Mass ratio of saponified product of vinyl acetate-diacetone acrylamide copolymer to unmodified polyvinyl alcohol having a saponification degree of 98 mol% or more (saponification product of vinyl acetate-diacetone acrylamide copolymer: saponification degree of 98 mol% or more) The biocompatible modifying gel material composition according to any one of (21) to (22), wherein (unmodified polyvinyl alcohol) is in the range of 10: 0.01 to 0.01: 10.
(24)
The living body according to any one of (21) to (23), wherein the diacetone acrylamide unit content in the saponified product of vinyl acetate-diacetone acrylamide copolymer is in the range of 0.1 mol% to 15 mol%. Adaptable modifying gel material composition.
(25)
A biocompatible modifying gel obtained by gelling the biocompatible modifying gel material composition according to any one of (21) to (24).
(26)
The biocompatible modifying gel according to (25), wherein the solvent having DMSO / water = 80/20 has a Young's modulus [MPa] in the range of 0.01 to 0.15.
(27)
A biocompatible gel obtained by reacting and binding a biocompatible molecule having an H 2 N—NH—CO— group to the biocompatible modifying gel according to any one of (25) to (26).
(28)
An artificial blood vessel manufactured using the biocompatible gel according to (27).
本発明によれば、生体適合性人工材料、特に人工血管の形成に適した生体適合性ゲルを得ることができる。本発明の生体適合性ゲルは、力学的性質が生体の血管と近似した人工血管を形成可能であり、化学修飾部位を介して所望の分子を共有結合させることによって所望の生体適合性を付与できる点で優れている。 According to the present invention, a biocompatible gel suitable for forming a biocompatible artificial material, in particular, an artificial blood vessel can be obtained. The biocompatible gel of the present invention can form an artificial blood vessel whose mechanical properties are similar to those of a living blood vessel, and can impart a desired biocompatibility by covalently bonding a desired molecule through a chemical modification site. Excellent in terms.
具体的な実施の形態をあげて、以下に本発明を詳細に説明する。本発明は、以下にあげる具体的な実施の形態に限定されるものではない。 The present invention will be described in detail below by giving specific embodiments. The present invention is not limited to the following specific embodiments.
［本発明のゲルの製造］
本発明の生体適合修飾性ゲルは、酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物、及びケン化度９８モル％以上の未変性ポリビニルアルコールを含む溶液を、冷却して、ゲルを形成する工程、を含む方法によって、製造することができる。
[Production of gel of the present invention]
The biocompatible modifying gel of the present invention is a step of cooling a solution containing a saponified vinyl acetate-diacetone acrylamide copolymer and an unmodified polyvinyl alcohol having a saponification degree of 98 mol% or more to form a gel. Can be manufactured by a method including:
さらに、本発明の生体適合性ゲルは、酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物、及びケン化度９８モル％以上の未変性ポリビニルアルコールを含む溶液を、冷却して、ゲルを形成する工程、ゲルに、Ｈ2Ｎ−ＮＨ−ＣＯ−基を有する生体適合性分子を反応させて、結合する工程、を含む方法によって、製造することができる。 Further, the biocompatible gel of the present invention forms a gel by cooling a solution containing a saponified vinyl acetate-diacetone acrylamide copolymer and an unmodified polyvinyl alcohol having a saponification degree of 98 mol% or more. It can be produced by a method comprising a step, a step of reacting and binding a biocompatible molecule having an H 2 N—NH—CO— group to a gel.
［酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物］
酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物（Ｄポリマー）は、次の式で表される構造を有するジアセトン変性ＰＶＡ（ジアセトン変性ポリビニルアルコール）であり、例えば、特許文献２に開示された方法によって得ることができる。なお、本発明で使用する酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物とは、このように特定される高分子と同じ構造の高分子であればよく、酢酸ビニルとジアセトンアクリルアミドの組み合わせによる共重合反応と鹸化反応を介して得られた高分子に限られるものではないことは、当業者の理解するところであり、例えば、特許文献２等に開示された公知の技術によって、製造することができる。
[Saponified product of vinyl acetate-diacetone acrylamide copolymer]
The saponified product (D polymer) of vinyl acetate-diacetone acrylamide copolymer is diacetone-modified PVA (diacetone-modified polyvinyl alcohol) having a structure represented by the following formula. For example, the method disclosed in Patent Document 2 Can be obtained by: The saponified product of vinyl acetate-diacetone acrylamide copolymer used in the present invention may be a polymer having the same structure as the polymer specified as described above, and depends on the combination of vinyl acetate and diacetone acrylamide. It is understood by those skilled in the art that the polymer is not limited to a polymer obtained through a copolymerization reaction and a saponification reaction. For example, it can be produced by a known technique disclosed in Patent Document 2 and the like. it can.
ただし、上記式中の繰り返し単位である、−ＣＨ2−ＣＨ（ＯＨ）−、及び−ＣＨ2−ＣＨ（ＣＯ−ＮＨ−Ｃ（ＣＨ3）2−ＣＨ2−ＣＯ−ＣＨ3）−は、いずれもランダムに導入されており、ｍ及びｎは、繰り返し単位の合計がそれぞれｍ及びｎであることを表す。 However, the repeating units in the above formula, —CH 2 —CH (OH) — and —CH 2 —CH (CO—NH—C (CH 3 ) 2 —CH 2 —CO—CH 3 ) — Both are introduced at random, and m and n represent that the total of repeating units is m and n, respectively.
好適な実施の態様において、酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物は、例えば５００〜３０００、好ましくは１５００〜２０００の重合度を有し、例えば９５．０〜９９．９％、好ましくは９８．５〜９９．５％の鹸化度を有するものとできる。酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物中のジアセトンアクリルアミド単位含有量は、例えば０．１モル％〜１５モル％、好ましくは１〜１０モル％、３〜７モル％とすることができる。 In a preferred embodiment, the saponified vinyl acetate-diacetone acrylamide copolymer has a degree of polymerization of, for example, 500 to 3000, preferably 1500 to 2000, for example 95.0 to 99.9%, preferably It can have a saponification degree of 98.5-99.5%. The diacetone acrylamide unit content in the saponified product of vinyl acetate-diacetone acrylamide copolymer is, for example, 0.1 mol% to 15 mol%, preferably 1 to 10 mol%, preferably 3 to 7 mol%. it can.
［ケン化度９８モル％以上の未変性ポリビニルアルコール］
ケン化度９８モル％以上の未変性ポリビニルアルコールとして、公知のケン化度９８モル％以上の未変性ポリビニルアルコールを使用できる。好適な実施の態様において、ケン化度９８モル％以上の未変性ポリビニルアルコールは、例えば５００〜３０００、好ましくは１５００〜２０００の重合度を有し、例えば９８．０〜９９．９％、好ましくは９８．５〜９９．５％の鹸化度を有することができる。
[Unmodified polyvinyl alcohol having a saponification degree of 98 mol% or more]
As the unmodified polyvinyl alcohol having a saponification degree of 98 mol% or more, a known unmodified polyvinyl alcohol having a saponification degree of 98 mol% or more can be used. In a preferred embodiment, the unmodified polyvinyl alcohol having a saponification degree of 98 mol% or more has a degree of polymerization of, for example, 500 to 3000, preferably 1500 to 2000, for example 98.0 to 99.9%, preferably It can have a degree of saponification of 98.5-99.5%.
［生体適合修飾性ゲル材料組成物］
本発明のゲルは、酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物、及びケン化度９８モル％以上の未変性ポリビニルアルコールを含む溶液を、生体適合修飾性ゲル材料組成物として使用して、形成できる。この溶液には、ゲル形成のための溶質として、酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物及びケン化度９８モル％以上の未変性ポリビニルアルコールが含まれており、その質量の和は、溶液全体の１００質量部に対して、例えば１〜３０質量部、好ましくは５〜２０質量部、さらに５〜１５質量部が好ましい。溶液の溶媒としては、後述の溶媒を使用できる。生体適合修飾性ゲル材料組成物の溶液には、生体適合性材料として所望の成分を、さらに添加してもよく、そのような成分としては、例えば、コラーゲン、ヒアルロン酸、をあげることができる。酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物とケン化度９８モル％以上の未変性ポリビニルアルコールの質量比（酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物：ケン化度９８モル％以上の未変性ポリビニルアルコール）が、１０：０．０１〜０．０１：１０の範囲、好ましくは１：９〜１：１の範囲とすることができる。
[Biocompatible modifying gel material composition]
The gel of the present invention uses a solution containing a saponified vinyl acetate-diacetone acrylamide copolymer and an unmodified polyvinyl alcohol having a saponification degree of 98 mol% or more as a biocompatible modifying gel material composition. Can be formed. This solution contains, as a solute for gel formation, a saponified product of vinyl acetate-diacetone acrylamide copolymer and unmodified polyvinyl alcohol having a saponification degree of 98 mol% or more. For example, 1 to 30 parts by mass, preferably 5 to 20 parts by mass, and more preferably 5 to 15 parts by mass with respect to 100 parts by mass of the whole solution. As the solvent of the solution, the solvents described later can be used. A desired component as a biocompatible material may be further added to the solution of the biocompatible modifying gel material composition. Examples of such a component include collagen and hyaluronic acid. Mass ratio of saponified product of vinyl acetate-diacetone acrylamide copolymer to unmodified polyvinyl alcohol having a saponification degree of 98 mol% or more (saponification product of vinyl acetate-diacetone acrylamide copolymer: saponification degree of 98 mol% or more) Unmodified polyvinyl alcohol) can be in the range of 10: 0.01 to 0.01: 10, preferably in the range of 1: 9 to 1: 1.
［溶媒］
酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物、及びケン化度９８モル％以上の未変性ポリビニルアルコールを含む溶液の溶媒として、水または水を含む混合溶媒を使用することができ、好ましくはＤＭＳＯと水の混合溶媒を使用することができる。あるいは、ＤＭＳＯに代えて、グリセリン、Ｎ−メチルピロリドンを使用してもよい。好適な実施の態様において、ＤＭＳＯと水の混合溶液は、ＤＭＳＯ／水の質量比を、例えば６０／４０〜９５／５の範囲、好ましくは７０／３０〜９０／１０の範囲とすることができる。
[solvent]
Water or a mixed solvent containing water can be used as a solvent of a solution containing a saponified vinyl acetate-diacetone acrylamide copolymer and an unmodified polyvinyl alcohol having a saponification degree of 98 mol% or more, preferably DMSO. A mixed solvent of water and water can be used. Alternatively, glycerin and N-methylpyrrolidone may be used in place of DMSO. In a preferred embodiment, the mixed solution of DMSO and water can have a DMSO / water mass ratio of, for example, a range of 60/40 to 95/5, preferably a range of 70/30 to 90/10. .
［冷却］
溶液を、冷却して、ゲルを形成する工程において、冷却は、例えば−５℃〜−８０℃の温度、好ましくは−１０℃〜−３０℃の温度で、例えば１〜７２時間、好ましくは２〜４８時間、３〜３０時間の間、冷却することによって行うことができる。
[cooling]
In the step of cooling the solution to form a gel, the cooling is performed at a temperature of, for example, -5 ° C to -80 ° C, preferably at a temperature of -10 ° C to -30 ° C, for example 1 to 72 hours, preferably 2 It can be carried out by cooling for 48 hours or 3 to 30 hours.
［加熱］
好適な実施の態様において、溶液を、冷却して、ゲルを形成する工程として、溶液を、加熱した後に、冷却して、ゲルを形成する工程を行うことができる。加熱は、例えば６０℃〜１８０℃の温度、好ましくは８０℃〜１６０℃の温度、１１０℃〜１３０℃の温度で、例えば０．５〜５時間、好ましくは１〜３時間の間、必要により加圧下で加熱することによって行うことができる。
[heating]
In a preferred embodiment, the step of cooling the solution to form a gel can be performed by heating the solution and then cooling to form the gel. The heating is performed at a temperature of, for example, 60 ° C. to 180 ° C., preferably at a temperature of 80 ° C. to 160 ° C., and at a temperature of 110 ° C. to 130 ° C., for example, for 0.5 to 5 hours, preferably 1 to 3 hours. This can be done by heating under pressure.
［ゲルの機械特性］
本発明のゲルは、人工血管に適した力学的特性（機械特性）を備えている。好適な実施の態様において、溶媒がＤＭＳＯ／水＝８０／２０であるゲルのヤング率［ＭＰａ］が、例えば０．０１〜０．１５、好ましくは０．０４〜０．１４、０．０６〜０．１３の範囲にある。好適な実施の態様において、溶媒を水に置換したゲルのヤング率［ＭＰａ］が、例えば０．１〜５．０、好ましくは０．５〜２．０の範囲にある。ヤング率は、実施例に開示する条件にしたがって公知の手段によって求めることができる。
[Mechanical properties of gel]
The gel of the present invention has mechanical properties (mechanical properties) suitable for artificial blood vessels. In a preferred embodiment, the Young's modulus [MPa] of the gel whose solvent is DMSO / water = 80/20 is, for example, 0.01 to 0.15, preferably 0.04 to 0.14, 0.06 to It is in the range of 0.13. In a preferred embodiment, the Young's modulus [MPa] of the gel in which the solvent is replaced with water is, for example, in the range of 0.1 to 5.0, preferably 0.5 to 2.0. The Young's modulus can be determined by known means according to the conditions disclosed in the examples.
［ゲルの表面官能基］
本発明のゲルは、ジアセトンアクリルアミド単位の側鎖として、−ＣＯ−ＮＨ−Ｃ（ＣＨ3）2−ＣＨ2−ＣＯ−ＣＨ3基を有し、これがゲル表面からアクセス可能に存在している。この基は、図４に示す反応原理によって、Ｈ2Ｎ−ＮＨ−ＣＯ−基と反応して、共有結合（−ＣＯ−ＮＨ−Ｃ（ＣＨ3）2−ＣＨ2−Ｃ（ＣＨ3）＝Ｎ−ＮＨ−ＣＯ−）を形成する。その結果、Ｈ2Ｎ−ＮＨ−ＣＯ−基を有する生体適合性分子を、ゲルに結合することができる。
[Surface functional group of gel]
The gel of the present invention has a —CO—NH—C (CH 3 ) 2 —CH 2 —CO—CH 3 group as a side chain of a diacetone acrylamide unit, which is accessible from the gel surface. . This group reacts with the H 2 N—NH—CO— group according to the reaction principle shown in FIG. 4 to form a covalent bond (—CO—NH—C (CH 3 ) 2 —CH 2 —C (CH 3 ) = N-NH-CO-). As a result, biocompatible molecules having H 2 N—NH—CO— groups can be bound to the gel.
［生体適合性分子］
生体適合性分子にＨ2Ｎ−ＮＨ−ＣＯ−基を付与することによって、本発明のゲルに共有結合可能である。そこで、本発明のゲルは、この生体適合性分子を適宜選択することによって、所望の生体適合性を付与することができる。好適な実施の態様において、本発明のゲルは、生体適合性分子として、血管内皮細胞の接着及び増殖に適した分子を選択することによって、血管内皮細胞を増殖させたハイブリッド型人工血管の材料として好適に使用できる。血管内皮細胞の接着及び増殖に適した分子としては、特に制限なく公知の分子を使用することができ、例えば、細胞接着性ペプチドであるＲＧＤ配列を有するペプチド、血管内皮細胞接着性ペプチドであるＲＥＤＶ配列を有するペプチド、コラーゲン、ラミニン、フィブロネクチンをあげることができる。なお、比較的に小さな分子や数アミノ酸長程度の小さなペプチドの場合には、いったんこれらをリンカーとなる分子に結合させて、そのリンカー分子にＨ2Ｎ−ＮＨ−ＣＯ−基を付与してもよく、すなわちリンカー分子を介して本発明のゲルと共有結合させてもよい。このようなリンカー分子として、例えばヒアルロン酸をあげることができる。
[Biocompatible molecules]
By attaching an H 2 N—NH—CO— group to the biocompatible molecule, it can be covalently bound to the gel of the present invention. Therefore, the gel of the present invention can impart desired biocompatibility by appropriately selecting this biocompatible molecule. In a preferred embodiment, the gel of the present invention is used as a material for a hybrid type artificial blood vessel in which vascular endothelial cells are grown by selecting a molecule suitable for adhesion and proliferation of vascular endothelial cells as a biocompatible molecule. It can be used suitably. As a molecule suitable for adhesion and proliferation of vascular endothelial cells, known molecules can be used without particular limitation. For example, a peptide having an RGD sequence which is a cell adhesion peptide, REDV which is a vascular endothelial cell adhesion peptide Peptides having the sequence, collagen, laminin, fibronectin can be mentioned. In the case of a relatively small molecule or a small peptide of about several amino acids in length, these may be once bound to a molecule that becomes a linker and an H 2 N—NH—CO— group may be added to the linker molecule. Well, that is, it may be covalently attached to the gel of the invention via a linker molecule. An example of such a linker molecule is hyaluronic acid.
［人工血管］
本発明の生体適合性ゲルは、力学的性質の点と、血管内皮細胞の接着性及び増殖性の付与の観点から、特に人工血管の形成に適している。生体適合性ゲルから人工血管を形成する場合には、所望により、公知の人工血管形成用材料をさらに組み合わせてもよい。本発明による人工血管は、血管内皮細胞の増殖によって閉塞を防ぐハイブリッド型人工血管とすることができることから、内径約５ｍｍ以下といった小口径の人工血管として好適に使用可能なものである。
[Artificial blood vessels]
The biocompatible gel of the present invention is particularly suitable for the formation of an artificial blood vessel from the viewpoint of mechanical properties and imparting adhesion and proliferation of vascular endothelial cells. When an artificial blood vessel is formed from a biocompatible gel, a known artificial blood vessel forming material may be further combined as desired. Since the artificial blood vessel according to the present invention can be a hybrid type artificial blood vessel that prevents occlusion by the proliferation of vascular endothelial cells, it can be suitably used as an artificial blood vessel having a small diameter of about 5 mm or less.
以下に実施例をあげて、本発明を詳細に説明する。本発明は、以下に例示する実施例に限定されるものではない。なお、実施例中、特にことわりのない限り「％」及び「部」はそれぞれ重量％及び重量部を示す。 Hereinafter, the present invention will be described in detail with reference to examples. The present invention is not limited to the examples illustrated below. In Examples, unless otherwise specified, “%” and “parts” represent “% by weight” and “parts by weight”, respectively.
［酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物（Ｄポリマー）の合成］
下記の方法により、酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物（Ｄポリマー）を合成した。鹸化度、４％水溶液粘度はＪＩＳ Ｋ−６７２６（１９９４）に準じて測定を行った。また、ジアセトンアクリルアミド含有量（変性度）については、Ｄポリマーをメタノールで十分洗浄したサンプルの窒素分析の結果から求めた。
[Synthesis of saponified product (D polymer) of vinyl acetate-diacetone acrylamide copolymer]
A saponified product (D polymer) of vinyl acetate-diacetone acrylamide copolymer was synthesized by the following method. The saponification degree and 4% aqueous solution viscosity were measured according to JIS K-6726 (1994). The diacetone acrylamide content (degree of modification) was determined from the results of nitrogen analysis of a sample in which D polymer was sufficiently washed with methanol.
［合成例１］
撹拌機、温度計、滴下ロート及び還流冷却器を取り付けたフラスコ中に、酢酸ビニル６８０部、ジアセトンアクリルアミド５部、及びメタノール１７２部を仕込み、系内の窒素置換を行った後、内温を６０℃まで昇温した。この系に２，２−アゾビスイソブチリロニトリル１部をメタノール５０部に溶解した溶液を添加し、重合を開始した。重合開始後、５時間かけて、ジアセトンアクリルアミド５０部をメタノール４３部に溶解した溶液を一定速度で滴下し、６時間後に重合禁止剤としてｍ−ジニトロベンゼンを添加し、重合を停止した。重合収率は７８％であった。得られた反応混合物にメタノール蒸気を加えながら残存する酢酸ビニルを留出し、ジアセトンアクリルアミド共重合成分を含有する酢酸ビニル系重合体の５０％メタノール溶液を得た。この混合物５００重量部にメタノール５０重量部と水酸化ナトリウムの４％メタノール溶液１０重量部とを加えてよく混合し、４０℃で鹸化反応を行った。得られたゲル状物を粉砕し、メタノールでよく洗浄した後に乾燥して、酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物を得た。この樹脂中のジアセトンアクリルアミド単位の含有率は５．０モル％であった。この樹脂の２０℃における４％水溶液粘度は２６．８ｍＰａ・ｓ、鹸化度は９８．４モル％であった。
[Synthesis Example 1]
A flask equipped with a stirrer, thermometer, dropping funnel and reflux condenser was charged with 680 parts of vinyl acetate, 5 parts of diacetone acrylamide, and 172 parts of methanol, and after substituting nitrogen in the system, the internal temperature was raised. The temperature was raised to 60 ° C. To this system, a solution of 1 part of 2,2-azobisisobutyronitrile dissolved in 50 parts of methanol was added to initiate polymerization. A solution obtained by dissolving 50 parts of diacetone acrylamide in 43 parts of methanol was dropped at a constant rate over 5 hours after the start of polymerization, and 6 hours later, m-dinitrobenzene was added as a polymerization inhibitor to stop the polymerization. The polymerization yield was 78%. The remaining vinyl acetate was distilled while adding methanol vapor to the resulting reaction mixture to obtain a 50% methanol solution of a vinyl acetate polymer containing a diacetone acrylamide copolymer component. To 500 parts by weight of this mixture, 50 parts by weight of methanol and 10 parts by weight of a 4% methanol solution of sodium hydroxide were added and mixed well, and a saponification reaction was carried out at 40 ° C. The obtained gel-like material was pulverized, washed thoroughly with methanol and then dried to obtain a saponified product of vinyl acetate-diacetone acrylamide copolymer. The content rate of the diacetone acrylamide unit in this resin was 5.0 mol%. This resin had a 4% aqueous solution viscosity at 2O 0 C of 26.8 mPa · s and a saponification degree of 98.4 mol%.
［Ｄポリマーの構造］
得られた酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物（Ｄポリマー）は、次の式で表される構造を有するジアセトン変性ＰＶＡ（ジアセトン変性ポリビニルアルコール）である（重合度：１７００）。
[D polymer structure]
The obtained saponified product (D polymer) of vinyl acetate-diacetone acrylamide copolymer is diacetone-modified PVA (diacetone-modified polyvinyl alcohol) having a structure represented by the following formula (polymerization degree: 1700).
ただし、上記式中の繰り返し単位である、−ＣＨ2−ＣＨ（ＯＨ）−、及び−ＣＨ2−ＣＨ（ＣＯ−ＮＨ−Ｃ（ＣＨ3）2−ＣＨ2−ＣＯ−ＣＨ3）−は、いずれもランダムに導入されており、ｍ及びｎは、繰り返し単位の合計がそれぞれｍ及びｎであることを表す。 However, the repeating units in the above formula, —CH 2 —CH (OH) — and —CH 2 —CH (CO—NH—C (CH 3 ) 2 —CH 2 —CO—CH 3 ) — Both are introduced at random, and m and n represent that the total of repeating units is m and n, respectively.
［実施例１］
［ＤポリマーとＰＶＡによる混合ゲルの形成］
ＰＶＡ（ポリビニルアルコール）（重合度：１７００、鹸化度：９８〜９９％）を用意して、上記合成したＤポリマーと混合して、ゲルを形成できるかを検討した。
ＰＶＡとジアセトン変性ＰＶＡ（重合度１７００）を合計１０ｇになるように混合したものをＤＭＳＯ／水（８０／２０ｗ／ｗ）溶液９０ｇに添加し、オートクレーブで１２１℃１時間溶解後、２ｍｍ厚の型に流し込んで−２０℃で低温結晶化処理してゲルを得た。詳細には混合ゲルの作成条件は以下である：
溶質（Ｄポリマー＋ＰＶＡ）濃度： １０％
溶媒： 蒸留水１８％、ＤＭＳＯ７２％
作成方法： 上記溶質と溶媒の混合溶液を１２０℃で１時間加熱し、２．０ｍｍ厚となるよう平底容器へ流し込み、マイナス２０℃で２４時間冷却して、混合ゲルの試料を作成した。
ＤポリマーとＰＶＡの混合割合： 次の表１に示す。
[Example 1]
[Formation of mixed gel by D polymer and PVA]
PVA (polyvinyl alcohol) (polymerization degree: 1700, saponification degree: 98 to 99%) was prepared and mixed with the synthesized D polymer to examine whether a gel could be formed.
A mixture of PVA and diacetone-modified PVA (degree of polymerization 1700) mixed to a total of 10 g is added to 90 g of DMSO / water (80/20 w / w) solution, dissolved in an autoclave at 121 ° C. for 1 hour, and then a 2 mm thick mold And was subjected to low-temperature crystallization at −20 ° C. to obtain a gel. In detail, the preparation conditions of the mixed gel are as follows:
Solute (D polymer + PVA) concentration: 10%
Solvent: 18% distilled water, 72% DMSO
Preparation method: The mixed solution of the solute and the solvent was heated at 120 ° C. for 1 hour, poured into a flat bottom container to a thickness of 2.0 mm, and cooled at −20 ° C. for 24 hours to prepare a mixed gel sample.
Mixing ratio of D polymer and PVA: shown in Table 1 below.
［機械特性試験］
得られたゲルを打ち抜いて試験片を作成して、この機械特性(ヤング率)を、以下の条件の引張試験によって評価した。
引張試験の条件：
引張速度［ｍｍ／ｍｉｎ］： ２００
初期荷重［Ｎ］： ０．０１
試験片： ＪＩＳダンベル７型
[Mechanical property test]
A test piece was prepared by punching the obtained gel, and this mechanical property (Young's modulus) was evaluated by a tensile test under the following conditions.
Tensile test conditions:
Tensile speed [mm / min]: 200
Initial load [N]: 0.01
Test piece: JIS dumbbell type 7
［混合ゲルの外見］
得られた各混合割合の混合ゲルの外見を目視によって観察した。得られた混合ゲル（厚さ２ｍｍ、直径５０ｍｍ）の外観写真を図１に示す。Ｄポリマーの混合割合を増加させると混合ゲルの透明度が減少していた。また、目視観察のための操作時の触感として、Ｄポリマーの混合割合を増加させると混合ゲルの堅さが減少していた。
[Appearance of mixed gel]
The appearance of the obtained mixed gel of each mixing ratio was visually observed. An appearance photograph of the obtained mixed gel (thickness 2 mm, diameter 50 mm) is shown in FIG. When the mixing ratio of the D polymer was increased, the transparency of the mixed gel was decreased. Further, as the tactile sensation during the operation for visual observation, when the mixing ratio of the D polymer was increased, the hardness of the mixed gel was decreased.
［混合ゲルの機械特性試験の結果］
得られた各混合割合の混合ゲルの機械特性(ヤング率)を上記のように測定した。Ｄポリマーの混合率と弾性率との関係を図２に示す。図２に示すように、Ｄポリマーの混合割合を増加させると混合ゲルの弾性率は減少することがわかった。
[Results of mechanical property test of mixed gel]
The mechanical properties (Young's modulus) of the obtained mixed gel of each mixing ratio were measured as described above. FIG. 2 shows the relationship between the mixing ratio of the D polymer and the elastic modulus. As shown in FIG. 2, it was found that the elastic modulus of the mixed gel decreased when the mixing ratio of the D polymer was increased.
［実施例２］
［混合ゲル表面の解析試験］
混合ゲルにおいてＤポリマーのジアセトン変性部分がゲル表面に存在することを確認するために、ＡＴＲ−ＦＴ−ＩＲ（日本分光、ＦＴ／ＩＲ−４０００）により、Ｄポリマーに含まれるアミド基（１６５０［ｃｍ-1］）の吸収スペクトルを測定した。測定は、混合ゲルをエタノール洗浄により脱溶媒を行い、乾燥した後に行った。
[Example 2]
[Analysis test of mixed gel surface]
In order to confirm that the diacetone-modified portion of the D polymer is present on the gel surface in the mixed gel, the amide group (1650 [cm -1 ]) was measured. The measurement was performed after the mixed gel was desolvated by ethanol washing and dried.
［吸収スペクトルの測定結果］
Ｄポリマーに含まれるアミド基の吸収スペクトルを測定した結果を図３に示す。図３では、上記試料Ｎｏ．１〜５の全てスペクトルの波形を同一グラフ中に対比して示している。いずれの混合割合の混合ゲルにおいても、その混合比に応じた量で、Ｄポリマーのジアセトン変性部分が、ゲル表面に存在することが確認できた。
[Measurement results of absorption spectrum]
The result of measuring the absorption spectrum of the amide group contained in the D polymer is shown in FIG. In FIG. Waveforms of all spectra 1 to 5 are shown in comparison in the same graph. It was confirmed that the diacetone-modified portion of the D polymer was present on the gel surface in an amount corresponding to the mixing ratio in any mixing ratio of the mixing gel.
［実施例３］
［混合ゲル表面の修飾試験］
混合ゲルにおいてＤポリマーのジアセトン変性部分がゲル表面に存在して、ヒドラジドとの反応を介して細胞接着性分子によって修飾できることを確認するために、混合ゲル表面の修飾試験を行った。Ｄポリマーのジアセトン変性部分と、ヒドラジドとの反応の原理を、図４に示す。図４に示すヒドラジド：Ｈ2Ｎ−ＮＨ−ＣＯ−〜〜の波線部分には、所望の細胞接着性分子を結合することができる。本試験では、ヒドラジドとして、次の構造式で示されるサリチルヒドラジドを使用した。
[Example 3]
[Modification test of mixed gel surface]
In order to confirm that the diacetone-modified portion of the D polymer was present on the gel surface in the mixed gel and could be modified by the cell adhesion molecule through reaction with hydrazide, a modification test on the mixed gel surface was performed. The principle of the reaction between the diacetone-modified portion of D polymer and hydrazide is shown in FIG. A desired cell adhesion molecule can be bound to the wavy line portion of hydrazide: H 2 N—NH—CO—˜ shown in FIG. In this test, salicyl hydrazide represented by the following structural formula was used as hydrazide.
本試験の手順を図５に示す。混合ゲルを乾燥した後に、直径１ｃｍのパンチで打ち抜いて試料片として、これを１％サリチルヒドラジド／メタノール溶液（５ｍｌ）中へ投入して、２４時間室温で浸漬した。その後、試料片を取り出して、十分量のメタノールで洗浄し、ＤＭＳＯ／水（８０／２０ｗ／ｗ）（５ｍｌ）中へ投入して、１２０℃で１５分間オートクレーブして溶解した。得られた溶解液を可視・紫外分光測定装置によって３００［ｎｍ］の吸光度を測定し、検量線からゲル表面に結合したサリチルヒドラジドの量を定量した。 The procedure of this test is shown in FIG. After the mixed gel was dried, it was punched out with a punch having a diameter of 1 cm to give a sample piece, which was put into a 1% salicylhydrazide / methanol solution (5 ml) and immersed at room temperature for 24 hours. Thereafter, the sample piece was taken out, washed with a sufficient amount of methanol, poured into DMSO / water (80/20 w / w) (5 ml), and dissolved by autoclaving at 120 ° C. for 15 minutes. The obtained lysate was measured for absorbance at 300 [nm] with a visible / ultraviolet spectrophotometer, and the amount of salicyl hydrazide bound to the gel surface was determined from the calibration curve.
［混合ゲル表面への結合量］
上記手順でサリチルヒドラジドのベンゼン環による吸収スペクトルをｖｉｓ−ＵＶによって測定し、混合ゲル表面の単位面積あたりに結合したサリチルヒドラジドの量を計算した。図６に、Ｄポリマー（変性ＰＶＡ）の混合割合（濃度）と混合ゲル表面におけるサリチルヒドラジドの量との関係を示す。図６に示されるように、混合ゲルはその混合比に応じた量で、サリチルヒドラジドを結合していた。このように、混合ゲルがジアセトン変性部分とヒドラジドの反応を介して、細胞接着性分子をゲル表面に結合できることがわかった。
[Binding amount to the surface of the mixed gel]
In the above procedure, the absorption spectrum of salicylhydrazide by the benzene ring was measured by vis-UV, and the amount of salicylhydrazide bound per unit area of the mixed gel surface was calculated. FIG. 6 shows the relationship between the mixing ratio (concentration) of D polymer (modified PVA) and the amount of salicylhydrazide on the surface of the mixed gel. As shown in FIG. 6, the mixed gel bound salicylhydrazide in an amount corresponding to the mixing ratio. Thus, it was found that the mixed gel can bind the cell adhesion molecule to the gel surface through the reaction between the diacetone-modified moiety and the hydrazide.
本発明によれば、生体適合性人工材料、特に人工血管の形成に適した生体適合性ゲルを得ることができる。本発明は産業上有用な発明である。 According to the present invention, a biocompatible gel suitable for forming a biocompatible artificial material, in particular, an artificial blood vessel can be obtained. The present invention is industrially useful.
Claims (14)
を含む、生体適合修飾性ゲルを製造する方法であって、
酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物とケン化度９８モル％以上の未変性ポリビニルアルコールの質量の和が、溶液の質量に対して、５〜２０質量％の範囲にあり、
酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物とケン化度９８モル％以上の未変性ポリビニルアルコールの質量比（酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物：ケン化度９８モル％以上の未変性ポリビニルアルコール）が、１：９〜１：１の範囲にある、方法。 A step of cooling a solution containing a saponified vinyl acetate-diacetone acrylamide copolymer and an unmodified polyvinyl alcohol having a saponification degree of 98 mol% or more to form a gel;
A method for producing a biocompatible modifying gel comprising:
The sum of the mass of the saponified vinyl acetate-diacetone acrylamide copolymer and the unmodified polyvinyl alcohol having a saponification degree of 98 mol% or more is in the range of 5 to 20 mass% with respect to the mass of the solution,
Mass ratio of saponified product of vinyl acetate-diacetone acrylamide copolymer to unmodified polyvinyl alcohol having a saponification degree of 98 mol% or more (saponification product of vinyl acetate-diacetone acrylamide copolymer: saponification degree of 98 mol% or more) Unmodified polyvinyl alcohol) is in the range of 1: 9 to 1: 1.
ゲルに、Ｈ2Ｎ−ＮＨ−ＣＯ−基を有する生体適合性分子を反応させて、結合する工程、
を含む、生体適合性ゲルを製造する方法であって、
酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物とケン化度９８モル％以上の未変性ポリビニルアルコールの質量の和が、溶液の質量に対して、５〜２０質量％の範囲にあり、
酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物とケン化度９８モル％以上の未変性ポリビニルアルコールの質量比（酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物：ケン化度９８モル％以上の未変性ポリビニルアルコール）が、１：９〜１：１の範囲にある、方法。 A step of cooling a solution containing a saponified vinyl acetate-diacetone acrylamide copolymer and an unmodified polyvinyl alcohol having a saponification degree of 98 mol% or more to form a gel;
Reacting a gel with a biocompatible molecule having an H 2 N—NH—CO— group,
A method for producing a biocompatible gel comprising :
The sum of the mass of the saponified vinyl acetate-diacetone acrylamide copolymer and the unmodified polyvinyl alcohol having a saponification degree of 98 mol% or more is in the range of 5 to 20 mass% with respect to the mass of the solution,
Mass ratio of saponified product of vinyl acetate-diacetone acrylamide copolymer to unmodified polyvinyl alcohol having a saponification degree of 98 mol% or more (saponification product of vinyl acetate-diacetone acrylamide copolymer: saponification degree of 98 mol% or more) Unmodified polyvinyl alcohol) is in the range of 1: 9 to 1: 1 .
溶液を、加熱した後に、冷却して、ゲルを形成する工程
である、請求項１〜３のいずれかに記載の方法。 The step of cooling the solution to form a gel comprises
The method according to any one of claims 1 to 3, which is a step of cooling the solution to form a gel after heating.
酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物とケン化度９８モル％以上の未変性ポリビニルアルコールの質量の和が、溶液の質量に対して、５〜２０質量％の範囲にあり、
酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物とケン化度９８モル％以上の未変性ポリビニルアルコールの質量比（酢酸ビニル−ジアセトンアクリルアミド共重合体の鹸化物：ケン化度９８モル％以上の未変性ポリビニルアルコール）が、１：９〜１：１の範囲にある、生体適合修飾性ゲル材料組成物。 A biocompatible modifying gel material composition comprising a saponified product of vinyl acetate-diacetone acrylamide copolymer and a solution containing unmodified polyvinyl alcohol having a saponification degree of 98 mol% or more,
The sum of the mass of the saponified vinyl acetate-diacetone acrylamide copolymer and the unmodified polyvinyl alcohol having a saponification degree of 98 mol% or more is in the range of 5 to 20 mass% with respect to the mass of the solution,
Mass ratio of saponified product of vinyl acetate-diacetone acrylamide copolymer to unmodified polyvinyl alcohol having a saponification degree of 98 mol% or more (saponification product of vinyl acetate-diacetone acrylamide copolymer: saponification degree of 98 mol% or more) Biocompatible modifying gel material composition wherein the unmodified polyvinyl alcohol) is in the range of 1: 9 to 1: 1.
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