JPH0975442A - Cell structure with in vivo decomposing and absorbing function - Google Patents
Cell structure with in vivo decomposing and absorbing functionInfo
- Publication number
- JPH0975442A JPH0975442A JP7260769A JP26076995A JPH0975442A JP H0975442 A JPH0975442 A JP H0975442A JP 7260769 A JP7260769 A JP 7260769A JP 26076995 A JP26076995 A JP 26076995A JP H0975442 A JPH0975442 A JP H0975442A
- Authority
- JP
- Japan
- Prior art keywords
- solvent
- cell structure
- molecular weight
- polymer
- copolymer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Materials For Medical Uses (AREA)
- Prostheses (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、医療用途に適した
生体内分解吸収性セル構造体に関する。TECHNICAL FIELD The present invention relates to a biodegradable and absorbable cell structure suitable for medical use.
【０００２】[0002]
【従来の技術】医療用途を目的とする生体内分解吸収性
のセル構造体（多孔体）としては、特公昭６３−６４９
８８号に開示された生体内分解吸収性スポンジや、特開
平２−６３４６５号に開示された歯周組織再建用素材な
どが知られている。2. Description of the Related Art As a cell structure (porous body) capable of being decomposed and absorbed in vivo for medical use, Japanese Patent Publication No. 63-649 is known.
No. 88, a biodegradable and absorbable sponge, and a material for periodontal tissue reconstruction disclosed in JP-A-2-63465 are known.
【０００３】前者の生体内分解吸収性スポンジは、手術
時の止血や生体の軟組織（例えば肝臓等の臓器）の縫合
時の補綴材料として使用されるもので、分子量（重量平
均分子量）が２千〜６０万のポリ乳酸等から形成された
連続気泡構造を有する柔軟なスポンジである。このスポ
ンジは、上記のポリ乳酸等をベンゼン又はジオキサンに
溶解させ、そのポリマー溶液を凍結乾燥する方法によっ
て製造される。The former biodegradable and absorbable sponge is used as a prosthetic material for hemostasis at the time of surgery or for suturing a soft tissue (organ such as a liver) of a living body, and has a molecular weight (weight average molecular weight) of 2,000. It is a flexible sponge having an open-cell structure formed of up to 600,000 polylactic acid. This sponge is produced by a method in which the above polylactic acid or the like is dissolved in benzene or dioxane and the polymer solution is freeze-dried.
【０００４】また、後者の歯周組織再建用素材は、重量
平均分子量が４万〜５０万の乳酸−カプロラクトン共重
合体等から形成された多孔質の柔軟なフィルム状もしく
はシート状の肉薄の素材であり、この素材も上記と同様
の溶剤を用いて凍結乾燥法により製造されるものであ
る。Further, the latter material for periodontal tissue reconstruction is a thin porous material in the form of a porous flexible film or sheet made of a lactic acid-caprolactone copolymer having a weight average molecular weight of 40,000 to 500,000. This material is also produced by a freeze-drying method using the same solvent as described above.
【０００５】両者の方法の主な目的の一つは、フロロカ
ーボン系の溶剤（フレオン）やヘキサフルオロイソプロ
パノール、ヘキサフルオロアセトンセスキヒドラートの
ようなフッ素系の特殊であり、生体に対して毒性があ
り、地球のオゾン層を破壊するような公害の恐れのある
溶剤を使わないことにある。しかし、上記のベンゼンや
ジオキサンなどの溶剤もまた完全に気泡体から除去する
ことは容易でなく、残留溶剤の毒性の危惧は否定できな
い。One of the main purposes of both methods is a fluorocarbon solvent (Freon) or a fluorine-based special solvent such as hexafluoroisopropanol or hexafluoroacetone sesquihydrate, which is toxic to the living body. , Not to use solvents that may cause pollution, such as destroying the ozone layer of the earth. However, it is not easy to completely remove the above-mentioned solvents such as benzene and dioxane from the foam, and the risk of toxicity of the residual solvent cannot be denied.
【０００６】[0006]
【発明が解決しようとする課題】前記のスポンジ状の補
綴材や組織の再建用素材のように重量平均分子量が６０
万以下のポリ乳酸や乳酸−カプロラクトン共重合体から
形成された多孔体は、柔軟で硬度や強度（引張強度、曲
げ強度等）が低く、脆いこと、および加水分解により低
分子量に早くなるため、生体内で数ケ月に亘って保形性
と相当の硬度及び強度が要求される医療用途には使用で
きないという問題がある。[Problems to be Solved by the Invention] Like the above-mentioned sponge-like prosthesis material and tissue reconstruction material, the weight average molecular weight is 60.
A porous body formed from 10,000 or less polylactic acid or lactic acid-caprolactone copolymer is flexible, has low hardness and strength (tensile strength, bending strength, etc.), is brittle, and is rapidly hydrolyzed to have a low molecular weight. There is a problem that it cannot be used for medical applications requiring shape retention and considerable hardness and strength for several months in vivo.
【０００７】加うるに生体内に埋入して使う医療材料
は、使用以前に必ず滅菌しなければならない。代表的な
滅菌方法は放射線（電子線）、エチレンオキサイドガス
（ＥＯＧ）および加圧蒸気による滅菌である。然るにセ
ル構造体の如き表面積の極めて大きな多孔体は、ガス滅
菌時にガスが完全に微孔内に拡散されているかどうか、
セル壁のポリマー内部まで滅菌できているかどうかが不
明であり、そのために分解過程で感染の恐れを常に危惧
しなければならない。ガス滅菌した多孔体では、まれに
感染が報告されることがある。そのために有効であり安
心できる方法は、材料の内部まで完全に滅菌できる放射
線あるいは加熱蒸気による滅菌である。しかるにポリ乳
酸などの生体内分解吸収性のα−ポリエステル系のポリ
マーは放射線により劣化し、加熱蒸気によっては加熱分
解、加水分解する。従って初期分子量の低いポリマーで
は、これらの滅菌により更に低い分子量のセル構造体に
変化するので、生体内での分解・吸収が早いものしか得
られない。実際の臨床の場では生体内での分解・吸収の
早さが種々異なるセル構造体が要望されているので、初
期重量平均分子量が６０万程度までの低いものはそのニ
ーズに応えるものではない。In addition, medical materials to be used by being implanted in the living body must be sterilized before use. Typical sterilization methods are sterilization by radiation (electron beam), ethylene oxide gas (EOG) and pressurized steam. Therefore, a porous body with an extremely large surface area, such as a cell structure, is used to determine whether the gas is completely diffused into the micropores during gas sterilization.
It is not known whether the inside of the polymer on the cell wall can be sterilized, and therefore the risk of infection must always be feared during the decomposition process. In rare cases, infection can be reported in gas-sterilized porous materials. An effective and reassuring method for that is sterilization by radiation or heated steam that can completely sterilize the inside of the material. However, biodegradable and absorbable α-polyester polymers such as polylactic acid are deteriorated by radiation, and are thermally decomposed and hydrolyzed by heated steam. Therefore, a polymer having a low initial molecular weight is converted into a cell structure having a lower molecular weight by these sterilizations, so that only a polymer that is rapidly decomposed and absorbed in vivo can be obtained. In an actual clinical setting, there is a demand for a cell structure having various in vivo decomposition / absorption rates. Therefore, a cell structure having an initial weight average molecular weight as low as about 600,000 cannot meet the needs.
【０００８】また、前記のスポンジや再建用素材のよう
に凍結乾燥法によって製造される多孔体は、せいぜい１
ｍｍ以下、普通には数１００μｍ以下の薄いフィルム状
ないしシート状の多孔体であり、これより厚いものを得
ようと試みても、凝固点以下の低温にて結晶化したベン
ゼン、ジオキサン等の溶剤の昇華に時間がかかり、長時
間昇華させてもなお溶剤が一部残留するので、生体内で
の安全性を損なう恐れがあるために、１ｍｍ以上の厚い
毒性のない多孔体を得ることは困難である。このような
薄いフィルム又はシート状の多孔体は、例えば生体内の
損傷部位の複雑な三次元空間に形状的にあてはめて、一
時的な補綴材としての機能を発揮させながら立体的な損
傷部位の再建を図るような場合には使用に値しないとい
う問題がある。[0008] Further, the porous body produced by the freeze-drying method like the above-mentioned sponge and reconstruction material is at most 1
It is a thin film-like or sheet-like porous material having a thickness of less than mm, usually several hundreds of micrometers or less, and even if an attempt is made to obtain a thicker material, a solvent such as benzene or dioxane which is crystallized at a low temperature below the freezing point is used. Sublimation takes a long time and some solvent remains even after sublimation for a long time, which may impair safety in vivo. Therefore, it is difficult to obtain a porous body with a thickness of 1 mm or more without toxicity. is there. Such a thin film or sheet-like porous material is, for example, geometrically applied to a complicated three-dimensional space of a damaged part in a living body, and the function as a temporary prosthesis material is exerted while the three-dimensional damaged part is damaged. There is a problem that it is not worth using when reconstructing.
【０００９】この問題をより詳しく述べる。組織再生
（regenerate organs）や細胞移植（cell transplantat
ion）のための足場（scaffold）が現在種々検討されて
いる。それには細胞の植付け（cell seeding）と細胞の
付着（cell attachment） に効率の良い、高い多孔度と
大きな表面積をもつセル構造体が有用であるとみなされ
ている。基材が生体内分解吸収生ポリマーである場合は
自らが徐々に消滅するので、新しい細胞が完全に再生
し、組織機能を復帰する可能性が大きいので、現在、こ
の種のポリマーのセル構造体の開発が真に要望されるわ
けである。失われた器官の機能を復元できるような生体
の組織をつくり出すことを目的とする組織工学（Tissue
Engineering）においては、例えば皮膚（Skin）、神経
（Nerve）、食道（Esophagus）、前十字靱帯（Anterior
Cruciate Ligament）、骨（Bone）、あるいは血管新生
などへの組織誘導（Tissue Induction）と軟骨（Cartil
age）、骨、尿道（Urothelium）、腸（Intestine）、神
経、肝臓（Liver）などの再生のために足場への細胞の
植付けが検討されている。そして、多孔質の生体内分解
吸収性ポリマーの足場をつくる方法には、繊維不織布
あるいは複数本の繊維の交差点で繊維を結合させた(Fib
er Bonding）メッシュ状の繊維、ポリマー溶液をキャ
スティング（casting） して蒸散した溶剤の空隙孔をつ
くり、多孔質とする溶液キャスティング（Solvent−Cas
ting）法、あるいは溶解性の粒径を選んだ微粒状の充填
材（食塩、クエン酸ソーダなど）をポリマーに混合分散
してキャスティングによりフィルム、シートをつくり、
この微粒子を浸出−溶出（Particulate-Leaching）する
方法、およびこれら両者の併用法がある。しかしの方
法の欠点は空隙率と孔のサイズを自由にコントロールす
ることが技術的に容易ではないこと、の方法は、孔の
大きさが充填粒子の大きさに依存するので比較的制御で
きるが、せいぜい２ｍｍ厚さの薄いウエファース（Wafe
rs）や膜（Menbranes） しかつくれないこと、である。
また、完全に微粒子を浸出−溶出することは容易でない
ので、充填粒子の毒性に配慮が必要である。そこでの
方法として、でつくった膜の表面を少量のクロロホル
ムに溶かして貼り合わせして厚い多孔体を得る膜ラミネ
ート（Membrane Lamination） 法により三次元の形状物
を得る方法が考案されているが、この方法は煩雑であ
り、ラミネート面で孔が不連続になるという欠点があ
る。This problem will be described in more detail. Tissue regeneration
(Regenerate organs) and cell transplantat
Various scaffolds for ion are currently under study. Cell structures with high porosity and large surface area, which are efficient for cell seeding and cell attachment, are considered to be useful for this purpose. When the base material is a biodegradable bioabsorbable polymer, it gradually disappears, and there is a high possibility that new cells will completely regenerate and restore tissue function.Currently, this type of polymer cell structure is present. That is the true demand for development. Tissue engineering (Tissue engineering) that aims to create biological tissues that can restore the functions of lost organs
In engineering, skin (Skin), nerve (Nerve), esophagus (Esophagus), anterior cruciate ligament (Anterior)
Cruciate Ligament), bone (Bone), or tissue induction (Tissue Induction) to angiogenesis
age), bones, urethra (Urothelium), intestine (Intestine), nerves, liver (Liver) and so on. Then, in a method of forming a scaffold of a porous biodegradable and absorbable polymer, fibers are bonded at a cross point of a fiber nonwoven fabric or a plurality of fibers (Fib
er Bonding) Solvent-casting is performed by casting mesh fiber or polymer solution to create pores of the evaporated solvent and making it porous.
ting) method, or by mixing and dispersing a fine-grained filler (table salt, sodium citrate, etc.) in which the particle size of solubility is selected into a polymer, and casting to form a film or sheet,
There is a method of leaching and eluting (particulate-leaching) these fine particles, and a method of using both of them in combination. However, the disadvantage of this method is that it is not technically easy to freely control the porosity and the pore size, but the method is relatively controllable because the pore size depends on the size of the packed particles. , Wafers with a thickness of at most 2 mm (Wafe
rs) and membranes (Menbranes) can only be made.
Moreover, since it is not easy to leach and elute the fine particles completely, it is necessary to consider the toxicity of the filled particles. As a method therefor, a method of obtaining a three-dimensional shape by a membrane laminating method in which the surface of the membrane prepared by is dissolved in a small amount of chloroform and bonded to obtain a thick porous body has been devised. This method is complicated and has a drawback that the holes are discontinuous on the laminated surface.
【００１０】また、先記の凍結乾燥法によって製造され
るポリ乳酸等の多孔体は、発泡倍率を高くする目的で大
量溶剤を含ませると、乾燥時に多孔体が歪曲する。特
に、重量平均分子量が６０万以下で厚さが１ｍｍ以上の
肉厚の場合は歪曲が顕著となるので、実際には高い発泡
倍率のものを得ることができない。また発泡倍率の低い
多孔体は、高倍率の多孔体に比べて材料の比率が高いの
で、生体内での加水分解の進行に伴って一時期に２０〜
３０μｍ程度の分解細片を局所に多量に発生する機会が
高発泡倍率と比較して多いため、その異物反応によって
一過性の炎症を起こしやすいという問題がある。Further, the porous material such as polylactic acid produced by the above-mentioned freeze-drying method is distorted during drying when a large amount of solvent is included for the purpose of increasing the expansion ratio. In particular, when the weight average molecular weight is 600,000 or less and the thickness is 1 mm or more, the distortion becomes remarkable, so that a high expansion ratio cannot be actually obtained. In addition, since a porous material having a low expansion ratio has a higher material ratio than a porous material having a high expansion ratio, it may be 20 to 20 times at a time with the progress of hydrolysis in a living body.
Since there are many opportunities to locally generate a large amount of decomposed particles of about 30 μm in comparison with a high expansion ratio, there is a problem that transient foreign substance reaction easily causes transient inflammation.
【００１１】[0011]
【課題を解決するための手段】本発明は上記の問題を全
て解決している。本発明の生体内分解吸収性セル構造体
は、ポリ乳酸、又は乳酸とグリコール酸との共重合体、
又は乳酸とカプロラクトンとの共重合体から形成された
連続気孔を有するセル構造体であって、その重量平均分
子量が６０万より高いことを特徴とするものである。こ
こに、セル構造体とは、気孔を取り囲む一つの構造単位
であるセルの壁が相互につながったネットワークからな
る固体のことであり、多孔体や発泡体と表現しても本質
的な差異がないものである。The present invention solves all of the above problems. The biodegradable and absorbable cell structure of the present invention is polylactic acid, or a copolymer of lactic acid and glycolic acid,
Alternatively, it is a cell structure having continuous pores formed from a copolymer of lactic acid and caprolactone, which is characterized by having a weight average molecular weight of more than 600,000. Here, the cell structure is a solid composed of a network in which the walls of cells, which are one structural unit that surrounds pores, are interconnected, and even if it is expressed as a porous body or a foam, there is an essential difference. There is no such thing.
【００１２】本発明のセル構造体は、上記のポリマー
を、ポリマーを溶解する溶剤と該溶剤より高沸点のポリ
マーを溶解しない非溶剤との混合溶媒に溶解し、このポ
リマー溶液から混合溶媒を溶剤の沸点より低温で気散さ
せることによってポリマーを沈殿させる方法（Solution
Precipitating Technique：ＳＰＴ）により得られるも
のである。そのセル構造形成の原理は以下のように考察
される。In the cell structure of the present invention, the above polymer is dissolved in a mixed solvent of a solvent that dissolves the polymer and a non-solvent that does not dissolve the polymer having a boiling point higher than that of the polymer, and the mixed solvent is removed from the polymer solution. A method of precipitating a polymer by evaporating it at a temperature lower than the boiling point of
Precipitating Technique (SPT). The principle of forming the cell structure is considered as follows.
【００１３】すなわち、上記のポリマー溶液から混合溶
媒を溶剤の沸点より低温で気散させると、沸点の低い溶
剤が優先的に気散して沸点の高い非溶剤の比率が次第に
上昇し、遂には、溶剤と非溶剤がある比率に達すると、
溶媒はポリマーを溶解できなくなる。そして、ある時
期、ある高い濃度に達するとポリマーが急激に沈殿し、
濃度の高くなった非溶剤のために沈殿したポリマーが収
縮、固化して固定化され、連結したポリマーの薄いセル
壁に混合溶媒が内包された状態のセル構造が形成され
る。その後は残りの溶剤がセル壁の一部分を破壊しなが
ら細孔をつくって気散し、沸点の高い非溶剤もまた徐々
に気散して、遂には非溶剤も完全に気散する。その結
果、セル壁に包まれていた溶媒の溜め跡が気孔として残
り、基本的に気孔が連続した連続気孔のセル構造体が得
られる。但し、これらの現象は条件により逐次、あるい
は同時に併行すると考えられる。That is, when the mixed solvent is vaporized from the above polymer solution at a temperature lower than the boiling point of the solvent, the solvent having the lower boiling point is preferentially vaporized and the ratio of the non-solvent having the higher boiling point is gradually increased, and finally , When solvent and non-solvent reach a certain ratio,
The solvent cannot dissolve the polymer. Then, at a certain time, when a high concentration is reached, the polymer rapidly precipitates,
The polymer precipitated due to the high concentration of the non-solvent contracts, solidifies and is fixed, and a cell structure in which the mixed solvent is enclosed in the thin cell wall of the linked polymer is formed. After that, the remaining solvent destroys a part of the cell wall to form pores and diffuses, and the non-solvent having a high boiling point also gradually diffuses, and finally the non-solvent also completely diffuses. As a result, the traces of the solvent stored in the cell wall remain as pores, and a cell structure of continuous pores having basically continuous pores can be obtained. However, it is considered that these phenomena occur concurrently or concurrently depending on the conditions.
【００１４】本発明のように重量平均分子量が６０万よ
り高いポリ乳酸又は上記の共重合体から形成された連続
気孔を有するセル構造体は、三次元的に連続するセル壁
が高分子量のポリマーからなるため、後述の実施例に示
すように低分子量のものより比較的強度（引張強度や曲
げ強度）があり、しかも、分子量が高いものほど生体内
での加水分解による低分子化が遅くなるので、生体内で
の強度持続の期間を長くすることができる。The cell structure having continuous pores formed of polylactic acid having a weight average molecular weight of more than 600,000 or the above-mentioned copolymer as in the present invention is a polymer having a high molecular weight in the three-dimensionally continuous cell walls. Therefore, as shown in the examples below, it has relatively higher strength (tensile strength and bending strength) than low molecular weight ones, and the higher the molecular weight, the slower the reduction of molecular weight due to hydrolysis in vivo. Therefore, the duration of strength in vivo can be extended.
【００１５】また、本発明のように材料ポリマー（ポリ
乳酸又は上記の共重合体）が６０万より高い重量平均分
子量を有するものであれば、ＳＰＴの方法によればポリ
マー溶液の濃度を調整することにより、発泡倍率が２〜
３０倍と広範囲に、しかも歪みのないセル構造体を容易
に得ることができる。その場合、ポリマー溶液を型内に
充填して混合溶媒を気散させる速さをコントロールする
と、厚さが１ｍｍ以上である所望の立体的な異形状のセ
ル構造体を容易に成形することができる。上記のような
高発泡倍率のセル構造体は、材料が量的に稀薄であるか
ら、生体内で加水分解して強度と形状を失って吸収され
る過程で、一時的に急激に多くの量の細片を生成するこ
とがないため、細片が惹起する異物反応による一過性の
炎症を起こす心配が殆どない。更に、上記のように成形
された肉厚のセル構造体は、生体内の損傷部位の複雑な
三次元空間に形状的にあてはめて埋入することにより、
一時的な補綴材（Prosthesis）や足場（Scaffold）とし
ての機能を発揮させることができる。If the material polymer (polylactic acid or the above-mentioned copolymer) has a weight average molecular weight higher than 600,000 as in the present invention, the concentration of the polymer solution is adjusted by the SPT method. As a result, the expansion ratio is 2
It is possible to easily obtain a cell structure having a wide area of 30 times and no distortion. In that case, by controlling the speed at which the polymer solution is filled into the mold and the mixed solvent is vaporized, a desired three-dimensionally irregularly shaped cell structure having a thickness of 1 mm or more can be easily formed. . Since the cell structure with high expansion ratio as described above is a material that is thin in quantity, it is temporarily and rapidly increased in quantity during the process of being hydrolyzed in vivo and losing its strength and shape. Since there is no generation of the strips, there is almost no fear of causing a temporary inflammation due to the foreign body reaction caused by the strips. Furthermore, the thick-walled cell structure molded as described above is geometrically fitted and embedded in a complicated three-dimensional space of a damaged site in a living body,
It can function as a temporary prosthesis or scaffold.
【００１６】斯かる重量平均分子量が６０万よりも遥か
に大きい高分子量のセル構造体は、放射線（γ線）や電
子線あるいは蒸気滅菌のような、ポリマー材料の内部ま
でも完全に滅菌できるような方法で滅菌したときに、そ
の分子量が低下してもなお、重量平均分子量が６０万以
上を維持することができる。これは、滅菌後でさえも高
い強度と分解して吸収されるまでのかなりの長い時間を
維持できるものである。Such a high molecular weight cell structure having a weight average molecular weight of far more than 600,000 can completely sterilize the inside of the polymer material such as radiation (γ ray), electron beam or steam sterilization. When sterilized by various methods, the weight average molecular weight can be maintained at 600,000 or more even if the molecular weight is reduced. It is capable of maintaining high strength and a fairly long time to decompose and be absorbed even after sterilization.
【００１７】ただし、初期の重量平均分子量Ｍｗが６０
万以上の高分子量であっても、Ｍｗ：６０万以下の任意
の低分子量のセル構造体をつくる場合は滅菌時間を長く
したり、滅菌回数を増せばよい。特に低分子量のポリマ
ー（Ｍｖ≒１０万以下、Ｍｗ≒３０万以下）を使って約
１０倍以上の高倍率のセル構造体をつくることは、本発
明法に限らず、他の方法においても実際は困難であるか
ら、高分子量で高倍率のセル構造体をつくって後に滅菌
を長時間行ったり、繰り返すことにより厚物、低分子
量、高倍率のセル構造体に変化させることは新規にして
且つ有効である。However, the initial weight average molecular weight Mw is 60.
Even if the molecular weight is 10,000 or more, in the case of producing a cell structure having an arbitrary low molecular weight of Mw: 600,000 or less, the sterilization time may be lengthened or the number of times of sterilization may be increased. In particular, it is not limited to the method of the present invention to actually form a cell structure having a high magnification of about 10 times or more by using a polymer having a low molecular weight (Mv≈100,000 or less, Mw≈300,000 or less). Since it is difficult, it is new and effective to make a cell structure with high molecular weight and high magnification and then sterilize it for a long time or repeat it to change to a thick, low molecular weight, high magnification cell structure. Is.
【００１８】凍結乾燥法によって得たＭｗ：６０万のス
ポンジは、上記の過酷な滅菌法では分子量の低下により
６０万よりもかなり低い、低分子量（例えばＭｗ：６０
万はＭｗ：３０万程度に低下する）の低倍率スポンジに
変化するので、３０万から６０万の間は空白となり、こ
の間の分子量を欲する用途に対応できない。The sponge having an Mw of 600,000 obtained by the freeze-drying method has a low molecular weight (for example, Mw: 60) which is considerably lower than 600,000 due to a decrease in the molecular weight in the above-mentioned severe sterilization method.
Since it changes to a low-magnification sponge with a Mw of about 300,000), it is blank between 300,000 and 600,000, and it cannot be used for applications that require a molecular weight during this period.
【００１９】[0019]
【発明の実施の形態】本発明のセル構造体に用いる材料
のポリ乳酸としては、Ｌ−乳酸のホモポリマーや、Ｌ−
乳酸とＤ−乳酸のランダムコポリマーが使用され、ま
た、共重合体としては、乳酸とグリコール酸、あるいは
乳酸とカプロラクトンのモル比が９９：１〜７５：２５
の範囲にあるものが使用される。グリコール酸やカプロ
ラクトンの比率が上記範囲より高くなると、得られるセ
ル構造体の耐加水分解性が低下し、早期に強度劣化を招
く恐れがあるので好ましくない。また高倍率体を得るこ
とが難しい。また、これらの共重合体以外にも、ポリ乳
酸とポリエチレングリコールの共重合体や、ポリ乳酸と
ポリプロピレングリコールとの共重合体も使用できる。BEST MODE FOR CARRYING OUT THE INVENTION Polylactic acid, which is a material used for the cell structure of the present invention, is a homopolymer of L-lactic acid or L-lactic acid.
A random copolymer of lactic acid and D-lactic acid is used, and as the copolymer, the molar ratio of lactic acid to glycolic acid or lactic acid to caprolactone is 99: 1 to 75:25.
Those in the range of are used. When the ratio of glycolic acid or caprolactone is higher than the above range, hydrolysis resistance of the obtained cell structure is lowered, which may lead to early strength deterioration, which is not preferable. Moreover, it is difficult to obtain a high magnification body. In addition to these copolymers, a copolymer of polylactic acid and polyethylene glycol or a copolymer of polylactic acid and polypropylene glycol can be used.
【００２０】これらのポリ乳酸や共重合体は、重量平均
分子量が６０万より高いものを使用することが必要であ
り、このような高分子量のポリ乳酸や共重合体を用いる
と、強度（引張強度や曲げ強度）があり、且つ、生体内
での強度維持期間が数ケ月以上と長い高発泡倍率のセル
構造体を得ることができる。ポリ乳酸や共重合体の重量
平均分子量が高くなればなるほど、セル構造体の硬度や
強度、強度保持期間等は向上するが、分子量があまり高
すぎるとポリマーが溶剤に溶け難くなるので、高発泡倍
率のセル構造体を得ることが難くなるから、重量平均分
子量が３００万以下のポリ乳酸や共重合体を使用するこ
とが望ましい。ポリ乳酸等の更に望ましい重量平均分子
量は６０万〜２００万の範囲である。また、場合によっ
ては、これらのポリ乳酸や共重合体に、重量平均分子量
が６０万以下とならない範囲内で、低分子量のものを適
量配合してもよい。このように低分子量のものを配合す
ると、セル構造体の初期の加水分解速度を適度に速める
ことが可能となる。It is necessary to use a polylactic acid or copolymer having a weight average molecular weight of more than 600,000. When such a polylactic acid or copolymer having a high molecular weight is used, the strength (tensile strength) It is possible to obtain a cell structure having a high expansion ratio, which has strength and bending strength) and has a long in-vivo strength maintenance period of several months or more. The higher the weight average molecular weight of polylactic acid or copolymer, the higher the hardness and strength of the cell structure, the strength retention period, etc., but if the molecular weight is too high, the polymer becomes difficult to dissolve in the solvent, so high foaming is achieved. Since it is difficult to obtain a cell structure having a magnification, it is desirable to use polylactic acid or a copolymer having a weight average molecular weight of 3,000,000 or less. A more desirable weight average molecular weight of polylactic acid or the like is in the range of 600,000 to 2,000,000. In addition, depending on the case, an appropriate amount of a low molecular weight compound may be blended with these polylactic acid and copolymers within a range where the weight average molecular weight does not become 600,000 or less. By blending such a low molecular weight compound, the initial hydrolysis rate of the cell structure can be appropriately increased.
【００２１】ここで、分子量及び分子量分布について記
述する。一般に、高分子の分子量は重量平均分子量Ｍ
ｗ、数平均分子量Ｍｎおよび粘度平均分子量Ｍｖのいず
れかを用いて表される。Ｍｎを求めるには末端基定量、
電子顕微鏡、浸透圧、蒸気圧、氷点降下および沸点上昇
などの方法があり、Ｍｗを求めるには光散乱、Ｘ線小角
散乱、沈降平衡、融液粘度による方法がある。しかし、
現在、最も簡便であり、一般に行われているのはＧＰＣ
（Gel Permeation Chromatography） による方法であ
る。そして、分子量分布を求めるには濁り度滴定法、超
遠心法、拡散法、あるいはＧＰＣによる方法等がある。
現在、最も簡便な方法であるＧＰＣ法によって測定した
Ｍｗ／Ｍｎ＝αを分子量分布として用いることが多い。
ＧＰＣ法で得られる平均分子量、分子量分布、αは使用
する分子篩いとしてのカラム内のゲルの種類によってそ
の値にかなりの幅がある。従って、ポリマーを実際に溶
液に溶かした粘度から測定した粘度平均分子量Ｍｖと対
比することにより、分子量の実際の大きさと分布を把握
することが肝要である。Here, the molecular weight and the molecular weight distribution will be described. Generally, the molecular weight of a polymer is the weight average molecular weight M
It is expressed using any one of w, number average molecular weight Mn, and viscosity average molecular weight Mv. To determine Mn, quantitative determination of end groups,
There are methods such as electron microscopy, osmotic pressure, vapor pressure, freezing point depression and boiling point increase, and there are methods based on light scattering, small angle X-ray scattering, sedimentation equilibrium, and melt viscosity for obtaining Mw. But,
GPC is currently the easiest and most commonly used
(Gel Permeation Chromatography). The turbidity titration method, ultracentrifugation method, diffusion method, GPC method, or the like can be used to obtain the molecular weight distribution.
At present, Mw / Mn = α measured by the GPC method, which is the simplest method, is often used as the molecular weight distribution.
The average molecular weight, molecular weight distribution, and α obtained by the GPC method have a considerable range depending on the type of gel in the column as the molecular sieve used. Therefore, it is important to grasp the actual size and distribution of the molecular weight by comparing with the viscosity average molecular weight Mv measured from the viscosity of the polymer actually dissolved in the solution.
【００２２】本発明のポリ乳酸あるいはその共重合体の
場合は、実際に使用するＧＰＣのカラムの種類、その連
結の数により異なるが、この種のポリマーの一般的な合
成法によって得たポリマーは経験的にはαはおよそ２〜
４の範囲であり、また、ＭｗとＭｖの比率Ｍｗ／Ｍｖは
およそ３〜４である。従って、Ｍｗが６０万以下の該ポ
リマーは、実際のＭｖは経験的に１５〜２０万以下に相
当する。この程度のＭｖのポリマーは、高い強度を要求
され、その強度を骨癒合に必要な３〜４ケ月間維持する
ことが必要な骨折固定材の原料ポリマーに使うには低き
に過ぎるので、高い強度が得られないことは周知であ
る。従って、本発明のセル構造体にあっても、高い強度
と適切な長期間の強度の維持は得られるものでない。ま
た、この程度までの分子量は低→中程度の分子量域であ
るから、分解・吸収の早さを調節するためにはあまり余
裕のあるものではない。In the case of the polylactic acid or its copolymer of the present invention, the polymer obtained by a general synthesis method of this type of polymer varies depending on the type of GPC column actually used and the number of connections. Empirically, α is about 2
4 and the ratio Mw / Mv of Mw / Mv is about 3-4. Therefore, the actual Mv of the polymer having Mw of 600,000 or less empirically corresponds to 150,000 to 200,000 or less. A polymer of Mv of this level is required to have a high strength, and is too low to be used as a raw material polymer for a fracture fixing material which needs to maintain the strength for 3 to 4 months required for bone union. It is well known that strength cannot be obtained. Therefore, even with the cell structure of the present invention, high strength and proper maintenance of strength for a long period of time cannot be obtained. In addition, the molecular weight up to this level is in the low-to-medium molecular weight range, so there is not much room for controlling the speed of decomposition / absorption.
【００２３】本発明のセル構造体は、上記のような高分
子量のポリ乳酸又は共重合体を、その溶剤とその溶剤よ
り高沸点の非溶剤との混合溶媒に溶解し、このポリマー
溶液から混合溶媒を溶剤の沸点より低温で気散させるこ
とによって、ポリ乳酸又は共重合体を沈殿させる溶液沈
殿法（Solution Precipitating Technique：ＳＰＴ）に
より得られるものであり、溶剤や非溶剤として以下のも
のが使用される。In the cell structure of the present invention, the high molecular weight polylactic acid or copolymer as described above is dissolved in a mixed solvent of the solvent and a non-solvent having a boiling point higher than that of the solvent, and mixed from the polymer solution. It is obtained by the solution precipitating technique (SPT) in which polylactic acid or a copolymer is precipitated by evaporating the solvent at a temperature lower than the boiling point of the solvent. The following are used as the solvent and non-solvent. To be done.
【００２４】即ち、溶剤としては、ポリ乳酸や共重合体
を溶解でき、常温よりやや高い温度で気散しやすい低沸
点の溶剤、例えば塩化メチレン（ＣＨ2Ｃｌ2）、クロロ
ホルム（ＣＨＣｌ3）、１，１−ジクロルエタン（ＣＨ3
ＣＨＣｌ2）などが使用される。この中では最も低い沸
点と最も高い蒸気圧を示す低毒性の塩化メチレンが最適
であり、クロロホルムも好適である。That is, as the solvent, a low boiling point solvent which can dissolve polylactic acid or a copolymer and easily disperses at a temperature slightly higher than room temperature, such as methylene chloride (CH 2 Cl 2 ), chloroform (CHCl 3 ), 1,1-dichloroethane (CH 3
CHCl 2 ) or the like is used. Of these, methylene chloride, which has the lowest boiling point and the highest vapor pressure and has low toxicity, is most suitable, and chloroform is also suitable.
【００２５】一方、非溶剤は、その沸点が上記の溶剤よ
り高く、且つ、上記の溶剤と相溶性があるものを使用す
る必要があり、相溶性に劣る非溶剤を用いると、発泡倍
率が高く均一で微細な気孔を有するセル構造体を得るこ
とが困難になる。この非溶剤の沸点は上限が１１０℃付
近（１気圧）までであり、溶剤と非溶剤との組合わせを
決める場合、溶剤の沸点よりもかなり高い沸点の非溶剤
を選ぶことが望ましい。非溶剤が１１０℃より高い沸点
を有するものであると、常温での蒸気圧が低く常温での
気散が遅すぎるために、セル構造体の製造に時間がかか
り、非溶剤がセル内に残留しやすくなる。また、非溶剤
と溶剤の沸点差が約１５℃より小さい場合は、溶剤が非
溶剤と共に気散し易くなるので、非溶剤の沈殿剤として
の働きが低下する。好ましい非溶剤としては、前記の塩
化メチレン等の溶剤と相溶性があり、沸点が６０℃〜１
１０℃（１気圧下）の範囲内にある一価アルコール、例
えばメタノール、エタノール、１−プロパノール、２−
プロパノール（イソプロピルアルコール）、２−ブタノ
ール、ｔｅｒ−ブタノール、ｔｅｒ−ペンタノールなど
が挙げられるが、毒性、臭などを考慮すると、エタノー
ル、１−プロパノール、２−プロパノールが特に好適に
使用される。また、これらの一価アルコールに少量の水
を加えた非溶剤も好適に使用される。水はアルコールよ
りもより強い沈殿剤としての働きを有し、ポリ乳酸や共
重合体の沈殿を促進するからである。On the other hand, it is necessary to use a non-solvent whose boiling point is higher than that of the above solvent and which is compatible with the above solvent. When a non-solvent having poor compatibility is used, the expansion ratio is high. It becomes difficult to obtain a cell structure having uniform and fine pores. The upper limit of the boiling point of the non-solvent is up to around 110 ° C. (1 atm), and when determining the combination of the solvent and the non-solvent, it is desirable to select a non-solvent having a boiling point considerably higher than the boiling point of the solvent. If the non-solvent has a boiling point higher than 110 ° C., the vapor pressure at room temperature is low and the vaporization at room temperature is too slow, so it takes time to manufacture the cell structure, and the non-solvent remains in the cell. Easier to do. On the other hand, if the difference in boiling point between the non-solvent and the solvent is less than about 15 ° C., the solvent is likely to evaporate together with the non-solvent, so that the function of the non-solvent as a precipitant is reduced. Preferred non-solvents are compatible with the above-mentioned solvents such as methylene chloride and have a boiling point of 60 ° C to 1
Monohydric alcohols within the range of 10 ° C (under 1 atm), such as methanol, ethanol, 1-propanol, 2-
Propanol (isopropyl alcohol), 2-butanol, ter-butanol, ter-pentanol and the like can be mentioned, but ethanol, 1-propanol and 2-propanol are particularly preferably used in view of toxicity and odor. Non-solvents obtained by adding a small amount of water to these monohydric alcohols are also preferably used. This is because water has a stronger function as a precipitant than alcohol and accelerates the precipitation of polylactic acid and copolymers.
【００２６】表１に、好ましい溶剤と非溶剤を列挙し、
それぞれの沸点と２０℃における蒸気圧を示す。また、
表２に、塩化メチレン、クロロホルムと各非溶剤との沸
点差及び蒸気圧差を示す。溶剤と非溶剤の組合わせは、
この表１の沸点と蒸気圧を勘案して適宜選択すればよ
く、溶剤に塩化メチレンやクロロホルムを選んだとき
は、表２に示す沸点差と蒸気圧差を勘案して非溶剤を選
択すればよい。Table 1 lists preferred solvents and non-solvents,
The respective boiling points and vapor pressures at 20 ° C. are shown. Also,
Table 2 shows the difference in boiling point and the difference in vapor pressure between methylene chloride and chloroform and each non-solvent. The combination of solvent and non-solvent
The solvent may be appropriately selected in consideration of the boiling point and vapor pressure in Table 1, and when methylene chloride or chloroform is selected as the solvent, a non-solvent may be selected in consideration of the boiling point difference and vapor pressure difference shown in Table 2. .
【表１】 [Table 1]
【表２】 [Table 2]
【００２７】ポリ乳酸や共重合体を溶解する混合溶媒
は、前記の溶剤と非溶剤の体積比率が一般に１０：１〜
１０：１０であればセル構造体を得ることができる。こ
れよりも溶剤の比率が大きいと、溶媒の気散終了時まで
ポリマーの溶解が続き、セル壁の沈殿が生ぜず、溶媒の
気散後に気泡を介在しない透明なポリマー塊ができるの
みである。一方、溶剤の比率が上記よりも小さい場合
は、僅かの溶剤が気散しただけでポリ乳酸等が一挙に沈
殿するため、セル間の溶着が不完全となり、セル間の物
理的つながりのない脆いセル構造体が出来上がったり、
型の形状とは全く異なる収縮、変形したセル構造体がで
きるので良くない。三次元空間的にセルが連結してしっ
かりした形状の安定なセル構造体が形成されるにふさわ
しい比率の範囲は、溶媒組成によって異なるが、１０：
１〜１０：７である。The mixed solvent for dissolving polylactic acid or the copolymer generally has a volume ratio of the above solvent to the non-solvent of 10: 1 to 1: 1.
If it is 10:10, a cell structure can be obtained. If the ratio of the solvent is larger than this, the polymer continues to be dissolved until the end of the vaporization of the solvent, the cell wall is not precipitated, and only a transparent polymer mass without bubbles is formed after the vaporization of the solvent. On the other hand, when the ratio of the solvent is smaller than the above, polylactic acid and the like are precipitated all at once with a slight amount of solvent being vaporized, resulting in incomplete welding between cells and brittleness without physical connection between cells. The cell structure is completed,
It is not good because it produces a contracted or deformed cell structure that is completely different from the shape of the mold. The range of the ratio suitable for forming a stable cell structure having a solid shape by connecting cells three-dimensionally spatially varies depending on the solvent composition, but is 10:
1 to 10: 7.
【００２８】上記の混合溶媒にポリ乳酸や共重合体を溶
解して調製したポリマー溶液は、型内に充填した後、溶
剤の沸点より低い温度、好ましくは２０℃以下の温度で
常圧又は減圧下に溶媒を気散させることが重要である。
溶剤の沸点以上の温度で溶媒を気散させると、溶剤が沸
騰してセル壁を破壊し、溶着するので、良質のセル構造
体を得ることはできない。この気散の工程を、気散した
溶媒を回収することのできる密閉された装置の中で行う
と、回収された溶媒を何度も繰り返して使用することが
でき、操作中に吸入することもないので安全かつ省資源
的である。また、ポリマー溶液の粘度を上げてセル壁の
固定化を図る目的で、溶媒を気散させる前に約１０℃以
下の低温に冷却して増粘し、減圧下に気散させる操作を
採用することも望ましい。この操作は肉厚のシート状や
異形状のセル構造体をつくる場合に有効である。A polymer solution prepared by dissolving polylactic acid or a copolymer in the above mixed solvent is filled in a mold, and then at a temperature lower than the boiling point of the solvent, preferably at a temperature of 20 ° C. or lower, at atmospheric pressure or reduced pressure. It is important to disperse the solvent below.
When the solvent is vaporized at a temperature equal to or higher than the boiling point of the solvent, the solvent boils, destroys the cell wall, and welds, so that a good cell structure cannot be obtained. When this gas diffusion step is performed in a sealed device capable of collecting the gaseous solvent, the collected solvent can be used repeatedly, and the solvent can be inhaled during the operation. It is safe and resource saving because there is no. Further, for the purpose of increasing the viscosity of the polymer solution and fixing the cell wall, an operation of cooling the solvent to a low temperature of about 10 ° C. or lower to thicken it and then vaporizing it under reduced pressure is adopted. Is also desirable. This operation is effective when making a thick sheet-like or irregularly shaped cell structure.
【００２９】このようにポリマー溶液から混合溶媒を気
散させると、数１００μｍ以下の薄いフィルム状やシー
ト状のセル構造体であれば、見ている間の短時間に製造
することができる。そして、１ｍｍ以上の厚肉のプレー
ト状又は異形状のセル構造体の場合も、型の深さや形状
を変えてポリマー溶液の充填量を増加させるだけで、少
し長い時間を要するが、同様に簡単に製造することがで
きる。このとき溶剤が型の全面から均等に気散できるよ
うに、型として、ポリ乳酸や共重合体を通過させないが
溶媒を通過させる微細な通気孔を無数に有する多孔質の
型、例えば素焼きの陶器製の型などを使用することも一
つの方法である。また、溶媒の気散を速めることと、構
造体内部のポリマー溶液の未沈殿部分への陥没と変形を
避けて形状を保つことを目的として、ポリマー溶液を約
１０℃以下の低温にて増粘し、減圧下に溶媒を強制的に
気散させる操作を採ることも望ましい一つの方法であ
る。ただし、溶媒の気散速度はポリマーの分子量、種
類、濃度、求めるセル構造体の厚さ、形状、倍率によっ
て微妙に調節する必要がある。このようにすれば、５ｃ
ｍ以上の厚さをもつブロック状あるいは異形状に成形さ
れたセル構造体を容易に製造することができる。By thus evaporating the mixed solvent from the polymer solution, a thin film-like or sheet-like cell structure having a thickness of several 100 μm or less can be manufactured in a short time while watching. In the case of a plate-shaped or irregularly shaped cell structure with a thickness of 1 mm or more, it takes a little longer time just by changing the mold depth and shape to increase the filling amount of the polymer solution, but it is also easy. Can be manufactured. At this time, as a mold, a porous mold that does not pass polylactic acid or a copolymer but has numerous fine ventilation holes that allow the solvent to pass, for example, a unglazed pottery, so that the solvent can be evenly diffused from the entire surface of the mold. Using a mold or the like is also one method. Further, for the purpose of accelerating the evaporation of the solvent and maintaining the shape of the polymer solution inside the structure while avoiding depression and deformation of the unprecipitated portion, the polymer solution is thickened at a low temperature of about 10 ° C. or lower. However, it is also a desirable method to forcibly diffuse the solvent under reduced pressure. However, the evaporation rate of the solvent needs to be delicately adjusted depending on the molecular weight, type and concentration of the polymer, the desired thickness, shape and magnification of the cell structure. In this way, 5c
It is possible to easily manufacture a block-shaped or irregularly-shaped cell structure having a thickness of m or more.
【００３０】セル構造体の発泡倍率は２〜３０倍の発泡
倍率、好ましくは５〜３０倍の高発泡倍率であることが
望ましく、このような発泡倍率のセル構造体は、生体内
での加水分解による細片の生成量が少ないため、異物反
応による一過性の炎症を起こす心配が殆どないという利
点を有する。It is desirable that the cell structure has a foaming ratio of 2 to 30 times, preferably 5 to 30 times, and a high foaming ratio of 5 to 30 times. Since the amount of small pieces produced by decomposition is small, there is an advantage that there is almost no fear of causing transient inflammation due to a foreign body reaction.
【００３１】セル構造体の発泡倍率を決定する要因に
は、ポリマー溶液の粘度、ポリマー濃度、ポリマーの分
子量、混合溶媒の組成比、溶媒の気散速度等が挙げられ
るが、ポリマー溶液が沈殿してセル構造体を形成する原
理からすれば、ポリマー濃度が最も重要な要因の一つで
ある。ポリマー濃度と発泡倍率は反比例の関係にあり、
ポリマー濃度が高くなるほど発泡倍率は低くなる。そし
て、ポリマー濃度が１０重量％より高くなると、５倍以
上の発泡倍率を有するセル構造体を得ることが難しくな
る。従って、高発泡倍率のセル構造体を得るためには、
ポリマー濃度を下げる必要があり、ポリマー濃度を２重
量％程度まで下げると、混合溶媒の組成比によって差異
はあるが、３０倍前後の発泡倍率を有するセル構造体を
得ることができる。しかし、ポリマー濃度を更に下げて
１重量％以下にすると、満足なセル構造体を得ることが
困難となる。Factors that determine the expansion ratio of the cell structure include the viscosity of the polymer solution, the polymer concentration, the molecular weight of the polymer, the composition ratio of the mixed solvent, the evaporation rate of the solvent, etc., but the polymer solution precipitates. The polymer concentration is one of the most important factors in terms of the principle of forming a cell structure by the method. There is an inverse relationship between the polymer concentration and the expansion ratio,
The higher the polymer concentration, the lower the expansion ratio. When the polymer concentration is higher than 10% by weight, it becomes difficult to obtain a cell structure having a foaming ratio of 5 times or more. Therefore, in order to obtain a cell structure having a high expansion ratio,
It is necessary to reduce the polymer concentration, and if the polymer concentration is reduced to about 2% by weight, a cell structure having a foaming ratio of about 30 times can be obtained, although there is a difference depending on the composition ratio of the mixed solvent. However, if the polymer concentration is further reduced to 1% by weight or less, it becomes difficult to obtain a satisfactory cell structure.
【００３２】また、ポリマーの分子量と発泡倍率の関係
は、ある分子量領域で発泡倍率が最も高くなり、分子量
がその領域より大きくなっても小さくなっても発泡倍率
は低下する傾向がある。後述の実施例のデーターから分
かるように、発泡倍率が最も高くなるポリマー（ポリ乳
酸又は共重合体）の重量平均分子量の領域は、Ｍｗ／Ｍ
ｖを３〜４とすると、７５〜１４０万ないし１０５〜１
４０万程度（粘度平均分子量では２５万〜３５万程度）
であり、ポリマーの重量平均分子量が６０万（粘度平均
分子量１５〜２０万）以下であり、特に４５万以下のと
きは発泡倍率の高いものを得難くなる。Regarding the relationship between the molecular weight of the polymer and the expansion ratio, the expansion ratio is highest in a certain molecular weight region, and the expansion ratio tends to decrease regardless of whether the molecular weight is higher or lower than that region. As can be seen from the data of Examples described below, the region of the weight average molecular weight of the polymer (polylactic acid or copolymer) having the highest expansion ratio is Mw / M.
If v is 3 to 4, 75 to 1.4 million to 105 to 1
About 400,000 (Viscosity average molecular weight is about 250,000-350,000)
And the weight average molecular weight of the polymer is 600,000 or less (viscosity average molecular weight 150,000 to 200,000), and particularly when it is 450,000 or less, it becomes difficult to obtain a polymer having a high expansion ratio.
【００３３】また、混合溶媒の組成比と発泡倍率の関係
については、後述の実施例のデーターから分かるよう
に、適当な溶媒の混合比の範囲内で非溶剤の比率が高く
なるほど、発泡倍率が高くなる関係にある。Regarding the relationship between the composition ratio of the mixed solvent and the expansion ratio, as will be understood from the data of the examples described later, the expansion ratio increases as the non-solvent ratio increases within the range of the appropriate solvent mixing ratio. There is a high relationship.
【００３４】従って、ポリマー濃度、ポリマーの分子
量、混合溶媒の組成比等を種々変化させれば、セル構造
体の発泡倍率を自由にコントロールすることができ、２
〜３０倍の発泡倍率を有するセル構造体を容易に製造す
ることができる。このような発泡倍率のセル構造体は、
連続気孔の平均孔径が３〜３００μｍ程度であり、この
範囲の中で１５０〜３００μｍ程度の孔径を選択すれ
ば、生体内の損傷部位に埋入したとき、体液や周囲の組
織細胞の侵入が容易であるので、組織再生や細胞移植の
ための生体内分解吸収性の基材として有用である。Therefore, the foaming ratio of the cell structure can be freely controlled by changing the polymer concentration, the molecular weight of the polymer, the composition ratio of the mixed solvent and the like.
A cell structure having a foaming ratio of up to 30 times can be easily manufactured. The cell structure having such a foaming ratio,
The average pore diameter of continuous pores is about 3 to 300 μm, and if a pore diameter of about 150 to 300 μm is selected within this range, it is easy for body fluid and surrounding tissue cells to invade when it is embedded in a damaged site in a living body. Therefore, it is useful as a biodegradable and absorbable base material for tissue regeneration and cell transplantation.
【００３５】[0035]
【実施例】以下、本発明の実施例を説明する。Embodiments of the present invention will be described below.
【００３６】［実施例１］溶剤に塩化メチレン（ＣＨ2
Ｃｌ2）、非溶剤（沈殿剤）にエタノール（Ｃ2Ｈ5Ｏ
Ｈ）を使用し、溶剤と非溶剤の体積比（溶剤／非溶剤）
を１０／０、１０／１、１０／３、１０／５、１０／
７、１０／９に変化させた６種類の混合溶媒に、重量平
均分子量が約１０５万（粘度平均分子量は約３０万、分
子量分布；分散度Ｍｗ／Ｍｎ＝２．５）のポリ−Ｌ−乳
酸を４ｇ／ｄｌの濃度に溶解してポリマー溶液を調製し
た。Example 1 Methylene chloride (CH 2
Cl 2 ) and ethanol (C 2 H 5 O in non-solvent (precipitating agent)
H) is used and the volume ratio of solvent and non-solvent (solvent / non-solvent)
10/0, 10/1, 10/3, 10/5, 10 /
Poly-L- with a weight average molecular weight of about 1.05 million (viscosity average molecular weight of about 300,000, molecular weight distribution; dispersity Mw / Mn = 2.5) in 6 kinds of mixed solvents changed to 7, 10/9 A polymer solution was prepared by dissolving lactic acid in a concentration of 4 g / dl.
【００３７】これらのポリマー溶液を、直径が１０ｃｍ
のシャーレに液面が１３ｍｍの高さとなるように注入
し、そのまま蓋をして室温（１０〜２０℃）で大気圧下
に静置してセル構造体をつくった。２４時間後にはポリ
マー溶液の溶媒は蒸散しており、溶媒の組成比（溶剤／
非溶剤）が１０／７と１０／９のもののみが僅かにエタ
ノール臭を残しているに過ぎなかった。その後、減圧乾
燥すると、ガスクロマトグラフで溶媒を検知できなくな
った。得られたセル構造体の性状等を下記の表３にまと
めて示す。These polymer solutions have a diameter of 10 cm.
The cell structure was prepared by injecting the liquid into a petri dish such that the height of the liquid surface was 13 mm, closing the lid as it was, and allowing it to stand at room temperature (10 to 20 ° C.) under atmospheric pressure. After 24 hours, the solvent of the polymer solution has evaporated, and the composition ratio of the solvent (solvent /
Only those with non-solvents of 10/7 and 10/9 left a slight odor of ethanol. Thereafter, when the solvent was dried under reduced pressure, the solvent could not be detected by gas chromatography. The properties of the obtained cell structure are summarized in Table 3 below.
【００３８】また、得られたセル構造体の硬度、曲げ強
度、引張強度を測定したところ、表３に示す結果が得ら
れた。なお、硬度はデュロメータ硬さの試験方法（ＪＩ
ＳＫ ７２１５）により、曲げ強度は３点曲げ試験方法
（ＪＩＳ Ｋ ７２２１）により、引張強度は万能試験
機により測定した（ＪＩＳ Ｋ ７１１３）ものであ
る。When the hardness, bending strength and tensile strength of the obtained cell structure were measured, the results shown in Table 3 were obtained. The hardness is a durometer hardness test method (JI
According to SK 7215), the bending strength is measured by a three-point bending test method (JIS K 7221), and the tensile strength is measured by a universal testing machine (JIS K 7113).
【表３】 [Table 3]
【００３９】さらに、１０／０及び１０／５の溶媒組成
比のものから得たセル構造体の３７℃のリン酸緩衝液中
における加水分解実験を行った結果は図１のようになっ
た。Further, the results of a hydrolysis experiment of cell structures obtained from the solvent composition ratios of 10/0 and 10/5 in a phosphate buffer at 37 ° C. are shown in FIG.
【００４０】以上の結果からすれば、塩化メチレンとエ
タノールの混合溶媒の場合は、溶媒の組成比（塩化メチ
レン／エタノール）が１０／１〜１０／６で比較的良好
なセル構造体が得られる。溶媒組成比が１０／５で発泡
倍率１０．０倍という高い値のセル構造体が得られ、発
泡倍率とともにセル構造体が厚くなった。これは溶液の
外気と接触している表面からポリマーが溶剤の気散によ
り直ちに沈殿、固化し、セル壁を形成して固定化したた
めに厚みが維持されたためと考えられる。この事実は、
ある発泡倍率のある厚みのセル構造体を要求するとき
は、溶媒の組成比とポリマー溶液の濃度を調節すればよ
いことを示唆している。From the above results, in the case of the mixed solvent of methylene chloride and ethanol, the composition ratio of the solvent (methylene chloride / ethanol) is 10/1 to 10/6, and a relatively good cell structure is obtained. . A cell structure having a solvent composition ratio of 10/5 and a high expansion ratio of 10.0 times was obtained, and the cell structure became thicker with the expansion ratio. It is considered that the thickness was maintained because the polymer immediately precipitated and solidified from the surface of the solution that was in contact with the outside air due to the vaporization of the solvent, and formed the cell wall to be immobilized. This fact is
It is suggested that when a cell structure having a certain expansion ratio and a certain thickness is required, the composition ratio of the solvent and the concentration of the polymer solution may be adjusted.
【００４１】溶剤のみの場合は、溶剤が気散完了するま
でポリマーを溶解しながら気散するので、溶剤の抜けが
らの孔は溶着して孔として残らない。そのために、ポリ
マー本来の透明なシートが形成された。In the case of using only the solvent, since the polymer is vaporized while being dissolved until the solvent is completely vaporized, the pores of the solvent escape are welded and do not remain as pores. As a result, a transparent sheet of the original polymer was formed.
【００４２】溶剤の比率が高い場合は、溶剤の気散によ
り体積が減少し、その分だけ厚みが低下したところで沈
殿、固化してセル壁の固定化がなされるために、セル構
造体の厚みと発泡倍率が低下したと考えられる。逆に初
期の非溶剤（沈殿剤）の比率が高い場合は、溶剤のわず
かな気散によって直ちに非溶剤の沈殿剤としての効果が
発現され、沈殿が一気に生成する。このとき、ポリマー
を溶解して連続したセル壁を形成するだけの量の溶剤が
残っていないので、孔が生成するときに大きく収縮した
り、沈殿したポリマーの粒子が単に溶着して連結体を形
成し、それが気孔を介在したような一種の焼結体のごと
きセル構造体を形成すると考えられる。実際に、溶媒組
成比が１０／７では沈殿、固化するときの収縮が厳し
く、表面に多くの皺のある変形したセル構造体が得ら
れ、溶媒組成比が１０／９では脆くて粒子が容易に脱落
するセル構造体が得られた。しかし、セル構造体を形成
する比率の上限は１０／１０と考えられる。この事実は
本発明のセル構造の生成機構を良く裏付けている。When the ratio of the solvent is high, the volume of the cell is reduced by the vaporization of the solvent, and when the thickness is reduced by that amount, the cell wall is fixed because it is precipitated and solidified to fix the cell wall. It is considered that the expansion ratio decreased. On the contrary, when the ratio of the initial non-solvent (precipitating agent) is high, the effect of the non-solvent as a precipitating agent is immediately exhibited due to the slight vaporization of the solvent, and the precipitate is generated all at once. At this time, there is not enough solvent left to dissolve the polymer to form a continuous cell wall, so that when the pores are formed, the solvent shrinks greatly, or the precipitated polymer particles are simply welded to form a connected body. It is believed that they form and that they form a cell structure such as a kind of sintered body with intervening pores. In fact, when the solvent composition ratio is 10/7, shrinkage during precipitation and solidification is severe, and a deformed cell structure with many wrinkles on the surface is obtained. When the solvent composition ratio is 10/9, the particles are brittle and particles are easily formed. Was obtained. However, the upper limit of the ratio for forming the cell structure is considered to be 10/10. This fact supports the generation mechanism of the cell structure of the present invention.
【００４３】また、溶媒の組成比が１０／１、１０／
３、１０／５となるに従って発泡倍率は大きくなる。そ
れにともなって硬度、強度ともに小さくなっている。こ
れは、発泡倍率が大きくなると、気孔の数あるいはその
大きさが大きくなるために、セルの壁の厚さが薄くなっ
て強度が低下したと考えられる。The composition ratio of the solvent is 10/1, 10 /
The expansion ratio increases as the ratio becomes 3, 10/5. Along with that, both hardness and strength have decreased. It is considered that when the expansion ratio becomes large, the number of pores or the size thereof becomes large, so that the wall thickness of the cell becomes thin and the strength is lowered.
【００４４】更に、３７℃リン酸緩衝液中における加水
分解実験では、溶媒の組成比が１０／０のものから得た
非セル構造の均質な固体と比較して、溶媒の組成比が１
０／５のものから得た発泡倍率の高いセル構造体は、水
が表面の細孔から内部に容易に浸透し水との接触面積が
拡がるために、分解が速くなったと考えられる。Further, in the hydrolysis experiment in a phosphate buffer at 37 ° C., the composition ratio of the solvent was 1 compared with the homogeneous solid of non-cell structure obtained from the composition ratio of the solvent of 10/0.
It is considered that the cell structure having a high expansion ratio of 0/5 was decomposed quickly because water easily penetrated from the surface pores to the inside and the contact area with water was expanded.
【００４５】［実施例２］溶媒の組成比（ＣＨ2Ｃｌ2／
Ｃ2Ｈ5ＯＨ）を１０／５に固定し、実施例１のポリ−Ｌ
−乳酸の濃度を１．０、２．０、３．０、４．０、５．
０、７．０ｇ／ｄｌに変えてポリマー溶液を調製した。
そして、これらのポリマー溶液を実施例１と同形のシャ
ーレに充填し、同様にしてセル構造体を得た。得られた
セル構造体の性状と、硬度、曲げ強度、引張強度を下記
表４にまとめて示す。Example 2 Solvent composition ratio (CH 2 Cl 2 /
C 2 H 5 OH) was fixed at 10/5, and poly-L of Example 1 was fixed.
-Lactic acid concentrations of 1.0, 2.0, 3.0, 4.0, 5.
A polymer solution was prepared by changing the amount to 0 and 7.0 g / dl.
Then, these polymer solutions were filled in a petri dish having the same shape as in Example 1, and a cell structure was obtained in the same manner. The properties, hardness, bending strength, and tensile strength of the obtained cell structure are summarized in Table 4 below.
【表４】 [Table 4]
【００４６】この結果から、発泡倍率が濃度に逆比例的
に依存することが明らかである。実施例１と同様にポリ
マー濃度が小さくなると、セル構造体の発泡倍率は大き
くなるが、それに伴って硬度、曲げ強度、引張強度は小
さくなった。これはセル構造体の気孔の数と大きさがポ
リマー濃度の減少に伴って増加し、セル壁の強度が脆く
なったためと考えられる。From this result, it is clear that the expansion ratio depends inversely on the concentration. When the polymer concentration decreased as in Example 1, the expansion ratio of the cell structure increased, but the hardness, bending strength, and tensile strength decreased accordingly. It is considered that this is because the number and size of the pores of the cell structure increased as the polymer concentration decreased, and the strength of the cell wall became brittle.
【００４７】［実施例３］実施例１で用いたポリ−Ｌ−
乳酸を、塩化メチレンとエタノールと水の混合溶媒（Ｃ
Ｈ2Ｃｌ2／Ｃ2Ｈ5ＯＨ／Ｈ2Ｏ＝１０／５／０．３）に
４ｇ／ｄｌの濃度で溶解してポリマー溶液を調製した。Example 3 Poly-L-used in Example 1
Lactic acid is mixed solvent of methylene chloride, ethanol and water (C
H 2 Cl 2 / C 2 H 5 OH / H 2 O = 10/5 / 0.3) was dissolved at a concentration of 4 g / dl to prepare a polymer solution.
【００４８】このポリマー溶液を、型内に液面が８ｃｍ
の高さとなるまで充填し、５日間、室温、常圧下に静置
した。その結果、厚さが３．１ｍｍ、発泡倍率が約１０
倍のセル構造体が得られた。このセル構造体は実施例１
の溶媒組成比が１０／１の場合のそれよりも硬かった。
これは水の影響によりポリマーの沈殿、固化が急激であ
り、結晶化度がやや高くなったこと、およびセル壁の固
定が強固になったためと考えられる。This polymer solution was placed in a mold with a liquid level of 8 cm.
The mixture was filled to the height of 10 mm, and left standing at room temperature and normal pressure for 5 days. As a result, the thickness is 3.1 mm and the expansion ratio is about 10.
Double cell structure was obtained. This cell structure is shown in Example 1.
It was harder than that when the solvent composition ratio was 10/1.
It is considered that this is because the precipitation and solidification of the polymer were rapid due to the influence of water, the crystallinity was slightly high, and the cell wall was firmly fixed.
【００４９】［実施例４］溶媒の組成比（ＣＨ2Ｃｌ2／
Ｃ2Ｈ5ＯＨ）を１０／５、ポリマー濃度を２ｇ／ｄｌに
固定し、Ｍｗが約１４０万（Ｍｖ：約４０万）、Ｍｗが
約１０５万（Ｍｖ：約３０万）、Ｍｗが約６５万（Ｍ
ｖ：約１８．５万）のポリ−Ｌ−乳酸をそれぞれ用い
て、実施例１と同様の方法でセル構造体を得た。得られ
たセル構造体の硬度、曲げ強度、引張強度を表５に示
す。[Example 4] Composition ratio of solvent (CH2Cl2 /
C2H5OH) is fixed at 10/5 and the polymer concentration is 2 g / dl. Mw is about 1.4 million (Mv: about 400,000), Mw is about 1.05 million (Mv: about 300,000), Mw is about 650,000 (M
(v: about 185,000) and using each of the poly-L-lactic acids, a cell structure was obtained in the same manner as in Example 1. Table 5 shows the hardness, bending strength, and tensile strength of the obtained cell structure.
【表５】 [Table 5]
【００５０】その結果、重量平均分子量が大きくなる
と、セル構造体の硬度、強度とも大きくなった。また、
Ｍｗが約１０５万のものとＭｗが約６５万のものを比較
すれば、Ｍｗが約６５万のセル構造体の方が発泡倍率が
小さいにもかかわらず、硬度、強度とも小さな値を示し
た。これは、平均分子量の違いがセル構造体の形成の難
易と関係し、Ｍｗが６０万より高いときのポリマー粘度
が本法によってセル構造体を容易に形成しやすいことの
裏付けである。そして良質のセル構造体の物性がセルの
均質さ、気孔の大きさ、数、セル壁の硬さにより影響を
受けたためと考えられる。As a result, the hardness and strength of the cell structure increased as the weight average molecular weight increased. Also,
Comparing the Mw of about 1.05 million and the Mw of about 650,000, the cell structure having an Mw of about 650,000 showed a smaller value in both hardness and strength, although the expansion ratio was smaller. . This is a proof that the difference in the average molecular weight is related to the difficulty of forming the cell structure, and that the polymer viscosity when Mw is higher than 600,000 easily forms the cell structure by this method. It is considered that the physical properties of the good quality cell structure were affected by the homogeneity of the cells, the size and number of the pores, and the hardness of the cell wall.
【００５１】［比較例１］Ｍｗが約６０万（Ｍｖ：約１
５万）、Ｍｗが約４０万（Ｍｖ：約１１．５万）のポリ
−Ｌ−乳酸をそれぞれ使用し、実施例４と同様にして溶
液沈殿法によりセル構造体を得た。このものは、実施例
４のセル構造体とは異なり、多孔質粒子が集合したよう
なセル構造体であった。この構造体の硬度、曲げ強度、
引張強度は表６に示すように、Ｍｗが６０万より高い表
５のセル構造体の値と比較すると小さく、脆弱な物質で
あった。[Comparative Example 1] Mw is about 600,000 (Mv: about 1)
50,000) and Mw of about 400,000 (Mv: about 115,000) were used, and a cell structure was obtained by the solution precipitation method in the same manner as in Example 4. This was a cell structure in which porous particles were aggregated, unlike the cell structure of Example 4. The hardness, bending strength of this structure,
As shown in Table 6, the tensile strength was small as compared with the value of the cell structure of Table 5 having Mw higher than 600,000, and it was a brittle substance.
【表６】 [Table 6]
【００５２】この事実により、Ｍｗが６０万より高いも
は、溶液沈殿法によって高倍率、肉厚、均一な気泡を有
して機械的強度にも優れたセル構造体を形成することが
明らかである。From this fact, it is clear that a cell structure having a Mw of more than 600,000 has a high magnification, a wall thickness, uniform cells and excellent mechanical strength by the solution precipitation method. is there.
【００５３】［比較例２］Ｍｗが約１４０万（Ｍｖ：約
４０万）、Ｍｗが約１０５万（Ｍｖ：約３０万）、Ｍｗ
が約６５万（Ｍｖ：約１８．５万）、Ｍｗが約６０万
（Ｍｖ：約１５万）、Ｍｗが約４０万（Ｍｖ：約１１．
５万）のポリ−Ｌ−乳酸をそれぞれ用いて溶液沈殿法に
よりセル構造体を得た。そして、これらのセル構造体を
加圧蒸気で滅菌した後の重量平均分子量を測定した。そ
の結果を表７に示す。Comparative Example 2 Mw of about 1.4 million (Mv: about 400,000), Mw of about 1.05 million (Mv: about 300,000), Mw
Is about 650,000 (Mv: about 18,000), Mw is about 600,000 (Mv: about 150,000), Mw is about 400,000 (Mv: about 110,000).
A cell structure was obtained by the solution precipitation method using each of 50,000 poly-L-lactic acids. Then, the weight average molecular weight after sterilizing these cell structures with pressurized steam was measured. The results are shown in Table 7.
【表７】 [Table 7]
【００５４】この表７から判るように、Ｍｗが６０万
（Ｍｖ：１５万）より大きい分子量のポリ−Ｌ−乳酸を
用いたセル構造体は、蒸気滅菌により分子量が低下して
も尚かなりの大きさの重量平均分子量を残しており、生
体内でかなりの時間、分解せずに残存する可能性がある
のに比べ、Ｍｗが６０万（Ｍｖ：１５万）以下のポリ−
Ｌ−乳酸を用いたセル構造体は、１回の滅菌後にＭｗが
４０万以下の低分子量となる。従って、生体内の補綴材
や足場として利用するには、前者は分解して低分子量に
なるまでに要する時間が適度であるから実用的である
が、後者は本来その強度が不足しているが、加えて分解
してより低分子になり吸収されるのが早すぎるので実用
的でないと言える。As can be seen from Table 7, the cell structure using poly-L-lactic acid having a molecular weight of Mw of more than 600,000 (Mv: 150,000) is still considerable even if the molecular weight is lowered by steam sterilization. It has a large weight average molecular weight and may remain without being decomposed in vivo for a considerable period of time, whereas it has a poly-molecular weight of Mw of 600,000 (Mv: 150,000) or less.
The cell structure using L-lactic acid has a low molecular weight of Mw of 400,000 or less after one sterilization. Therefore, in order to use it as a prosthesis or scaffold in a living body, the former is practical because the time required for decomposition into a low molecular weight is appropriate, but the latter originally lacks its strength. In addition, it can be said to be impractical because it decomposes into smaller molecules and is absorbed too quickly.
【００５５】［実施例５］重量平均分子量Ｍｗが１０５
万（粘度平均分子量Ｍｖ：３０万）のポリ−Ｌ−乳酸を
用いて、溶媒の組成比（ＣＨ2Ｃｌ2／Ｃ2Ｈ5ＯＨ）を１
０／１〜１０／６、濃度を１〜４ｇ／ｄｌの範囲となる
ようにポリマー溶液を調製し、実施例１と同様の方法で
セル構造体を得た。Example 5 The weight average molecular weight Mw is 105.
The composition ratio (CH 2 Cl 2 / C 2 H 5 OH) of the solvent was 1 using poly-L-lactic acid of 10,000 (viscosity average molecular weight Mv: 300,000).
A polymer solution was prepared so that the concentration was 0/1 to 10/6 and the concentration was 1 to 4 g / dl, and a cell structure was obtained by the same method as in Example 1.
【００５６】このセル構造体の断面を走査電子顕微鏡
（ＳＥＭ）を用いて観察し、セル構造体の気孔の大きさ
を測定した。その結果を表８に示す。The cross section of this cell structure was observed with a scanning electron microscope (SEM) to measure the size of the pores of the cell structure. Table 8 shows the results.
【表８】 [Table 8]
【００５７】［実施例６］グリコール酸（ＧＡ）とＬ−
乳酸（ＬＡ）の共重合体（ＧＡ／ＬＡのモル比：１０／
９０、重量平均分子量Ｍｗ：７３万）を、溶媒の組成比
（ＣＨ2Ｃｌ2／Ｃ2Ｈ5ＯＨ）が１０／３、１０／５であ
る混合溶媒に、４ｇ／ｄｌのポリマー濃度となるように
溶解し、実施例１と同様の方法によりセル構造体を得
た。このセル構造体の性状、硬度、強度等を表９に示
す。[Example 6] Glycolic acid (GA) and L-
Lactic acid (LA) copolymer (GA / LA molar ratio: 10 /
90, weight average molecular weight Mw: 730,000) in a mixed solvent having a solvent composition ratio (CH 2 Cl 2 / C 2 H 5 OH) of 10/3 and 10/5, resulting in a polymer concentration of 4 g / dl. Thus, a cell structure was obtained by the same method as in Example 1. Table 9 shows the properties, hardness, strength and the like of this cell structure.
【表９】 [Table 9]
【００５８】この結果、グリコール酸が１０％モル比結
合することにより、Ｌ−乳酸単体のセル構造体よりも発
泡倍率、強度は小さくなるが、硬度はほとんど同等であ
った。しかし、ＰＬＬＡのセル構造体と比較すると、や
や軟らかいセル構造体であった。As a result, when the glycolic acid was bonded at a molar ratio of 10%, the expansion ratio and the strength were smaller than the cell structure of L-lactic acid alone, but the hardness was almost the same. However, the cell structure was slightly softer than that of the PLLA cell structure.
【００５９】なお、乳酸−カプロラクトン共重合体も同
様にしてセル構造体をつくることができる。A lactic acid-caprolactone copolymer can also be used to form a cell structure in the same manner.
【００６０】[0060]
【発明の効果】以上の説明から理解できるように、本発
明のセル構造体は、硬度や強度（曲げ強度、引張強度）
があり、加水分解により強度を失う期間が早くないの
で、生体内で数ケ月のあいだ強度を維持することがで
き、しかも、製造が簡単で有害なベンゼン等の溶剤が全
く含有、残存しないため安全であり、生体材料として極
めて有用である。そして、１ｍｍ以上の厚肉のセル構造
体は、生体内の損傷部位の複雑な三次元空間に形状的に
あてはめて埋入することにより、一時的な補綴材や足場
として、或は移植細胞の増殖用基材として機能を発揮さ
せることができる。また、この２〜３０倍の発泡倍率の
セル構造体は、生体内での加水分解によって生ずる細片
の量が少ないため、異物反応による一過性の炎症を起こ
す心配が殆どなく、更に、３〜３００μｍの平均孔径を
任意に有するようにすることのできるセル構造体は、体
液、周囲組織細胞の侵入やフィブリン糊、ゼラチン糊等
の生体接着剤の含浸もまた容易である。As can be understood from the above description, the cell structure of the present invention has hardness and strength (bending strength, tensile strength).
Since it does not lose strength quickly due to hydrolysis, it can maintain its strength in vivo for several months, and is easy to manufacture and does not contain harmful benzene or other solvents at all and remains safe. And is extremely useful as a biomaterial. A cell structure with a thickness of 1 mm or more is geometrically fitted and embedded in a complicated three-dimensional space at a damaged site in a living body to be used as a temporary prosthesis or scaffold, or as a transplant cell. It can function as a base material for proliferation. In addition, since the cell structure having a foaming ratio of 2 to 30 times has a small amount of fine particles generated by hydrolysis in the living body, there is almost no fear of causing transient inflammation due to a foreign body reaction. The cell structure capable of arbitrarily having an average pore size of ˜300 μm is also easy to invade body fluid, surrounding tissue cells and impregnated with a bioadhesive such as fibrin glue or gelatin glue.
【図１】本発明の実施例のセル構造体についての加水分
解期間と粘度平均分子量との関係を示すグラフである。FIG. 1 is a graph showing the relationship between the hydrolysis period and the viscosity average molecular weight for cell structures of Examples of the present invention.
Claims (7)
重合体、又は乳酸とカプロラクトンとの共重合体から形
成された連続気孔を有するセル構造体であって、上記の
ポリ乳酸又は共重合体の重量平均分子量が６０万より高
いことを特徴とする生体内分解吸収性セル構造体。1. A cell structure having continuous pores formed from polylactic acid, a copolymer of lactic acid and glycolic acid, or a copolymer of lactic acid and caprolactone, wherein the polylactic acid or copolymer A biodegradable and absorbable cell structure characterized in that the weight average molecular weight of the coalescence is higher than 600,000.
リ乳酸又は共重合体を、その溶剤とその溶剤より高沸点
の非溶剤との混合溶媒に溶解し、このポリマー溶液から
混合溶媒を溶剤の沸点より低温で気散させることによ
り、前記のポリ乳酸又は共重合体を沈殿させて形成した
請求項１に記載の生体内分解吸収性セル構造体。2. A polylactic acid or copolymer having a weight average molecular weight of more than 600,000 is dissolved in a mixed solvent of the solvent and a non-solvent having a boiling point higher than that of the solvent, and the mixed solvent is removed from the polymer solution. The biodegradable and absorbable cell structure according to claim 1, which is formed by causing the polylactic acid or the copolymer to precipitate by being vaporized at a temperature lower than the boiling point of.
項２に記載の生体内分解吸収性セル構造体。3. The biodegradable and absorbable cell structure according to claim 1, which has a thickness of 1 mm or more.
し請求項３のいずれかに記載の生体内分解吸収性セル構
造体。4. The biodegradable and absorbable cell structure according to any one of claims 1 to 3, wherein the expansion ratio is 2 to 30 times.
である請求項１ないし請求項４のいずれかに記載の生体
内分解吸収性セル構造体。5. The biodegradable and absorbable cell structure according to claim 1, wherein the continuous pores have an average pore diameter of about 3 to 300 μm.
り、非溶剤が６０〜１１０℃（１気圧下）の範囲内で沸
点を有する一価アルコール又は該アルコールと少量の水
である請求項２に記載の生体内分解吸収性セル構造体。6. The solvent according to claim 2, wherein the solvent is methylene chloride or chloroform, and the non-solvent is a monohydric alcohol having a boiling point within the range of 60 to 110 ° C. (under 1 atmosphere) or the alcohol and a small amount of water. In vivo degradable and absorbable cell structure.
のセル構造体を放射線滅菌又は蒸気滅菌した重量平均分
子量が６０万以下の生体内分解吸収性セル構造体。7. A biodegradable and absorbable cell structure having a weight average molecular weight of 600,000 or less obtained by subjecting the cell structure according to any one of claims 1 to 6 to radiation sterilization or steam sterilization.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP26076995A JP3610504B2 (en) | 1995-09-12 | 1995-09-12 | Biodegradable absorbable cell structure |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP26076995A JP3610504B2 (en) | 1995-09-12 | 1995-09-12 | Biodegradable absorbable cell structure |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0975442A true JPH0975442A (en) | 1997-03-25 |
| JP3610504B2 JP3610504B2 (en) | 2005-01-12 |
Family
ID=17352479
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP26076995A Expired - Lifetime JP3610504B2 (en) | 1995-09-12 | 1995-09-12 | Biodegradable absorbable cell structure |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3610504B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005046538A (en) * | 2003-07-31 | 2005-02-24 | Jms Co Ltd | Porous body for medical treatment and method for manufacturing it |
-
1995
- 1995-09-12 JP JP26076995A patent/JP3610504B2/en not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005046538A (en) * | 2003-07-31 | 2005-02-24 | Jms Co Ltd | Porous body for medical treatment and method for manufacturing it |
Also Published As
| Publication number | Publication date |
|---|---|
| JP3610504B2 (en) | 2005-01-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Ma et al. | Synthetic nano‐scale fibrous extracellular matrix | |
| US5102983A (en) | Process for preparing foamed, bioabsorbable polymer particles | |
| Sarazin et al. | Controlled preparation and properties of porous poly (L-lactide) obtained from a co-continuous blend of two biodegradable polymers | |
| US6562374B1 (en) | Biodegradable porous polymer scaffolds for tissue engineering prepared from an effervescent mixture and its preparation | |
| US7557167B2 (en) | Polyester compositions, methods of manufacturing said compositions, and articles made therefrom | |
| US5948020A (en) | Implantable bioresorbable membrane and method for the preparation thereof | |
| JP5085128B2 (en) | Tissue repair and replacement | |
| US9968711B2 (en) | Bone regeneration using biodegradable polymeric nanocomposite materials and applications of the same | |
| US6861087B2 (en) | Preparation method of biodegradable porous polymer scaffolds having an improved cell compatibility for tissue engineering | |
| Sultana | Biodegradable polymer-based scaffolds for bone tissue engineering | |
| KR20130027572A (en) | Biodegradable film having honeycomb structure | |
| Liu et al. | Surface modification of porous PLGA scaffolds with plasma for preventing dimensional shrinkage and promoting scaffold–cell/tissue interactions | |
| JP3451417B2 (en) | Bioceramic-containing cell structure and method for producing the same | |
| KR100464930B1 (en) | Barrier membrance for guided tissue regeneration and the preparation thereof | |
| JP3586815B2 (en) | Manufacturing method of cell structure | |
| WO2009045176A1 (en) | Method of making a scaffold for tissue and bone applications | |
| JP3610504B2 (en) | Biodegradable absorbable cell structure | |
| US20030146532A1 (en) | Process for preparing porous bioresorbable material having interconnected pores | |
| JP3721343B2 (en) | Cell structure containing bioceramics | |
| KR0180585B1 (en) | Biodegradability shielding film for alveolar organ | |
| WO2004075939A1 (en) | Biodegradable resin, medical material for regeneration containing calcium phosphate and process for producing the same | |
| US20040099979A1 (en) | Process for preparing porous material having interconnected pores | |
| Budnicka et al. | Manufacturing of substitutes for spongy bone with increased absorbability | |
| EP1325755B1 (en) | Process for preparing porous bioresorbable material having interconnected pores | |
| Koelling et al. | In vitro real-time aging and characterization of poly (L/D-lactic acid) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20040907 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20041007 |
|
| R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20071029 Year of fee payment: 3 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20081029 Year of fee payment: 4 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20081029 Year of fee payment: 4 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20091029 Year of fee payment: 5 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20091029 Year of fee payment: 5 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20091029 Year of fee payment: 5 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20101029 Year of fee payment: 6 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20101029 Year of fee payment: 6 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20111029 Year of fee payment: 7 |
|
| S531 | Written request for registration of change of domicile |
Free format text: JAPANESE INTERMEDIATE CODE: R313531 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20111029 Year of fee payment: 7 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20111029 Year of fee payment: 7 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20121029 Year of fee payment: 8 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20121029 Year of fee payment: 8 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20121029 Year of fee payment: 8 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20131029 Year of fee payment: 9 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| EXPY | Cancellation because of completion of term |