JP5468783B2 - Tissue regeneration film - Google Patents
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- JP5468783B2 JP5468783B2 JP2009004628A JP2009004628A JP5468783B2 JP 5468783 B2 JP5468783 B2 JP 5468783B2 JP 2009004628 A JP2009004628 A JP 2009004628A JP 2009004628 A JP2009004628 A JP 2009004628A JP 5468783 B2 JP5468783 B2 JP 5468783B2
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Description
本発明は、神経や腱を手術した際に有用な組織再生用のフィルムに関する。さらに詳しくは、末梢神経組織や腱の手術をした後の損傷部位や縫合部位に巻きつけることで、自然治癒力による組織再生を最大限に活かすことができる組織再生用の人工のフィルムに関する。 The present invention relates to a tissue regeneration film useful when a nerve or a tendon is operated. More specifically, the present invention relates to an artificial film for tissue regeneration that can make maximum use of tissue regeneration by natural healing power by wrapping around a damaged site or a suture site after surgery for peripheral nerve tissue or tendon.
末梢神経組織を手術した際に神経再生を促すために使用される人工材料としては、これまで筒状またはチューブ状の生分解性高分子材料がいくつか報告されている。例えば特許文献１には、生体吸収性高分子からなる管状被覆材と、前記管状被覆材の管腔内に前記管状被覆材の長手方向に略平行に、管腔占有率が１０〜６０％となるように配置された、生体吸収性合成高分子からなる繊維の束とを含有する神経再生チューブが記載されている。しかしながら、本発明のような平面フィルム状の人工材料よりなる神経再生材料については報告されていない。 As an artificial material used for promoting nerve regeneration when a peripheral nerve tissue is operated, several biodegradable polymer materials having a cylindrical shape or a tube shape have been reported so far. For example, Patent Document 1 discloses that a tubular covering material made of a bioabsorbable polymer and a lumen occupation ratio of 10 to 60% in the lumen of the tubular covering material, approximately parallel to the longitudinal direction of the tubular covering material. A nerve regeneration tube containing a bundle of fibers made of a bioabsorbable synthetic polymer arranged in such a manner is described. However, no nerve regeneration material made of an artificial material in the form of a flat film as in the present invention has been reported.
腱の手術時においても、組織再生を促すために用いるための人工材料として、いくつか報告がある。たとえば特許文献２には、生分解性材料で成型された糸状物で形成された長手方向の中空部を有するメッシュ構造の筒状体であって、その中空部長手方向に、生分解性材料で成型された糸状物の束が充填されている腱もしくは靱帯組織再生器具が記載されている。しかしながら、本発明のような平面フィルム状の人工材料よりなる腱の再生材料については記載されていない。 There have been several reports as artificial materials for use in promoting tissue regeneration even during tendon surgery. For example, Patent Document 2 discloses a tubular body having a mesh structure having a hollow portion in the longitudinal direction formed of a thread-like material molded from a biodegradable material, and the biodegradable material is formed in the longitudinal direction of the hollow portion. A tendon or ligament tissue regeneration device is described that is filled with a bundle of molded filaments. However, there is no description of a tendon regenerating material made of an artificial material in the form of a flat film as in the present invention.
特許文献３には、手術によって傷つけられた生体組織表面が癒着するのを防止するために生分解性高分子からなるハニカム構造を有するフィルムが記載されており、そのフィルムは癒着防止材として有用であることが記載されている。しかしながら、手術後の神経や腱の再生を促す材料としては何ら知見がなく、示唆もされていない。 Patent Document 3 describes a film having a honeycomb structure made of a biodegradable polymer in order to prevent adhesion of the surface of a living tissue damaged by surgery, and the film is useful as an adhesion preventing material. It is described that there is. However, there is no knowledge or suggestion as a material that promotes regeneration of nerves and tendons after surgery.
本発明が解決しようとする課題は、神経や腱の再生に優れた新しいフィルム状の人工材料を提供することである。特に外科的手術において神経や腱を縫合した際や、神経や腱の周囲の組織が傷ついた後の組織の再生を促すために用いる生分解性の人工材料を提供することである。 The problem to be solved by the present invention is to provide a new film-like artificial material excellent in regeneration of nerves and tendons. In particular, it is an object to provide a biodegradable artificial material that is used to promote tissue regeneration when a nerve or tendon is sutured in a surgical operation or after tissue around the nerve or tendon is damaged.
本発明の発明者らは、神経や腱の再生に優れた材料について鋭意研究した。従来の神経再生材料は、円筒状やチューブ状の生分解性材料が用いられている。そして、特許文献１に記載されている通り、手術後の日常生活において患部にかかる応力による変形を防ぐために、一定の力学強度を有した円筒体が好ましいとされてきた。しかし驚くべきことに、薄くてやわらかく、変形が容易なフィルムであり、その片面にだけ特定の構造を有する生分解性の高分子フィルムが神経や腱の再生に優れていることを見出し、本発明を完成するに至った。 The inventors of the present invention diligently studied materials excellent in regeneration of nerves and tendons. Conventional nerve regeneration materials use cylindrical or tube-shaped biodegradable materials. And, as described in Patent Document 1, in order to prevent deformation due to stress applied to the affected part in daily life after surgery, a cylindrical body having a certain mechanical strength has been considered preferable. Surprisingly, however, it was found that a biodegradable polymer film having a specific structure only on one side of the film is thin, soft and easily deformed, and is excellent in regeneration of nerves and tendons. It came to complete.
すなわち本発明は、生分解性の高分子材料からなるフィルムであって、フィルム面に沿って液体が流動できる孔または溝を片面にのみ有し、液体を通さないことを特徴とする神経または腱の組織再生用フィルムである。 That is, the present invention is a film made of a biodegradable polymer material, and has a hole or groove through which liquid can flow along the film surface only on one surface, and does not allow liquid to pass through. It is a film for tissue regeneration.
本発明の神経または腱の組織再生用フィルムは、良好な再生機能を有する。とりわけ、損傷、切断された末梢神経や腱の組織の周りに本発明フィルムの凹凸面、すなわち液体が流動できる孔や溝が加工された面を当てて組織を包みこむことで、メカニズムは不明であるが、優れた神経再生、腱の再生効果を発揮する。 The nerve or tendon tissue regeneration film of the present invention has an excellent regeneration function. In particular, the mechanism is unknown by wrapping the tissue by applying the uneven surface of the film of the present invention around the damaged and cut peripheral nerve or tendon tissue, that is, the surface processed with holes and grooves through which liquid can flow. There are excellent nerve regeneration and tendon regeneration effects.
本発明に用いられる高分子材料からなるフィルムは、有機高分子を成型加工して得られるフィルムであれば特に限定されない。
好ましくは膜厚が１５μｍ以下であるのがよく、さらに好ましくは１０〜２μｍの厚みを有するものである。２μｍよりも薄いと液体が流れる孔や溝を形成するに高度な技術が必要で、フィルムとしての自己支持性も弱くなる。
The film made of the polymer material used in the present invention is not particularly limited as long as it is a film obtained by molding an organic polymer.
The film thickness is preferably 15 μm or less, more preferably 10 to 2 μm. If it is thinner than 2 μm, a high level of technology is required to form holes and grooves through which the liquid flows, and the self-supporting property as a film is weakened.
フィルムは、透明であっても不透明であっても半透明であってもよい。好ましくは、患部に貼り付けた際にフィルムを目視で確認できるものがよく、半透明の白色あるいは赤色以外の色素を含有したフィルムがよい。 The film may be transparent, opaque or translucent. It is preferable that the film can be visually confirmed when pasted on the affected part, and a film containing a pigment other than translucent white or red is preferable.
本発明のフィルムは、液体を通さない。そのため、フィルムの片面は平滑面を有する。液体がフィルム断面を貫通するような穴、たとえば成型加工プロセスの途上で生じるピンホールのような穴は製造過程で形成される場合があるが、無いほうが好ましい。 The film of the present invention is impermeable to liquids. Therefore, one side of the film has a smooth surface. A hole through which the liquid penetrates the cross section of the film, for example, a pinhole generated in the course of the molding process, may be formed in the manufacturing process, but it is preferable that there is no hole.
その反対側の面には、フィルム面に沿って液体が流動できる孔または溝を有することを特徴としている。ここで、フィルム面に沿って液体が流動できる孔または溝とは、フィルムの面に配置された孔が互いに連結した構造を有しており、連結した部位に入り込んだ液体が流動できる構造を有する。これにより、患部よりしみでる血液や体液がフィルム表面の孔や溝を通って拡散できる。 The opposite surface is characterized by having holes or grooves through which the liquid can flow along the film surface. Here, the hole or groove through which the liquid can flow along the film surface has a structure in which the holes arranged on the surface of the film are connected to each other, and has a structure in which the liquid entering the connected portion can flow. . Thereby, blood and body fluid that ooze from the affected area can diffuse through the holes and grooves on the film surface.
孔や溝の形状の具体例としては、その断面が角柱状、円柱状、三角柱状、楕円状やこれらに近似した不定形な形状で、その一部がフィルム表面と交わって液体が入り込める溝になっている形状を挙げることができる。かかる孔や溝の直径は、体液や血液が毛管現象で入り込める大きさであれば特に制限はないが、１〜１５μｍが好ましく、さらに好ましくは３〜１０μｍである。これよりも孔が小さいと、液体の流動がおこりにくく、大きいと、患部へのフィルムの接着性が低くなるため、好ましくない。孔や溝の深さは、２μｍ以上であり、フィルムの厚みよりも少ないものが好ましい。特に、フィルム断面の４０〜８０％の深さを有する構造がよい。 Specific examples of the shape of the hole or groove include a prismatic, cylindrical, triangular prism, elliptical cross section, or an irregular shape similar to these, with a part of the groove crossing the film surface and entering the liquid. The shape which has become can be mentioned. The diameter of the hole or groove is not particularly limited as long as body fluid or blood can enter through capillary action, but is preferably 1 to 15 μm, and more preferably 3 to 10 μm. If the hole is smaller than this, it is difficult for the liquid to flow. The depth of the hole or groove is 2 μm or more, and is preferably less than the thickness of the film. In particular, a structure having a depth of 40 to 80% of the film cross section is preferable.
これらの孔や溝は、少なくとも平面に沿った２方向以上に液体が流れていく構造が好ましく、より好ましくは、いくつもの孔や溝が連結した構造が好ましい。
具体的な孔や溝の構造の例を、図１および図２に示す。
These holes and grooves preferably have a structure in which liquid flows in at least two directions along the plane, and more preferably have a structure in which a number of holes and grooves are connected.
Examples of specific hole and groove structures are shown in FIGS.
これらの孔や溝を形成させる方法としては特に制限はなく、金型や鋳型を用いた転写による形成方法、フォトレジストやレーザー照射によるパターン形成方法、異なる高分子を混合させたときに生じる相分離を形成させ、後ほど特定の高分子のみを洗い出す方法、凍結乾燥による方法、界面活性剤の存在下、高分子の有機溶媒溶液の表面に水滴を形成させ、これを鋳型とする方法などが活用できる。 There are no particular restrictions on the method for forming these holes and grooves, and the formation method by transfer using a mold or mold, the pattern formation method by photoresist or laser irradiation, or the phase separation that occurs when different polymers are mixed. A method of washing only a specific polymer later, a method of lyophilization, a method of forming water droplets on the surface of an organic solvent solution of a polymer in the presence of a surfactant, and using this as a template can be utilized. .
これらの中でも好ましい構造としては、孔や溝はフィルム内部で連結しているが、表面にはいくつかの橋渡し構造が形成され、組織との接着面積が向上している構造が好ましい。具体的にはフィルム表面の孔や溝に、橋をかけるような微細構造を多く形成させた構造を有するものが、体液や血液を吸収しながらも組織との接着面積を増加させることができるために好ましい。 Among these, as a preferable structure, the holes and grooves are connected inside the film, but a structure in which several bridging structures are formed on the surface and the adhesion area with the tissue is improved is preferable. Specifically, those having a structure in which a lot of fine structures that bridge the film surface holes and grooves are formed can increase the adhesion area with the tissue while absorbing body fluid and blood. Is preferable.
好ましい構造の例として、ハニカム状の構造を挙げることができる。この構造は、ポリマーが有機溶媒に溶解したドープをガラス板上にキャストしてフィルムを形成する際、結露によって表面に水滴を形成させることで、水滴が鋳型となって形成される構造である。このハニカム状のパターン構造は、フィルム内部に形成された均一な大きさの孔が互いに連結した構造を有し、６方向に連結しているため、患部の血液や体液の移動が早く、フィルムが患部に張り付きやすい特徴を有する。フィルムの片面にハニカム状の構造を形成させる方法としては、特許文献３に記載しているようなリン脂質を界面活性剤として用いることでポリ乳酸のハニカム状で相互に連結した孔を形成することができる。 An example of a preferable structure is a honeycomb structure. In this structure, when forming a film by casting a dope in which a polymer is dissolved in an organic solvent on a glass plate, water droplets are formed on the surface by condensation, so that the water droplets are formed as a template. This honeycomb pattern structure has a structure in which holes of uniform size formed inside the film are connected to each other and are connected in six directions, so that the blood and body fluids in the affected area move quickly, and the film It has the characteristic that it is easy to stick to an affected part. As a method for forming a honeycomb-like structure on one side of a film, a polylactic acid honeycomb-like interconnected hole is formed by using a phospholipid as described in Patent Document 3 as a surfactant. Can do.
フィルムを構成するポリマーの具体例としては以下のものを挙げることができる。ポリアミノ酸などのポリアミド、ポリエチレンテレフタレートなどの芳香族ポリエステル、ポリブチレンサクシネートやポリヒドロキシアルカノエート、ポリ乳酸、ポリグリコール酸、ポリカプロラクトンなどの脂肪族ポリエステル、ポリウレタン、ポリジメチルシロキサンなどの重縮合体、ポリメチルメタクリレート、ポリエチレン、エチレン酢酸ビニル、ポリテトラフルオロエチレン、ポリプロピレン、ポリビニルアルコールなどのビニル重合体、ヒアルロン酸ナトリウム、アルギン酸ナトリウム、カラギーナン、プルラン、カードランなどの多糖類、カルボキシメチルセルロース、カルボキシメチルデキストラン、カルボキシメチルキチン、ヒドロキシエチルスターチなどの多糖類誘導体、コラーゲン、ゼラチン、エラスチン、フィブリン、フィブロイン、セリシンやケラチンなどのタンパク質またはペプチド類などが挙げられる。これらの材料は単独で用いても組み合わせて用いてもよい。 Specific examples of the polymer constituting the film include the following. Polyamides such as polyamino acids, aromatic polyesters such as polyethylene terephthalate, polybutylene succinates and polyhydroxyalkanoates, aliphatic polyesters such as polylactic acid, polyglycolic acid and polycaprolactone, polycondensates such as polyurethane and polydimethylsiloxane, Vinyl polymers such as polymethyl methacrylate, polyethylene, ethylene vinyl acetate, polytetrafluoroethylene, polypropylene, polyvinyl alcohol, polysaccharides such as sodium hyaluronate, sodium alginate, carrageenan, pullulan, curdlan, carboxymethyl cellulose, carboxymethyl dextran, Polysaccharide derivatives such as carboxymethyl chitin, hydroxyethyl starch, collagen, gelatin, elastin, fib Emissions, fibroin, like proteins or peptides such as sericin or keratin. These materials may be used alone or in combination.
これらの中では、安全性に優れ、生分解性を有し、水や血液に溶解しない材料が好ましく、ポリヒドロキシアルカノエート、ポリ乳酸、ポリグリコール酸、ポリカプロラクトンといった脂肪族ポリエステルやそれらの共重合体を好ましく挙げることができる。さらに好ましくは、ポリ乳酸、ポリグリコール酸、ポリカプロラクトンやそれらの共重合体である。 Among these, materials that are excellent in safety, biodegradable and do not dissolve in water or blood are preferable. Aliphatic polyesters such as polyhydroxyalkanoate, polylactic acid, polyglycolic acid, and polycaprolactone, and their co-polymers are preferred. Preferred examples include coalescence. More preferred are polylactic acid, polyglycolic acid, polycaprolactone and copolymers thereof.
これらの材質からなるフィルムは、生体内での分解期間が４週間以上であることが好ましい。ここで分解期間とは、手術後４週間が経過した後、フィルムは完全に消失されているか、あるいは加水分解や酵素分解による断片化が進み、フィルム全体６０％以上が消失している状態をいう。４週間よりも分解期間が短いと、神経や腱の修復が十分ではなく好ましくない。 Films made of these materials preferably have an in vivo degradation period of 4 weeks or longer. Here, the degradation period refers to a state in which the film is completely disappeared after 4 weeks from the operation or the fragmentation by hydrolysis or enzymatic degradation has progressed and 60% or more of the entire film has disappeared. . If the degradation period is shorter than 4 weeks, nerve and tendon repair is not sufficient, which is not preferable.
以下、実施例により本発明の実施形態の例を説明するが、これらは本発明の範囲を制限するものではない。 Examples of embodiments of the present invention will be described below by way of examples, but these do not limit the scope of the present invention.
［実施例１］片面にハニカム状の連結孔を有するポリ乳酸フィルムの作製
ポリ乳酸（ＰＬＡ、分子量２０００００、多木化学製）のクロロホルム溶液（５ｇ／Ｌ）に、ホスファチジルエタノールアミンジオレオイル（日油（株）製、ＣＯＡＴＳＯＭＥ ＭＥ−８１８１）を、２００：１の割合で混合し、ガラス基板上にキャストし、室温、湿度７０％の条件下に静置し、溶媒を徐々に飛ばすことでハニカム構造体を調製した。得られた構造体のハニカム構造の空隙内径の大きさは５μｍで、膜厚は７μｍであった。
[Example 1] Production of polylactic acid film having honeycomb-shaped connecting holes on one side. A solution of polylactic acid (PLA, molecular weight 200000, manufactured by Taki Chemical Co., Ltd.) in chloroform solution (5 g / L) was added with phosphatidylethanolamine dioleoyl (day Oil Co., Ltd., COATSOME ME-8181) was mixed at a ratio of 200: 1, cast on a glass substrate, allowed to stand at room temperature and 70% humidity, and the solvent was gradually blown away to form a honeycomb. A structure was prepared. The honeycomb structure of the obtained structure had a pore inner diameter of 5 μm and a film thickness of 7 μm.
［実施例２］ラット筋肉湿重量測定による神経再生評価
８週齢のルイスラット（体重２４０〜２８０ｇ）の坐骨神経を展開して、坐骨神経の上周膜を全周性に５ｍｍにわたり切除するextensive internal neurolysisモデルを作成した。神経と接する二頭筋をバイポーラで凝固焼却した。ラット両足の坐骨神経のうち、左側は剥離のみ行うコントロール群とし、右側は実施例１で作製したハニカムフィルムを用い、微細加工のあるハニカム面を神経側にあたるように被覆した。術後４、６週後に組織を採取し、前脛骨筋と腓腹筋の湿重量を測定した。
その結果、組織所見でハニカム群は、フィルムと神経が密着していた。筋湿重量比（前脛骨筋と腓腹筋の合計÷体重×１０００００）の平均は、術後４週で３９３±８０ｇ、術後６週で６０１±１２３ｇであった。フィルムを置かなかったコントロール群は、術後４週で３０３±６８ｇ、術後６週で４３４±４８ｇであり、いずれも統計学的有意差（ｐ＜０．０５）を認めた。
[Example 2] Evaluation of nerve regeneration by wet muscle weight measurement of rats Extensive in which the sciatic nerve of an 8-week-old Lewis rat (body weight 240 to 280 g) is expanded, and the epiperitoneum of the sciatic nerve is resected over 5 mm. An internal neurolysis model was created. The biceps muscles in contact with the nerves were bipolarly coagulated and burned. Among the sciatic nerves of both legs of the rat, the left side was a control group in which only exfoliation was performed, and the right side was coated with the honeycomb film prepared in Example 1 so that the honeycomb surface with fine processing was on the nerve side. Tissues were collected 4 and 6 weeks after the operation, and the wet weights of the anterior tibial muscle and gastrocnemius were measured.
As a result, in the honeycomb findings, the film and the nerve were in close contact with the honeycomb group. The average of the muscle wet weight ratio (the total of the anterior tibial muscle and gastrocnemius / body weight × 100,000) was 393 ± 80 g at 4 weeks after surgery and 601 ± 123 g at 6 weeks after surgery. The control group in which no film was placed was 303 ± 68 g at 4 weeks after surgery and 434 ± 48 g at 6 weeks after surgery, and both showed statistically significant differences (p <0.05).
［比較例１］両面が平滑なキャストフィルムの作製
ポリ乳酸（分子量２０００００）のクロロホルム溶液（１００ｇ／Ｌ）をガラス基板上にキャストして室温条件下に静置し、自然乾燥にて溶媒を除去することで、両面が平滑なキャストフィルムを作成した。
[Comparative Example 1] Production of cast film with smooth both surfaces A chloroform solution (100 g / L) of polylactic acid (molecular weight 200000) was cast on a glass substrate and allowed to stand at room temperature, and the solvent was removed by natural drying. By doing so, the cast film with smooth both sides was created.
［実施例３］ラット神経伝達速度による神経再生評価
実施例２で用いたラット２４匹を用い、その４８肢を実験に用いた。ハニカムフィルムを置いた群（Ｈ群）、両面が平滑なＰＬＡキャストフィルム（Ｃａ群）、何も置かなかったコントロール群（Ｃ群）、展開のみで未処置（以下Ｎ群）の４群（各ｎ＝１２）に分けた。６週後に運動神経伝導速度（ＭＣＶ）と筋湿重量を測定した。
ＭＣＶの平均はＮ、Ｈ、Ｃａ、Ｃ群それぞれ２５．９±３．２、１８．８±４．４、１６．３±２．５、１４．２±２．１mm／sであり、Ｎ群が他群に、Ｈ群はＣ群に対して有意に速かった。筋湿重量比とＭＣＶは相関していた（ｒ＝０．８８５）。
[Example 3] Evaluation of nerve regeneration based on rat nerve transmission rate Twenty-four rats used in Example 2 were used and 48 limbs were used in the experiment. 4 groups (group H) in which the honeycomb film was placed (group H), PLA cast film (Ca group) having smooth surfaces, control group (group C) in which nothing was placed, and untreated (hereinafter referred to as group N) n = 12). After 6 weeks, motor nerve conduction velocity (MCV) and muscle wet weight were measured.
The average MCV is 25.9 ± 3.2, 18.8 ± 4.4, 16.3 ± 2.5, 14.2 ± 2.1 mm / s for the N, H, Ca and C groups, respectively. The group was significantly faster than the other group, and the H group was significantly faster than the C group. Muscle wet weight ratio and MCV were correlated (r = 0.85).
以上のことから、片面に連結した孔を有するフィルムを損傷した神経組織に処置することにより、神経機能回復を有意に促進し、有用な神経の組織再生用フィルムであることが確認された。 From the above, it was confirmed that treating a damaged nerve tissue with a film having pores connected to one side significantly promotes recovery of nerve function and is a useful nerve tissue regeneration film.
本発明の神経または腱の組織再生用フィルムは、損傷した末梢神経や腱などの組織の周りにおいておくだけで組織の再生を促すことができるため、手術後の神経機能の回復を早める材料として利用でき、臨床成績の向上と患者ＱＯＬの改善に役立てることができる。 The tissue regeneration film for nerves or tendons of the present invention can be used to accelerate the recovery of nerve function after surgery because it can promote tissue regeneration just by placing it around tissues such as damaged peripheral nerves and tendons. It can be used to improve clinical results and improve patient QOL.
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