JP2009131358A - Artificial dura mater - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an artificial dura mater comprising a biodegradable and absorbable synthetic polymer having high flexibility and mechanical strength to be sutured. <P>SOLUTION: The artificial dura mater having a multilayer structure comprising the biodegradable and absorbable synthetic polymer is provided with an outermost layer which comprises a lactide/ε-caprolactone copolymer and whose fusion enthalpy originating in crystal is 1 to 10 J/g, and is also provided with a reinforcing layer comprising a fibrous structure composed of the biodegradable and absorbable high polymer. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

The present invention relates to an artificial dura mater composed of a biodegradable and absorbable synthetic polymer having high flexibility and sewable mechanical strength.

The dura mater interposed between the skull and the brain and covering the spinal cord mainly functions to protect the brain and spinal cord and prevent leakage of cerebrospinal fluid. When performing an operation to open the dura mater in an operation associated with a neurosurgical region, it is necessary to compensate for a deficient or contracted dura mater. Conventionally, a lyophilized product of human dura mater has been used as the filling material. However, such human dura mater has difficulty in product uniformity and supply, and there is a report of the possibility of Creutz felt-Jacob disease infection via human dura mater (Non-patent Document 1). A notice of ban on use was issued by the Ministry of Health and Welfare.

An artificial dura mater made of a fluororesin is put on the market as a replacement material to replace the human dura mater. However, it has been reported that an artificial dura mater made of a fluororesin may cause granulation due to infection or refractory skin fistula due to long-term embedding (Non-patent Document 2).

On the other hand, an artificial dura mater composed of a biodegradable and absorbable polymer that decomposes and absorbs after playing a role for a certain period of time has been proposed. As artificial dura mater, those made of natural polymer collagen (Non-patent Document 3) and gelatin (Non-patent Document 4) have been tried. It has not been put to practical use due to various problems such as the required suture strength cannot be obtained and the risk of infection remains because it is derived from nature.

On the other hand, Patent Document 1 describes an artificial dura mater composed of a biodegradable and absorbable synthetic polymer, particularly a lactide / ε-caprolactone copolymer. Such an artificial dura mater has sufficient strength to obtain sufficient suturing strength in addition to almost no risk of infection, and further, since it decomposes after playing a role for a certain period of time, it is harmful to long-term implantation. Can be prevented.
However, the artificial dura mater may be required to have a high degree of flexibility to follow a delicate curvature depending on the application site, and the end portion is sufficient to prevent liquid leakage from surrounding tissues after suturing. Needs to adhere to the dura mater. Conventional artificial dura mater may be insufficient in terms of such flexibility.
Japanese Patent Laid-Open No. 8-80344 Neurosurgery; 21 (2), 167-170, 1993 Neurosurgery Journal; 16 (7), 555-560, 2007 Journal of Biomedical Materials Research; Vol. 25 267-276, 1991 Brain and nerves; 21, 1089-1098, 1969

An object of the present invention is to provide an artificial dura mat composed of a biodegradable and absorbable synthetic polymer having high flexibility and sutureable mechanical strength.

The present invention is an artificial dura mater having a multilayer structure composed of a biodegradable and absorbable synthetic polymer, which is composed of a lactide / ε-caprolactone copolymer, and has a melting enthalpy derived from a crystal of 1 to 10 J / g. And an artificial dura mater having a reinforcing layer made of a fiber structure made of a biodegradable and absorbable polymer.
The present invention is described in detail below.

The lactide / ε-caprolactone copolymer used in the artificial dura mat described in Patent Document 1 is inherently extremely flexible, but is flexible after being melted by heating and processed into a sheet shape. There was a problem that the property decreased (hereinafter also referred to as “self-curing”). In addition, when polymerizing a copolymer of lactide and ε-caprolactone, in order to avoid a biased polymerization due to a difference in reactivity between lactide and ε-caprolactone and to obtain a copolymer with a high degree of polymerization, Technical common sense is that it is essential to add higher alcohols as initiators, but higher alcohols may remain in the final processed artificial dura mater, and there is concern about the effect on the human body. It had been.

As a result of intensive studies, the present inventors have found that when a copolymerization reaction is performed at a high temperature exceeding 130 ° C., a copolymer having a sufficient degree of polymerization can be obtained without using a higher alcohol as a polymerization initiator. It was. A copolymer obtained by reacting at a high temperature exceeding 130 ° C. without using a higher alcohol as a polymerization initiator does not contain a higher alcohol, so that it has high safety, It was found that even when it was done, it showed high flexibility without progressing self-curing. As a result of further intensive studies, a reinforcing layer made of a fiber structure capable of realizing a high stitching strength as an inner layer, with the sheet made of such a highly flexible lactide / ε-caprolactone copolymer not self-curing as the outermost layer. It has been found that an artificial dura mater having a high flexibility and a mechanical strength capable of suturing has led to the completion of the present invention.

The artificial dura mater of the present invention has a multilayer structure composed of biodegradable synthetic polymers.
The artificial dura mater of the present invention is composed of a lactide / ε-caprolactone copolymer and has an outermost layer having a melting enthalpy derived from crystals of 1 to 10 J / g.

The lactide / ε-caprolactone copolymer constituting the outermost layer (hereinafter also simply referred to as “copolymer”) has a preferred lower limit of 40 mol% and a preferred upper limit of 60 mol% of the molar ratio of lactide. When the molar ratio of lactide or ε-caprolactone is higher than 60 mol%, the crystallinity is increased and the hardness is increased, and sufficient flexibility may not be obtained. A more preferred lower limit is 45 mol%, and a more preferred upper limit is 55 mol%.

The copolymer constituting the outermost layer has a preferable lower limit of the weight average molecular weight of 100,000 and a preferable upper limit of 500,000. If it is less than 100,000, sufficient strength may not be secured, and if it exceeds 500,000, the melt viscosity is high and the moldability may be poor. A more preferred lower limit is 150,000, and a more preferred upper limit is 450,000.

The copolymer constituting the outermost layer preferably does not contain a higher alcohol component. When a higher alcohol component is contained, depending on its concentration, there is a concern about the influence on the human body, and it may be difficult to use it as an artificial dura mater.

The outermost layer has a lower limit of melting enthalpy derived from crystals of 1 J / g and an upper limit of 10 J / g. If it is less than 1 J / g, the mechanical strength may be significantly reduced, or the dimensions may change during storage. If it exceeds 10 J / g, the crystallinity becomes high and becomes hard, and the flexibility is increased. It may be damaged, the brain surface may be damaged, or the end part may float at the time of suturing, and liquid leakage may occur between surrounding tissues even if the suturing is performed.

In the present specification, the melting enthalpy derived from the crystal means the calorie per unit weight observed when the biodegradable polymer is measured with a differential scanning calorimeter (DSC). Mean value. It can be said that the higher the melting enthalpy value, the higher the crystallinity.
The copolymer of lactide and ε-caprolactone can have a melting enthalpy of 10 J / g or less, that is, a low crystalline state relatively easily immediately after polymerization. However, in order to produce an artificial dura using the copolymer, it is necessary to form a sheet-like molded body by heating and melting. In the conventional copolymer of lactide and ε-caprolactone, the melting enthalpy derived from the crystal is remarkably increased (that is, crystallized) through such a processing step, and the flexibility is lowered.
The copolymer used in the present invention is characterized in that the melting enthalpy derived from the crystals after passing through the heating and melting step is 10 J / g or less, that is, the change in melting enthalpy derived from the crystals is extremely small.

Although it does not specifically limit as thickness of the said outermost layer, A preferable minimum is 50 micrometers and a preferable upper limit is 800 micrometers. When the thickness is less than 50 μm, the thickness of the entire artificial dura is insufficient, and the strength may be insufficient or liquid leakage may occur. When the thickness exceeds 800 μm, the thickness of the entire artificial dura is thick. Too much flexibility may be lost. A more preferable lower limit is 100 μm, and a more preferable upper limit is 300 μm.

The lactide / ε-caprolactone copolymer used in the present invention is a copolymerization of a conventionally known lactide and ε-caprolactone, 1) no higher alcohol is added as a polymerization initiator, and 2) the reaction temperature exceeds 130 ° C. The temperature can be obtained.
By not adding a higher alcohol, it is possible to ensure that the resulting copolymer does not contain a higher alcohol component. In the conventional technical common sense, higher alcohol was considered as an essential component, but no inconvenience occurs when the reaction temperature is set to a temperature exceeding 130 ° C. Furthermore, by setting the reaction temperature to a temperature exceeding 130 ° C., it is possible to obtain a resin with a very small change in melting enthalpy derived from crystals. On the other hand, when the reaction temperature is 140 ° C. or higher, the crystallinity is almost lost and the film becomes very flexible. On the other hand, the mechanical strength of the resulting sheet may be remarkably lowered or the dimensions may change during storage.

Lactide and ε-caprolactone differ greatly in activation energy required for ring opening, and lactide has lower activation energy required for ring opening than ε-caprolactone. That is, as the polymerization is performed at a lower temperature, the lactide is polymerized first, and the chain length of the lactide becomes longer and the crystallinity becomes higher. On the other hand, the higher the polymerization temperature, the shorter the chain length of lactide and ε-caprolactone, and the monomers are randomly arranged in the molecular chain, so that the crystallinity can be lowered. By setting the reaction temperature to a temperature exceeding 130 ° C., the crystallinity of the resulting copolymer can be lowered, and crystallization can be prevented from progressing greatly even after a processing step such as heating and melting.

In the copolymerization of lactide and ε-caprolactone, an organometallic compound such as tin, zinc, iron, nickel, aluminum, potassium, sodium, titanium, antimony, bismuth, or a salt thereof may be used as a polymerization catalyst. Among these, a tin compound is preferable from the viewpoint of actual use and easy handling during polymerization, and tin octylate is more preferable from the viewpoint of reaction rate and stability.

In order to use for artificial dura mater use, it is preferable not to contain a metal compound harmful to the human body as much as possible. For example, tin octylate is known to have a relatively low toxicity to living organisms, but the effect is considered to be extremely small if it is particularly less than 1 ppm.
When a polymerization catalyst is used in the copolymerization of lactide and ε-caprolactone, it is preferable to remove the metal catalyst from the copolymer after polymerization.

The method for removing the metal catalyst is not particularly limited. For example, a method using a catalyst remover is simple and effective.
As the catalyst removing agent, those composed of an organic acid and an alcohol are preferable, and among them, those composed of acetic acid as an organic acid and isopropanol as an alcohol are preferable from the viewpoint of safety and ease of recovery. . Here, the composition ratio between the organic acid and the alcohol is such that the higher the ratio of the organic acid within the range in which the copolymer is not dissolved, the more effective catalyst removal is possible.
Specifically, for example, an acetic acid / isopropanol = 15/85 to 35/65 (volume ratio) is preferable. If the concentration of acetic acid is less than 15% by volume, the catalyst may not be removed to 1 ppm or less, and if it exceeds 35% by volume, the copolymer may be dissolved and recovery may be difficult.

The artificial dura mater of the present invention has a reinforcing layer made of a fiber structure made of a biodegradable and absorbable polymer. The reinforcing layer constitutes one of the inner layers of the multilayer structure, and imparts a high suture strength to the artificial dura mater of the present invention. In addition, there is an effect of suppressing the expansion of the needle hole at the time of suturing, thereby effectively preventing liquid leakage from the needle hole.

The biodegradable absorbable polymer constituting the reinforcing layer is not particularly limited, but those having a melting point higher than that of the lactide / ε-caprolactone copolymer used for the outermost layer and not soluble in the same solvent are suitable. In addition, when a transparent polymer is selected, the transparency of the entire artificial dura can be ensured, and the internal situation can be observed through the artificial dura during or after the filling operation, so that trouble can be detected early. You can also.
Examples of such biodegradable and absorbable polymers include polyglycolide, glycolide / ε-caprolactone copolymer, lactide / glycolide copolymer, lactide / glycolide / ε-caprolactone copolymer, polydioxanone, and the like. .

Although it does not specifically limit as said fiber structure, For example, a cloth, a textile fabric, a knitted fabric, a web, a lace, a felt, a nonwoven fabric etc. are mentioned.

The basis weight of the reinforcing layer is not particularly limited, but a preferred lower limit is 15 g / m ² and a preferred upper limit is 45 g / m ² . If it is less than 15 g / m ² , a sufficient reinforcing effect may not be obtained, and if it exceeds 45 g / m ² , the flexibility of the entire artificial dura may be impaired. A more preferred lower limit is 20 g / m ² and a more preferred upper limit is 40 g / m ² .

Although it does not specifically limit as thickness of the said reinforcement layer, A preferable minimum is 50 micrometers and a preferable upper limit is 200 micrometers. When the thickness is less than 50 μm, a sufficient reinforcing effect may not be obtained. When the thickness exceeds 200 μm, the flexibility of the entire artificial dura may be impaired. A more preferable lower limit is 80 μm, and a more preferable upper limit is 120 μm.

In addition to the outermost layer and the reinforcing layer, the artificial dura mater of the present invention includes, for example, a stretchable layer for suppressing cerebrospinal fluid leakage from a needle hole, a hydrophilic gel layer for maintaining a wet state, and the like. You may have.

The artificial dura mater of the present invention has a preferable lower limit of 1.5 and a preferable upper limit of a static friction coefficient of the surface measured by a method according to ASTM D 1894. If it is less than 1.5, it may become slippery at the time of suturing operation and may damage the brain surface. If it exceeds 10, it may be difficult to peel off when the artificial dura mates are in close contact with each other, resulting in poor operability. .

Artificial dura mater of the present invention, preferable lower limit of the bending stiffness as measured by a method analogous KES system 0.1gf ^· cm 2 / cm, preferably the upper limit is 1.0gf · ^cm 2 / ^cm. If it is less than 0.1 gf · cm ² / cm, it may be easily bent by its own weight, and the operability may be inferior. If it exceeds 1.0 gf · cm ² / cm, artificial hardening may occur in the undulation of the tissue site to be compensated. The membrane may not follow, and it may be difficult to sew the wound around the filling tissue and prevent leakage.

The artificial dura mater of the present invention has a preferred lower limit of tensile fracture strength measured by a method according to JIS K 7113 and a preferred upper limit of 15 MPa. If it is less than 5 MPa, there may be inconveniences such as easy breakage during suturing or inability to withstand brain pressure, and if it exceeds 15 MPa, the risk of breakage during suturing is avoided. It has its own hard properties and increases the risk of damaging brain surfaces and tissues.

In the artificial dura mater of the present invention, the preferable lower limit of the elastic modulus at 10% elongation measured by a method according to JIS K 7113 is 10 MPa, and the preferable upper limit is 20 MPa. If the pressure is less than 10 MPa, the deformation of the suture site may increase at the time of stretching, and the risk of cerebrospinal fluid leakage may increase.

The method for producing the artificial dura mater of the present invention is not particularly limited, and examples thereof include a method of integrating the outermost layer and the reinforcing layer separately produced by vacuum pressing while heating.
The sheet constituting the outermost layer can be prepared, for example, by melt-molding the lactide / ε-caprolactone copolymer with an extruder.
The fiber structure constituting the reinforcing layer can be prepared by, for example, a method of melt-blowing biodegradable synthetic polymer as a raw material using an extruder.

According to the present invention, it is possible to provide an artificial dura mater composed of a biodegradable / absorbable synthetic polymer having high flexibility and sutureable mechanical strength.

Hereinafter, embodiments of the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples.

(Example 1)
(1) Synthesis of lactide / ε-caprolactone copolymer 1440 g of L-lactide, 1140 g of ε-caprolactone, and 300 ppm of tin 2-ethylhexanoate were placed in a separable flask and polymerized at 135 ° C. for 7 days in a nitrogen atmosphere after decompression. .
The obtained lactide / ε-caprolactone copolymer was treated with an isopropanol solution of acetic acid (acetic acid / isopropanol = 30/70 v / v) and dried at 40 ° C. under vacuum.
The obtained copolymer had a weight average molecular weight of 320,000 (measured by GPC) and a metal content of less than 0.5 ppm (determined by IPC emission spectroscopic analysis).

(2) Preparation of outermost layer sheet The obtained copolymer was melt-molded by an extruder to obtain a sheet having a thickness of 100 µm.
An 8 mg sample was cut out from the obtained sheet, subjected to DSC measurement (DSC heating rate 10 ° C./min), and the melting enthalpy derived from the crystal part of the sheet was measured.

(3) Preparation of fiber structure Polyglycolic acid (inherent viscosity 1.8) was melt-molded by a melt blow method using an extruder to prepare a nonwoven fabric having a basis weight of 30 g / m ² .

(4) Manufacture of artificial dura mater A sheet made of a copolymer is laminated on both sides of the obtained polyglycolic acid nonwoven fabric and integrated by vacuum pressing under conditions of 150 ° C. and 100 kg / cm ^2. An artificial dura mater (thickness: about 200 μm) was obtained.

(Comparative Example 1)
1440 g of L-lactide, 1140 g of ε-caprolactone, and 300 ppm of tin 2-ethylhexanoate were placed in a separable flask and polymerized at 140 ° C. for 7 days in a nitrogen atmosphere after decompression.
The obtained lactide / ε-caprolactone copolymer was treated with an isopropanol solution of acetic acid (acetic acid / isopropanol = 30/70 v / v) and dried at 40 ° C. under vacuum.
The obtained copolymer had a weight average molecular weight of 300,000 (measured by GPC) and a metal content of less than 0.5 ppm (determined by IPC emission spectroscopic analysis).
An artificial dura was manufactured in the same manner as in Example 1 except that the obtained copolymer was used.

(Comparative Example 2)
1440 g of L-lactide, 1140 g of ε-caprolactone, and 300 ppm of tin 2-ethylhexanoate were placed in a separable flask and polymerized at 130 ° C. for 7 days in a nitrogen atmosphere after decompression.
The obtained lactide / ε-caprolactone copolymer was treated with an isopropanol solution of acetic acid (acetic acid / isopropanol = 30/70 v / v) and dried at 40 ° C. under vacuum.
The obtained copolymer had a weight average molecular weight of 350,000 (measured by GPC) and a metal content of less than 0.5 ppm (determined by IPC emission spectroscopic analysis).
An artificial dura was manufactured in the same manner as in Example 1 except that the obtained copolymer was used.

(Evaluation)
The artificial dura mater produced in Example 1 and Comparative Examples 1 and 2 was evaluated by the following method.
The results are shown in Table 1.

(1) Measurement of static friction coefficient The surface of the artificial dura mater was measured for the static friction coefficient using a friction coefficient measuring machine (manufactured by Shinto Kagaku Co., Ltd .: HEIDON-14DR) by a method based on ASTM D 1894. .

(2) KES-bending test Each artificial dura was cut into 50 mm x 100 mm test pieces, and the bending hardness was measured using a pure bending tester (KES-FB2).

(3) Tensile test Each artificial dura mater was cut into 10 mm x 80 mm test pieces and subjected to a tensile test at a distance between chucks of 40 mm and a tensile speed of 50 mm / min to measure the tensile breaking strength and the elastic modulus at 10% elongation. .

表１より、実施例１で製造した人工硬膜では、最表層の結晶に由来する融解エンタルピーが２．０Ｊ／ｇであり、静止摩擦係数、曲げ硬さ、引張破断強度、１０％伸張時の弾性率の全てが人工硬膜の用途に必要とされる性能を発揮した。
これに対して、比較例１で製造した人工硬膜では、最表層の結晶に由来する融解エンタルピーが観測されず（即ち、１Ｊ／ｇ未満）であり、曲げ硬さ、１０％伸張時弾性率が共に低下して実施例１で製造したものよりも柔軟な特性を有しているものの、表面の静止摩擦係数が高く操作性が悪く。また、引張破断強度も生体硬膜より低くなり要求される物性を満足しない。
比較例２で製造された人工硬膜では、最表層の結晶に由来する融解エンタルピーが１９．４と実施例１のものと比較して高く、結晶性が高いことがわかる。この場合、人工硬膜全体として非常に硬くなってしまい、人工硬膜として所望される物性を満足しない。

From Table 1, in the artificial dura mat produced in Example 1, the melting enthalpy derived from the outermost layer crystal is 2.0 J / g, and the static friction coefficient, bending hardness, tensile strength at break, and 10% elongation All of the elastic modulus exhibited the performance required for artificial dura mater applications.
In contrast, in the artificial dura mat manufactured in Comparative Example 1, no melting enthalpy derived from the outermost layer crystal was observed (that is, less than 1 J / g), bending hardness, and 10% elastic modulus at elongation. Although both of these properties are lowered and have more flexible characteristics than those manufactured in Example 1, the surface static friction coefficient is high and the operability is poor. In addition, the tensile strength at break is lower than that of the biological dura mater and does not satisfy the required physical properties.
In the artificial dura mater manufactured in Comparative Example 2, the melting enthalpy derived from the outermost layer crystal is 19.4, which is higher than that of Example 1, indicating that the crystallinity is high. In this case, the entire artificial dura is extremely hard and does not satisfy the physical properties desired for the artificial dura.

According to the present invention, it is possible to provide an artificial dura mater composed of a biodegradable / absorbable synthetic polymer having high flexibility and sutureable mechanical strength.

Claims (2)

An artificial dura mater having a multilayer structure composed of biodegradable and absorbable synthetic polymers,
An outermost layer comprising a lactide / ε-caprolactone copolymer and having a melting enthalpy derived from crystals of 1 to 10 J / g, and
An artificial dura mater comprising a reinforcing layer made of a fiber structure made of a biodegradable absorbable polymer. The lactide / ε-caprolactone copolymer has a molar ratio of lactide to ε-caprolactone (lactide / ε-caprolactone) of 40/60 to 60/40 and a weight average molecular weight of 100,000 to 500,000 or less. 2. The artificial dura mater according to claim 1, which does not contain a higher alcohol component.