WO2018199263A1

WO2018199263A1 - Medical substrate

Info

Publication number: WO2018199263A1
Application number: PCT/JP2018/017074
Authority: WO
Inventors: 明郎萩原
Original assignee: 明郎萩原
Priority date: 2017-04-28
Filing date: 2018-04-26
Publication date: 2018-11-01
Also published as: JP6967265B2; JP2018186903A

Abstract

Provided is a medical substrate suitable for reproduction of a circulatory system, the medical substrate being suitable for a blood vessel in which a clot readily forms, e.g., a relatively narrow artificial blood vessel that has a lumen diameter of 6-8 mm or less and is exposed to high pressure from the lumen, such as venous system blood vessel or an artery. The medical substrate according to the present invention is sheet-shaped, tube-shaped, or a combination of these shapes, and is transplanted into a body and used to reproduce a circulatory system, the medical substrate having a multilayer structure provided with at least an inner layer disposed on an inner membrane side of a circulatory system, and an outer layer disposed further toward an outer membrane side of the circulatory system than the inner layer, the layer disposed further toward the outer membrane side of the circulatory system than the inner layer being formed in a porous shape so that a feeding blood vessel reaches the inner layer or can penetrate to the vicinity of the inner layer, and with regard to a rigidity index a determined by a specific method, the ratio of the rigidity index a of the outer layer of the tube-shaped medical substrate to the rigidity index a of a transplanted blood vessel being 7.5 or less.

Description

Medical substrate

The present invention relates to a medical base material, and more particularly to a medical base material suitable for regeneration of relatively thin blood vessels in the circulatory system.

The most important function in blood vessels is anticoagulation. And this anticoagulant property is preventing blood from coagulating in a blood vessel and damaging the blood flow. In addition, this anticoagulant property is maintained by the intimal layer present in the outermost surface layer of the luminal surface of the blood vessel, and this intimal layer is stably formed.

Well, conventional artificial blood vessels are made of materials that remain permanently in the living body (so-called non-bioabsorbable materials, such as polyester, nylon, silk thread, etc.), for a certain period of time. Materials that decompose in vivo (called biodegradable materials, such as polylactic acid, caprolactone, PGA, gelatin, collagen, etc.), or non-bioabsorbable materials and biodegradable materials Even if it is made of a combination of the two, when it is transplanted as an artery in a living body, the state where the intimal layer is stably formed and maintained on the lumen surface cannot be maintained.

For this reason, conventional artificial blood vessels cause various obstacles such as thrombus formation, abnormal tissue growth, and abnormal morphology on the lumen surface of the wall, and the function as an artery may be deteriorated relatively early. It was. In particular, relatively thin artificial blood vessels with a lumen diameter of 6 to 8 mm or less have insufficient anticoagulant properties. When transplanted as an artery, blood vessel function deteriorates due to thrombus formation or abnormal tissue growth within 6 months. It was easy (see Patent Documents 1 and 2, Non-Patent Document 1).

JP2013-031595A Japanese Unexamined Patent Publication No. 2016-158765

The present invention is a medical substrate suitable for the regeneration of the circulatory system, and is exposed to high pressure from a lumen such as a blood vessel that is prone to thrombus, such as a venous blood vessel or an artery, and has a lumen diameter. It is an object to provide a medical base material suitable for relatively thin artificial blood vessels of 6 to 8 mm or less.

As a result of intensive studies, the inventors have found that an intimal layer is formed and stably maintained in an artificial blood vessel, and a part or all of the layers constituting the wall of the artificial blood vessel have a specific strength described below. It has a layer made of a material having a deterioration period (this portion is described as an outer layer below), and the outer layer has a certain range of rigidity (in other words, appropriate elasticity), and constitutes the outer layer It has been determined that the fiber spacing of the fabric needs to be wider than a certain range. And when the outer layer has a certain range of rigidity and fiber spacing, it has an inner membrane layer similar to that of natural blood vessels and an inner portion of the inner membrane that touches the outer side (viewed from the lumen side). It was confirmed that a similar structure was formed in the lumen of the artificial blood vessel, and stable anticoagulability could be maintained for a long time. And when satisfy | filling these conditions, it confirmed that the favorable function as an artificial blood vessel was fulfilled.

Note that the material having a specific strength deterioration period that constitutes the outer layer is stereocomplex polylactic acid, a bioabsorbable polymer that has a slower strength deterioration in vivo, or a non-absorbable polymer (that is, an infinite strength deterioration period). Large polymer). To describe a specific strength deterioration period specifically, (When an artificial blood vessel made of stereocomplex PLA is transplanted into an artery, it takes at least 6 months to 10 months or more to deteriorate its strength. When normal PLLA is used in the same way, it refers to the period of strength deterioration of 6 months or more to 10 months or more (based on our experimental results where strength deterioration was observed from less than 6 months).

That is, the medical substrate of the present invention has a sheet shape, a tube shape, or a combination thereof, and is a medical substrate used for regeneration of a circulatory system by transplanting into the body, The outer layer is formed in a porous shape so that the vegetative blood vessels reach the inner layer or enter the vicinity of the inner layer, and a tube-shaped medical substrate is used for the stiffness index a determined by the following method. The medical base material has a ratio of the stiffness index a of the outer layer of the material / the stiffness index a of the blood vessel to be transplanted within 7.5.

[Method of determining stiffness index a]
(1) Hold an L-shaped jig between the upper and lower chucks of the tensile tester, and pass the tube-shaped object to be measured between the two L-shaped jigs to keep the section of the object to be measured round and circular. The inner wall of the object to be measured becomes parallel, but the force is not applied, and the measurement is started at the time when the measurement is started. D0 is the length in the tensile direction, L0 is the length in the vertical axis direction of the object to be measured, and T0 is the wall thickness of the object to be measured.
(2) Measure the tension Nx, the length Dx in the tensile direction, the length Lx in the vertical direction of the object to be measured, and the wall thickness Tx multiple times while pulling at the same pulling speed from the start of measurement.
(3) The elongation rate X is calculated by the formula X = (Dx−D0) / D0 × 100 (%).
(4) When the stress σx in the tensile direction applied to the inner wall of the object to be measured is calculated by equation (4a), and this stress is assumed to be caused by the internal pressure of the object to be measured having the inner radius Rx by equation (4b) Calculate the tube internal pressure Yx corresponding to
(4a) σx = Nx / (Tx × Lx × 2)
(4b) Yx = σx × Tx / Rx = π × Nx / 2 (Dx × Lx)
(5) Constants a and b are determined by the method of least squares so that the obtained elongation rate X and the corresponding internal pressure Y approximate a linear function Y = aX + b (a and b are constants).

In addition, it is preferable that the ratio of the rigidity index a of the medical base material / the rigidity index a of the blood vessel to be transplanted is within 5.5. The fabric constituting the outer layer is preferably a woven fabric or a knitted fabric when it is desired to make the diameter, arrangement, and distribution of the holes into which the nutrient blood vessels enter as uniform as possible.

The inner layer of the medical base material of the present invention is composed of polyglycolic acid, a copolymer of lactic acid and caprolactone, L-polylactic acid, D-polylactic acid, a copolymer of glycolic acid and lactic acid, gelatin, collagen, and elastin. You may be comprised by the at least 1 sort (s) of material chosen more. The inner layer may be made of a cloth made of a fiber material. The cloth constituting the inner layer may be a nonwoven fabric, a woven fabric, or a knitted fabric.

The medical base material of the present invention can be used for regeneration of a circulatory system such as blood vessels such as arteries and veins, heart, and lymphatic vessels because the outer layer has appropriate rigidity. Can stably regenerate and maintain arteries (especially over the intima and media) for a long time, and blood vessels that are prone to thrombus formation, such as venous blood vessels and lumen diameters of 6-8 mm or less Even small arteries can be stably regenerated and maintained.

FIG. 1 is an external perspective view (a) and a cross-sectional view (b) of a medical base material according to the present invention. FIG. 2 is a diagram for explaining a method for determining the rigidity index a of the outer layer constituting the medical base material according to the present invention. FIG. 3 is an external perspective view (a) and a sectional view (b) of another medical base material according to the present invention. FIG. 4 is a drawing-substituting photograph showing the result of transplanting the medical substrate (Example 1) according to the present invention into a dog. FIG. 5 is a drawing-substituting photograph showing the result of transplanting a medical substrate (Example 2) according to the present invention into a dog. FIG. 6 is a drawing-substituting photograph showing the result of transplanting a medical substrate (Example 3) according to the present invention into a dog. FIG. 7 is a drawing-substituting photograph showing the result of transplanting a medical substrate (Example 4) according to the present invention into a dog. FIG. 8 is a drawing-substituting photograph showing the result of transplanting the medical substrate (Example 5) according to the present invention into a dog. FIG. 9 is a drawing-substituting photograph showing the result of transplanting a conventional medical substrate (Comparative Example 1) to a dog. FIG. 10 is a drawing-substituting photograph showing the result of observing the aortic wall of a dog not implanted with a medical substrate.

1. Medical base material The medical base material of the present invention has a sheet shape, a tube shape, or a combination of these, and is treated by a procedure such as a surgical operation such as an artificial blood vessel, an intravascular stent or an intravascular stent graft. It is transplanted into the body and used to regenerate the circulatory system.

Therefore, the case where the medical base material of the present invention is used as an artificial blood vessel will be described below with reference to the drawings. In addition, the use of the medical base material of the present invention is not limited to an artificial blood vessel.

FIG. 1 is an external perspective view (a) and a cross-sectional view (b) of a medical substrate 1 according to the present invention. As shown in this figure, the medical base material 1 includes an outer layer 11 and an inner layer 12 disposed on the inner side. Here, the inner layer 12 may be integrated with the outer layer 11, or may be installed in multiple layers. In addition, such a medical base material 1 can be manufactured by, for example, manufacturing each layer separately and then fitting them by hand or a known machine.

2. Outer layer The outer layer 11 constituting the medical base material 1 of the present invention is a hollow cylindrical cloth made of a non-bioabsorbable material, a biodegradable material, or a combination thereof, and has a constant stiffness index a described later. It falls within the range. The outer layer refers to a layer made of a material having a specific strength deterioration period described below, which is a part or the whole of the artificial blood vessel wall.

The material having a specific strength deterioration period constituting the outer layer is a stereocomplex polylactic acid or a bioabsorbable polymer having a slower strength deterioration in vivo or a non-absorbable polymer (that is, the strength deterioration period is Infinite polymer).

To describe a specific strength deterioration period specifically, (When an artificial blood vessel made of stereocomplex PLA is transplanted into an artery, it takes at least 6 months to 10 months or more to deteriorate its strength. When normal PLLA is used in the same way, it refers to the period of strength deterioration of 6 months or more to 10 months or more (based on our experimental results where strength deterioration was observed from less than 6 months).

(1) Non-bioabsorbable material, biodegradable material All non-bioabsorbable materials can be used for the outer layer. Biodegradable materials include polybutylene succinate, polyesteramide, copolyester, modified polyester, polyethylene succinate, polybutylene succinate, polyhydroxybutyrate, polyvinyl other than stereocomplex polylactic acid. Alcohol, copolymers containing these, bacterial cellulose, and the like can be used. In addition, although it is medically considered that polyurethane does not cause deterioration in strength in vivo, in practice, it has been observed that the deterioration in strength due to hydrolysis is observed after one year of observation. Included in bioabsorbable polymers with slow strength degradation in vivo.

In the case where a biodegradable material or a material containing the same is used for the outer layer 11, after transplanting the medical base material 1, a certain period (6 months to 10 months or more) until the endometrial cells are replaced, The stiffness index a needs to be within a certain range. Therefore, when a biodegradable material is used, it is preferable to use a material having a long strength deterioration time of 6 months to 10 months or more, for example, stereocomplex lactic acid, even if it is used for a blood vessel wall.

(2) Cloth In this specification, a cloth is a material obtained by processing a large number of fibers into a thin and wide plate shape, and the cloth is classified into a woven fabric, a knitted fabric, and a non-woven fabric. As the fiber constituting the outer layer 11, a single fiber may be used, or a plurality of fibers may be blended and used. Moreover, as a fiber which comprises cloth, although a monofilament, twisted yarn, and roving yarn may be sufficient, twisted yarn is preferable.

The cloth constituting the outer layer 11 is not particularly limited, and can be manufactured from a non-bioabsorbable material, a biodegradable material, or the like by a known method. Specifically, it may be produced as a woven fabric or a knitted fabric (including mesh-like ones, hereinafter the same unless otherwise specified) by a known loom or knitting machine, and known electrospinning method, melt blowing method, etc. You may manufacture as a nonwoven fabric by the method of.

(3) Rigidity index a
The stiffness index a is an index representing the stiffness of the outer layer 11 and blood vessels, and is a value measured by a method described later. The index a of the rigidity of the outer layer portion of the artificial blood vessel is 1.0 to 30 mmHg, and preferably 1.2 to 12 mmHg. Further, the ratio between the stiffness index a of the outer layer portion of the artificial blood vessel and the stiffness index a of the blood vessel to be transplanted is within 7.5, and preferably within 5.5.

(4) Method for Determining Stiffness Index a FIG. 2 is a diagram for explaining a method for determining the stiffness index a. With reference to this figure, the artificial blood vessel and the rigidity index a of the blood vessel are determined by the following procedures 1) to 5).

1) Insert an L-shaped jig between the upper and lower chucks of the tensile tester. The outer layer or blood vessel of the artificial blood vessel is cut into a constant and sufficiently long length (for example, 100 mm) in the vertical axis direction to be a measurement object. Pass the object to be measured between two L-shaped jigs. From the state in which the cross section of the object to be measured is maintained in a round and circular shape, it is pulled at a constant pulling speed (for example, a sufficiently slow speed such as 10 mm / min), and the inner walls facing each other are parallel as shown in FIG. However, the force was practically not applied, and this was set as the measurement start time. In this state, the length of the measured object in the vertical axis direction is defined as L0 (mm), the length in the tensile direction is defined as D0 mm (mm), and the thickness of the measured object wall is defined as T0 mm (mm).

2) From the start of measurement, while pulling at the same pulling speed, as shown in Fig. 2 (b), the tension Nx (N), the length Dx (mm) in the tensile direction of the object to be measured, and the object to be measured orthogonal to this The length Lx (mm) of the object in the vertical axis direction and the wall thickness Tx (mm) of the object to be measured are measured a plurality of times.

3) The elongation rate x is calculated by the formula X = (Dx−D0) / D0 × 100 (%).

4) When the stress σx in the tensile direction applied to the inner wall of the object to be measured is calculated by equation (4a), and this stress is assumed to be caused by the internal pressure of the object to be measured having the inner radius Rx by equation (4b). The corresponding tube internal pressure Yx (mmHg) is calculated.
(4a) σx = Nx / (Tx × Lx × 2)
(4b) Yx = σx × Tx / Rx = π × Nx / 2 (Dx × Lx)

5) Constants a and b are determined by the method of least squares so that the obtained elongation rate X and the corresponding internal pressure Y approximate the linear function Y = aX + b (a and b are constants). The unit of the constant a obtained is millimeter of mercury (mmHg).

(5) Fiber length, fiber diameter, fiber spacing, etc. When the fabric constituting the outer layer 11 is a fabric made of a fiber material such as woven fabric, knitted fabric, or nonwoven fabric, the fiber length, fiber diameter, fiber of the fibers constituting the fabric The ratio between the diameter and the length is not particularly limited as long as the strength condition is satisfied. However, considering the strength conditions, the fiber diameter is preferably 0.1 to 50 μm, more preferably 0.5 to 30 μm in terms of median value. When used as a vascular stent, it is preferably 50 μm or more, more preferably 100 μm or more.

The distance from any one of the fiber stumps recognized in the cross section of the fabric to the stump of the adjacent fiber (hereinafter abbreviated as fiber spacing) varies depending on the fabric structure and the thickness of the blood vessel. Specifically, in terms of the structure of the fabric, in the case of a nonwoven fabric, the median value is preferably 5 μm to 1000 μm, more preferably 15 μm to 500 μm. If it is smaller than 5 μm, it becomes difficult for cells and particularly vegetative blood vessels to enter and settle, and it is difficult for the cloth to self-organize including blood vessels to stably regenerate and maintain the vascular wall structure. In addition, if it is larger than 1000 μm, blood or the like may leak from the medical base material 1 due to internal pressure such as blood pressure. For the same reason, in the case of a woven fabric or a knitted fabric, the fiber spacing is preferably 15 μm to 2000 μm, more preferably 30 μm to 1500 μm. Speaking from the thickness of the blood vessel, it is in the range between 20 μm and 1/4 of the outer circumference of the blood vessel, preferably between 100 μm and 1/6 of the outer circumference of the blood vessel, and 250 μm to the outer circumference of the blood vessel. It is more preferable that the length is 1/8.

When the outer layer is stacked several times around the inner layer, when the medical substrate includes an intermediate layer to be described later, the fiber spacing of the fibers constituting the outer layer may be 1 mm to 4 mm.

The fiber length, the fiber diameter, the ratio between the fiber diameter and the length, and the fiber interval of the fibers constituting the cloth may be single, but it is preferable that there is variation. This is because (a) it is advantageous for cell proliferation and tissue regeneration by following the fibers constituting the extracellular structure in the living body. (B) If the deterioration rate differs according to the variation, the strength change of the regenerated tissue is changed. This is because it gradually changes, so that there is less risk of abnormalities in the shape of regenerated tissue (abnormal dilation, rupture, stenosis, occlusion) and component abnormalities (scarring, calcification, etc.).

(6) Measuring method of fiber diameter and fiber interval The fiber diameter and fiber interval of the fibers constituting the cloth shown in (5) are the median values measured as follows. The median value is one of the representative values, and is a value located at the center when a finite number of data are arranged in order of size. When the number of data is an even number, the arithmetic average value of two values close to the center is obtained.

1) In the case of knitted fabric and woven fabric (a) Fiber diameter The fiber diameter of the knitted fabric and woven fabric is obtained as follows. First, cut the cloth and photograph the cut surface with an optical microscope (20x to 100x). Next, the photographed image is taken into a computer image system, and the fiber diameter is measured using distance measurement software (theoretically, measurement is possible up to 0.01 μm).

In addition, the woven fabric and the knitted fabric are bundled with a plurality of monofilament fibers to form a single woven or knitted yarn. Therefore, the fiber diameter of 50 monofilaments with a round cross section selected at random is measured, and the median value is taken as the fiber diameter of the cloth.

(B) Fiber space | interval The fiber space | interval of a knitted fabric and a woven fabric is calculated | required with the following method. First, the surface of the cloth is photographed with a stereomicroscope (magnification of 10x or less, light source irradiation from both the front and back sides). Captured images are captured into a computer image system, and the captured images are measured for fiber spacing using distance measurement software (theoretically, measurement is possible up to 0.01 μm).

In addition, the woven fabric and the knitted fabric are bundled with a plurality of monofilament fibers to form a single woven or knitted yarn. Therefore, the fiber interval is determined based on the size of the stitch (knitting) formed between the edges of the adjacent weaving yarn (or knitting yarn) and the weaving yarn (or knitting yarn). Since this weave (knitting) has a substantially triangular shape, a quadrangular shape, or a pseudo-circular shape, how to obtain the fiber spacing in each case will be described below. In addition, description is each described in the case where there are a plurality of shapes and sizes of textures (knitting).

When the weave (stitch) is substantially triangular, this is regarded as a triangle, and the average value of the three heights of the triangle is taken as the fiber spacing of this triangle. Then, the median value of the fiber intervals of 30 triangles selected at random is set as the fiber interval of the cloth.

When the weave (stitch) is substantially square, the maximum value and the minimum value of the distance between a pair of opposing two sides and the maximum value and minimum value of the distance between another pair of opposing sides Find the average value of. Then, the weighted average of these four numerical values is defined as the fiber spacing of this square. And the median value of the fiber intervals of 30 squares selected at random is set as the fiber interval of the cloth.

When the weave (stitch) is a pseudo circle, this is regarded as a circle, and the diameter of the circle is defined as the fiber interval of this circle. Then, the median of the fiber intervals of 30 randomly selected pseudo circles is set as the fiber interval of the cloth.

2) In the case of a nonwoven fabric (a) Fiber diameter The fiber diameter of a nonwoven fabric is calculated | required as follows. First, the nonwoven fabric to be measured is frozen and cured with liquid nitrogen and then cut. Next, the cut surface of the nonwoven fabric is photographed with a scanning electron microscope. Then, 50 fibers are randomly selected from the many fiber cross sections exposed on the cut surface of the nonwoven fabric, and the fiber stump diameter is measured. The median value of the measured fiber diameter is defined as the fiber diameter of the nonwoven fabric.

(B) Fiber interval The fiber interval of a nonwoven fabric is calculated | required as follows. First, the nonwoven fabric to be measured is frozen and cured with liquid nitrogen and then cut. Next, the cut surface of the nonwoven fabric is photographed with a scanning electron microscope. Then, randomly select one fiber from the many fiber cross sections exposed on the cut surface of the nonwoven fabric, select 30 other fibers in order of distance from the selected fiber, and the fiber spacing with the selected fiber. And the median of the measured fiber spacing is calculated. Similarly, three median values are obtained for one nonwoven fabric, and the median value of the obtained three median values is set as the fiber interval of the nonwoven fabric.

3. Inner layer The inner layer 12 which comprises the medical base material 1 of this invention is comprised by the easily biocompatible cloth, and does not maintain the external shape of the medical base material 1, but promotes engraftment of endothelial cells etc. Thus, the self-renewal of the circulatory system such as the aorta is promoted, and finally replaced with vascular endothelial cells. The easy biocompatibility means that it has a higher affinity than the material of the outer layer 11. For this reason, the inner layer 12 is rapidly absorbed by the living body, and is preferably absorbed by the living body in about 1 to 12 months, for example.

(1) Easy biocompatible fabric The material of the easy biocompatible fabric constituting the inner layer 12 can be used without particular limitation as long as it is rich in biocompatibility. For example, polyglycolic acid, lactic acid and caprolactone And known bioabsorbable polymers such as L-polylactic acid, D-polylactic acid, copolymers of glycolic acid and lactic acid, gelatin, collagen, and elastin.

Note that the weight ratio of the monomers constituting the bioabsorbable polymer is not particularly limited as long as the biocompatibility is satisfied. In addition, one kind of bioabsorbable polymer may be used alone, or two or more kinds of bioabsorbable polymers may be mixed and used as long as easy biocompatibility is satisfied.

The readily biocompatible fabric constituting the inner layer 12 can be produced by a known method without particular limitation as long as it satisfies the easily biocompatible property. Specifically, it may be produced as a woven fabric or a knitted fabric by a known loom or knitting machine, and may be produced as a nonwoven fabric by a known method such as an electrospinning method or a melt blow method.

When the cloth constituting the inner layer 12 is made of a fiber material such as a woven cloth, a knitted cloth or a non-woven cloth, the fiber length of the fibers constituting the inner layer 12, the fiber diameter, and the ratio of the fiber diameter to the length are easily biocompatible. As long as the characteristics are satisfied, there is no particular limitation. However, the fiber diameter is preferably 20 μm or less, more preferably 10 μm or less, in terms of the median value. The reason is that if the fiber diameter is too large, blood turbulence is likely to occur, and the risk of closure of the blood vessel lumen due to thrombus formation increases.

The fiber spacing of the fibers of the readily biocompatible fabric constituting the inner layer 22 is preferably 100 μm or less, and more preferably 60 μm or less, in terms of the median value. Further, when the inner layer 22 is a porous body, the fiber interval (pore diameter) is preferably 200 μm or less, more preferably 100 μm or less, as indicated by its median value. When the fiber interval (pore diameter) is large, there is a high risk that the blood vessel will be blocked by thrombus formation when used for blood vessel regeneration, and it will not be possible to prevent leakage of liquid such as blood from the blood vessel wall.

The fiber length, the fiber diameter, the ratio between the fiber diameter and the length, and the fiber interval of the fibers constituting the easy biocompatible fabric may be single, but it is preferable that there is variation. The reason is the same as that of the outer layer 11. Further, the measurement method of the fiber diameter and the fiber interval of the fibers constituting the readily biocompatible fabric is the same as that of the outer layer 11.

4. Intermediate Layer The medical base material of the present invention may be provided with an intermediate layer between the inner layer and the outer layer. FIG. 3 is an external perspective view (a) and a cross-sectional view (b) of another medical base material 2 according to the present invention. As shown in this figure, the medical substrate 2 includes an outer layer 21, an inner layer 22, and an intermediate layer 23 disposed between the outer layer and the inner layer.

In addition, such a medical base material 2 can be manufactured by, for example, manufacturing each layer separately and then fitting them by hand or a known machine. Moreover, since the outer layer 21 and the inner layer 22 are the same structures as the outer layer 11 and the inner layer 12 of the medical base material 1, respectively, description is abbreviate | omitted.

The intermediate layer 23 is composed of a biodegradable cloth, and while maintaining the outer shape of the medical base material 2 together with the outer layer 21, helps the regeneration of nutrient blood vessels and media, and is finally absorbed by the body. (Hereinafter, abbreviated as absorption conditions).

As the material of the cloth constituting the intermediate layer 23, any known material can be used without particular limitation as long as the absorption condition is satisfied. Specifically, known bioabsorbable polymers such as polyglycolic acid, a copolymer of lactic acid and caprolactone, L-polylactic acid, D-polylactic acid, a copolymer of glycolic acid and lactic acid, gelatin, collagen, and elastin. Can be mentioned.

In addition, the weight ratio of the monomers constituting the bioabsorbable polymer is not particularly limited as long as the absorption condition is satisfied. If the absorption condition is satisfied, one type of bioabsorbable polymer may be used alone, or two or more types of bioabsorbable polymers may be mixed and used.

The cloth constituting the intermediate layer 23 can be manufactured by a known method without particular limitation as long as the absorption condition is satisfied. Specifically, it may be produced as a woven fabric or a knitted fabric by a known loom or knitting machine, and may be produced as a nonwoven fabric by a known method such as an electrospinning method or a melt blow method.

When the cloth constituting the intermediate layer 23 is made of a fiber material such as a woven cloth, a knitted cloth, or a non-woven cloth, the fiber length of the fibers constituting the cloth, the fiber diameter, and the ratio of the fiber diameter to the length are the absorption conditions. If it satisfies, there is no particular limitation. However, the fiber diameter of the fibers constituting the cloth constituting the intermediate layer 23 is preferably 50 μm or less, and more preferably 20 μm or less, as indicated by its median value.

In the case of a nonwoven fabric, the fiber spacing of the cloth constituting the intermediate layer 23 is preferably 3 to 300 μm, more preferably 5 to 100 μm, as indicated by its median value. In the case of woven or knitted fabric, the median value is preferably 15 μm to 1000 μm, more preferably 30 μm to 300 μm.

The fiber length, the fiber diameter, the ratio between the fiber diameter and the length, and the fiber interval of the fabric fibers constituting the intermediate layer 23 may be single, but it is preferable that there is variation. The reason is the same as that of the outer layer 11 described above. Further, the measurement method of the fiber diameter and the fiber interval of the fibers constituting the cloth is the same as that of the outer layer 11.

In addition, the medical base material of the present invention may be in the form of a sheet, for example, in addition to the tube shape shown in FIGS. For example, the sheet-like medical base material is wound around an affected area and used for regeneration thereof. In the case of this medical base material, the inner layer (innermost layer) arranged on the innermost side of the affected part promotes regeneration of the affected part by engraftment of endothelial cells and the like. On the other hand, the outer layer of the innermost layer, that is, the layer disposed on the outer membrane side of the circulatory system maintains the strength of the medical base material until the affected part is regenerated, and reaches the innermost layer or the feeding blood vessels reach the innermost layer. Since it is formed in a porous shape so as to penetrate into the vicinity, it helps the growth of vegetative blood vessels and the growth of engrafted endothelial cells and promotes the regeneration of the affected area.

Moreover, the medical base material of the present invention may include other layers as necessary in addition to the outer layer, the inner layer, and the intermediate layer shown in FIGS. For example, a protective layer may be provided to protect the anastomosis when the medical substrate is anastomosed to the aorta. Further, the outer layer may be overlapped a plurality of times around the inner layer.

Furthermore, the outer layer, the inner layer, and the intermediate layer may be thin porous bodies other than cloth, and when they are porous bodies, they can be produced by a known method without any particular limitation.

In addition, instead of sewing the cloth into a cylinder, the cloth may be manufactured in advance by a manufacturing method such as electrospinning or a flat knitting machine.

The present invention will be described in more detail below based on examples and the like. In addition, this invention is not limited by the following examples etc. in any meaning.

1. Performance comparison The effect of the difference in the materials composing the medical substrate on its performance was investigated by preparing artificial blood vessels and transplanting them into the arteries of experimental animals. Specifically, the experiment was performed as follows.

(1) Experimental animals and their acclimatization Female beagle dogs of around 1 year old who were not pregnant and purchased from Shimizu Experimental Animals Co., Ltd. were used as experimental animals (hereinafter abbreviated as dogs). During the experimental period, dogs were individually bred, kept under standard conditions for at least one week before the experiment, and were allowed free access to standard dog food and water.

(2) Production of artificial blood vessel Artificial blood vessels, Examples 1 to 5 and Comparative Examples 1 and 2 having different outer layer stiffness indices a were produced. Below, the detail of the produced artificial blood vessel is demonstrated.

1) Example 1
The outer layer and the intermediate layer fabric were overlapped, the overlapped fabric and the inner layer fabric were each rolled into a cylindrical shape, and the wall was sewn with 6-0 polypropylene single thread suture to produce a tube. These tubes were fitted together by hand to produce an artificial blood vessel (length 24 mm, inner diameter 5 mm to 6 mm). Finally, the stump of the artificial blood vessel was treated by heat melting, and the artificial blood vessel was further reinforced by applying a polylactic acid / caprolactone copolymer solution. The artificial blood vessel was sterilized with ethylene oxide gas before use.

Outer layer:
Non-run knitted fabric, which is a commercial pantyhose fabric, support yarn in which monofilament nylon yarn is entangled with elastomer yarn Fiber spacing: approx. 300 to 700 μm (because the mesh is irregular)
Number of fabric rolls: 3 times (6 times)
Stiffness index a: 3.3mmHg

Middle layer:
PLLA / CL (75% / 25%) copolymer fiber electrospun non-woven fabric Fiber spacing: 32μm (using spacers to extend the fiber spacing)
Thickness: 200 (140 to 260, depending on the part) μm
Number of fabric rolls: 3 times

Inner layer:
Polylactic acid electrospun nonwoven fiber spacing (average): 30 μm,
Fiber diameter (average): 3.9μm
Thickness: 200μm

2) Example 2
In the same manner as in Example 1, an artificial blood vessel (length 30 mm, inner diameter 6 mm) was produced.

Outer layer:
Stereocomplex polylactic acid fiber knitted fabric Molecular weight of stereocomplex polylactic acid: approx. 200,000 Crystal melting point of stereocomplex polylactic acid: 200-230 ° C
Monofilament diameter: 16-20μm,
Number of monofilaments / twisted yarn: 78 Uses false twisted yarn Interval between twisted yarns: There is a width due to irregular stitches, but average 400-1000μm
Number of fabric turns: 3 times Stiffness index a: 12mmHg

Middle layer:
PLA / CL (75% / 25%) electrospun non-woven fabric of copolymer fiber Fiber spacing: 32μm (use spacer)
Thickness: 200 (140 to 260, depending on the part) μm
Number of fabric rolls: 3 times

Inner layer:
PLA / CL (50% / 50%) copolymer fiber electrospun nonwoven fabric Electrospun nonwoven fabric Fiber spacing: 11μm
Fiber diameter: 0.8μm
Thickness: about 200μm

3) Example 3
In the same manner as in Example 1, an artificial blood vessel (length 30 mm, inner diameter 6 mm) was produced.

Outer layer:
Stereocomplex polylactic acid fiber knitted fabric (plain knitting)
Stereocomplex polylactic acid molecular weight: about 200,000 Crystalline melting point of stereocomplex polylactic acid: 200-230 ° C
Monofilament diameter: 16-20μm
Number of monofilaments / twisted yarn: 42,
Twist yarn interval: approx.
Number of fabric turns: 3 times Stiffness index a: 8.5mmHg

Inner layer:
PLA / CL (50% / 50%) electrospun nonwoven fabric of copolymer fibers Fiber spacing: 6.5μm
Fiber diameter: 0.8μm
Thickness: about 200μm

4) Example 4
In the same manner as in Example 1, an artificial blood vessel (length 30 mm, inner diameter 6 mm) was produced.

Outer layer:
Stereocomplex polylactic acid fiber knitted fabric (plain)
Stereocomplex polylactic acid molecular weight: about 200,000 Stereocomplex polylactic acid molecular weight: Crystal melting point = 200-230 ° C
Monofilament diameter: 16-20μm
Number of monofilaments / twisted yarn: 42,
Twisted yarn spacing: 700-1300μm
Number of fabric turns: 2 times Stiffness index a: 1.2mmHg

Middle layer:
PLA / CL (75% / 25%) electrospun non-woven fabric of copolymer fibers Fiber spacing: 32μm (use spacer)
Thickness: 200 (140 to 260, depending on the part) μm
Number of fabric turns: 2

Inner layer:
PLA / CL (50% / 50%) copolymer fiber electrospun non-woven fabric Fiber spacing: 6.5μm
Fiber diameter: 0.8μm
Thickness: about 200μm

5) Example 5
An artificial blood vessel (length: 34 mm, inner diameter: 7 mm) was produced by covering a commercially available tube-shaped artificial blood vessel with a soft shape processed as it was on the inner layer. Finally, the stump of the artificial blood vessel was treated by heat melting, and the artificial blood vessel was reinforced by applying a polylactic acid / caprolactone copolymer solution. The artificial blood vessel was sterilized with ethylene oxide gas before use.

Outer layer:
Cloth made by adding tanning to a commercially available artificial blood vessel (polyester cloth, manufactured by Terumo Corp.) Fiber spacing: 10.6 μm
Number of rolls of fabric: 1 time Stiffness index a: 27mmHg

Middle layer:
None.

Inner layer:
PLA / CL (75% / 25%) copolymer fiber electrospun nonwoven fabric Fiber spacing: 32μm
Fiber diameter: 4.8μm
Thickness: 300-350μm

6) Comparative Example 1
An artificial blood vessel (length 20 mm, inner diameter 6 mm) was prepared. The following commercially available artificial blood vessel (made of polyester, 7 mm inner diameter) was used as an outer layer, and it was used by covering it with an inner layer (6 mm inner diameter). Finally, the stump of the artificial blood vessel was treated by heat melting, and the artificial blood vessel was reinforced by applying a polylactic acid / caprolactone copolymer solution. The artificial blood vessel was sterilized with ethylene oxide gas before use.

Outer layer:
A commercially available artificial blood vessel (made of polyester, Terumo Corp., inner diameter: 7 mm) was used as an outer layer in a hard state as it was.
Fiber spacing: 7.0μm or less Stiffness index a: 53mmHg

Middle layer:
None.

Inner layer:
PLA electrospun nonwoven fabric Fiber spacing: 30μm
Fiber diameter: 3.9μm
Thickness: 440μm (use spacer)

7) Comparative Example 2
Artificial blood vessels (length 25 mm, inner diameter 6 mm) were prepared. The following commercially available artificial blood vessel (made of polytetrafluoroethylene, 7 mm inner diameter) was used as it was as an outer layer in a hard state, and this was put on the inner layer (6 mm inner diameter) for use. Finally, the stump of the artificial blood vessel was treated by heat melting, and the artificial blood vessel was reinforced by applying a polylactic acid / caprolactone copolymer solution. The artificial blood vessel was sterilized with ethylene oxide gas before use.

Outer layer:
Commercially available artificial blood vessels (made of polytetrafluoroethylene, with outer wall reinforcement, manufactured by Nippon Gore Co., Ltd.) are used in the hard state as they are. Space between gaps of walls: 30 μm or less Stiffness index a: 147 mmHg

Middle layer:
None.

Inner layer:
PLA electrospun nonwoven fiber spacing: 30μm
Fiber diameter: 3.9μm
Thickness: 200μm (use spacer)

(3) Experimental Method All the following surgical procedures were performed under aseptic conditions by a single surgical team. The dog was anaesthetized with 34 mg / kg intravenous anesthesia of pentobarbital, a respiratory tube was intubated into the trachea of the dog, and general anesthesia was performed with inhalation anesthesia of 40% oxygen and sevoflurane or isoflurane. Under general anesthesia, the dog was fixed in the supine position and the abdominal body hair was shaved. The skin was cleaned with 80% ethanol solution containing 5% chlorhexidine and disinfected with 10% povidone iodine solution.

A 15 cm open wound was placed in the midline of the abdomen, and the retroperitoneum was incised. The peripheral abdominal aorta from the renal artery bifurcation was exposed to the common iliac bifurcation. During this detachment, the lumbar artery was ligated and disconnected. The connective tissue around the artery was removed. After intravenous injection of 1000 units / kg body weight of low molecular heparin, the aorta was grasped with two forceps. The aorta was excised over a length of 10 mm between the two forceps. Two stumps of the aorta were washed with a heparin saline, an artificial blood vessel having a length of 25 mm and an inner diameter of 5 to 7 mm was interposed between the two stumps of the aorta, and the aorta and the tube were anastomosed to each other. That is, the tube stump and the aortic wall stump were sewn together with 12 needle sutures of 6-0 polypropylene single thread suture. The peritoneal incision edges were sewn together and the laparotomy wound was closed with a two-layer suture. After surgery, anticoagulant therapy with 2000 units of low molecular weight heparin and 100 mg aspirin or 1 mg warfarin was performed per day.

10 to 18 months after surgery, dogs were euthanized by intravenous injection of 100 mg / kg pentobarbital. The abdomen was resumed, and surgically resected in a lump including the aorta in the part where the artificial blood vessel was implanted and the surrounding tissue, and the resected specimen was examined macroscopically and microscopically.

After the macroscopic evaluation of this excised specimen, it is fixed in 10% neutral formalin solution, made into a microscopically sliced specimen with a thickness of 4μm using standard techniques, and hematoxylin / eosin staining (HE staining) is applied to the optical microscope. Observed at. For comparison, the aortic wall of a dog (natural) to which an artificial blood vessel was not transplanted was also observed with an optical microscope.

(4) Experimental Results The results of macroscopic observation of the parts transplanted with the artificial blood vessels of Examples 1 to 4 and Comparative Examples collected from dogs and the results of observation of the excised specimen with a microscope are briefly described below. In addition, the results of observation with a microscope are shown in FIGS.

1) Results of Example 1 After 12 months, the dog was euthanized, and the artery where the artificial blood vessel was implanted was collected and observed. Visual observation showed no abnormal findings such as thrombus formation, aneurysm or stenosis. Further, in the microscopic observation (FIG. 4), the formation of the inner part of the intima and the media was already stable and good at 6 months and was very similar to the natural aortic structure shown in FIG. Thus, the overall evaluation of Example 1 was good.

2) Results of Example 2 After 10 months, the dog was euthanized, and the artery where the artificial blood vessel was implanted was collected and observed. Visual observation showed no abnormal findings such as thrombus, aneurysm or stenosis. Further, in the microscopic observation (FIG. 5), the formation of the inner part of the inner membrane and the inner membrane was stable and good. Thus, the overall evaluation of Example 2 was good.

3) Results of Example 3 After 17 months, the dog was euthanized, and the arterial portion of the grafted artificial blood vessel was collected and observed. Visual observation showed no abnormal findings such as thrombus, aneurysm or stenosis. Further, in the microscopic observation (FIG. 6), the formation of the inner part of the inner membrane and the inner membrane was stable and good. Thus, the overall evaluation of Example 3 was good.

4) Results of Example 4 After 10 months, the dog was euthanized, and the artery where the artery scaffold was transplanted was collected and observed. Visual observation showed no abnormal findings such as thrombus, aneurysm or stenosis. Moreover, in the microscopic observation (FIG. 7), the formation of the inner part of the inner membrane and the inner membrane was stable and good. Thus, the overall evaluation of Example 4 was good.

5) Results of Example 5 After 10 months, the dog was euthanized, and the artery where the artery scaffold was transplanted was collected and observed. Visual observation showed no abnormal findings such as thrombus, aneurysm or stenosis. Moreover, in the microscopic observation (FIG. 8), the formation of the inner part of the inner membrane and the inner membrane was stable and good. Thus, the overall evaluation of Example 5 was good.

6) Results of Comparative Example 1 After 10 months, the dog was euthanized, and the arterial portion of the grafted artificial blood vessel was collected and observed. Macroscopically, the lumen was completely obstructed with an organized thrombus. Further, in microscopic observation (FIG. 9), polyester fibers and PLLA fibers were found in contact with the organized thrombus in the lumen. Thus, the overall evaluation of Comparative Example 1 was poor.

7) Results of Comparative Example 2 After 10 months, the dog was euthanized, and the arterial portion of the grafted artificial blood vessel was collected and observed.
As a result of macroscopic observation and microscopic observation, formation of intima and media in the lumen surface was unstable, and artificial blood vessels were also exposed in part of the lumen. Thus, the overall evaluation of Comparative Example 2 was poor.

In summary, after transplanting the artificial blood vessel of the example, when the transplanted part was observed with the naked eye, it was confirmed that it functions as a regenerating aorta. That is, it was confirmed that the aorta blood flowed in the transplanted portion and had a lumen without a thrombus. On the other hand, when the artificial blood vessel of the comparative example was transplanted, it was confirmed that the transplanted portion was blocked by a thrombus.

Also, when the aorta implanted with the artificial blood vessel of the example was observed with a microscope, the inner membrane layer and the inner portion of the media were regenerated, and the structure was very similar to the structure of the natural aorta. Moreover, even if some of the artificial blood vessels remained, the regeneration of part of these intima layers and media layers was good, and thrombus formation, abnormal tissue growth, stenosis / occlusion were not observed. On the other hand, when the artificial blood vessel of the comparative example was transplanted, the formation of the intima and media in the transplanted part was unstable, and the artificial blood vessel was also exposed in a part of the lumen of the transplanted part. .

Furthermore, Table 1 summarizes the stiffness index a and its performance for the examples and comparative examples. As shown in Table 1, the stiffness index a of Examples 1 to 4 was 1.2 to 12, and was distributed between 1/5 and 5.5 times the stiffness index a of the aorta to be transplanted. The stiffness index a in Example 5 was 27, 4.5 to 24 times the stiffness index a of the aorta to be transplanted. On the other hand, the stiffness index a of Comparative Examples 1 and 2 was 53 and 147, which was 8.8 to 67 times the stiffness index a of the aorta to be transplanted.

Thus, the ratio of the stiffness index a of the artificial blood vessel and the stiffness index a of the portion to be transplanted (here, the aorta) may be within an average of 7.5 times (Example 5). It has been found that double (Examples 1 to 4 are all within this range) is more preferable. On the contrary, it was found that it is not preferable that the ratio is 8.8 times or more (Comparative Examples 1 and 2).

In addition, the effect of the fiber spacing of the fabric constituting the outer layer of the artificial blood vessel on the transplantation results was also considered. As shown in Table 1, Example 1 (average 300 to 700 μm), Example 2 (average 400 to 1000 μm), Example 3 (about 100 to 200 μm), and Example 4 (700 to 1300 μm) have sufficiently large fiber intervals. ) Had a good evaluation.

On the other hand, the evaluation result of Example 5 in which the fiber spacing was only 10.6 μm at the maximum was slightly good, and the evaluation result of Comparative Example 1 in which the maximum fiber spacing was only 7.0 μm was poor. Thus, it was found that the large fiber spacing is also related to the favorable evaluation results.

In addition to Examples 1 to 5, an artificial blood vessel having various configurations was prepared by combining the outer layer fabric described in Table 2, the intermediate layer fabric described in Table 3, and the inner layer fabric described in Table 4. Then, it was transplanted into a dog, and the change over time was observed with an ultrasonic diagnostic apparatus over 6 months (20 months at the longest). The observation results are summarized in Table 5.

As shown in Table 5, the artificial blood vessels of the examples (total 38) are arteries with abnormal progress such as arteriosclerosis, stenosis / occlusion, rupture, aneurysmization, etc. during the observation period of 6 to 20 months. Only 4 reproductions were recognized. In contrast, 15 artificial blood vessels in the comparative example (18 in total) were abnormal within the observation period (of which 4 were abnormal within 2 months).

Thus, the aorta could be regenerated with a high probability by transplanting the artificial blood vessel of the present invention. In contrast, even with the same configuration, an artificial blood vessel (comparative example) having an outer layer with the stiffness index a deviating from a certain range could not properly regenerate the aorta. That is, it was found that the stiffness index a of the outer layer is related to aortic regeneration.

The medical base material of the present invention is a medical base material suitable for regeneration of the circulatory system, and in particular, when exposed to a high pressure from the lumen like an artery, a lumen diameter that easily forms a thrombus Is suitable for relatively thin artificial blood vessels of 6 to 8 mm or less, venous and portal vein systems that tend to form thrombus even when thick, and blood vessels for artificial dialysis shunts.

1, 2

Medical base material

11, 21

Outer layer

12, 22 Inner layer 23 Intermediate layer

Claims

A medical base material that has a sheet shape, a tube shape, or a combination thereof, and is used for regeneration of the circulatory system by transplanting it into the body, and is disposed on the inner membrane side of the circulatory system It has a multilayer structure comprising at least an inner layer and an outer layer disposed on the outer membrane side of the circulatory system from the inner layer,
The layer arranged on the outer membrane side of the circulatory system with respect to the inner layer is formed in a porous shape so that the nutrient blood vessels reach the inner layer or enter the vicinity of the inner layer,
For the stiffness index a determined by the following method, the ratio of the stiffness index a of the outer layer of the tubular medical substrate to the stiffness index a of the grafted blood vessel is within 7.5,
[Method of determining stiffness index a]
(1) Hold an L-shaped jig between the upper and lower chucks of the tensile tester, and pass the tube-shaped object to be measured between the two L-shaped jigs to keep the section of the object to be measured round and circular. The inner wall of the object to be measured becomes parallel, but the force is not applied, and the measurement is started at the time when the measurement is started. D0 is the length in the tensile direction, L0 is the length in the vertical axis direction of the object to be measured, and T0 is the wall thickness of the object to be measured.
(2) Measure the tension Nx, the length Dx in the tensile direction, the length Lx in the vertical direction, and the wall thickness Tx multiple times while pulling at the same pulling speed from the start of measurement.
(3) The elongation rate x is calculated by the formula X = (Dx−D0) / D0 × 100 (%).
(4) When the stress σx in the tensile direction applied to the inner wall of the object to be measured is calculated by equation (4a), and this stress is assumed to be caused by the internal pressure of the object to be measured having the inner radius Rx by equation (4b) Calculate the tube internal pressure Yx corresponding to
(4a) σx = Nx / (Tx × Lx × 2)
(4b) Yx = σx × Tx / Rx = π × Nx / 2 (Dx × Lx)
(5) Constants a and b are determined by the method of least squares so that the obtained elongation rate X and the corresponding internal pressure Y approximate a linear function Y = aX + b (a and b are constants).
2. The medical base material according to claim 1, wherein the ratio of the rigidity index a of the outer layer of the tubular medical base material / the rigidity index a of the grafted blood vessel is within 5.5.
The medical substrate according to claim 2, wherein the cloth is a woven fabric or a knitted fabric.
The inner layer is at least one selected from the group consisting of polyglycolic acid, a copolymer of lactic acid and caprolactone, L-polylactic acid, D-polylactic acid, a copolymer of glycolic acid and lactic acid, gelatin, collagen, and elastin. The medical base material according to any one of claims 1 to 3, which is made of a material.
The medical base material according to claim 4, wherein the inner layer is composed of an easily biocompatible cloth made of a fiber material.