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WO2018199263A1 - Substrat médical - Google Patents

Substrat médical Download PDF

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Publication number
WO2018199263A1
WO2018199263A1 PCT/JP2018/017074 JP2018017074W WO2018199263A1 WO 2018199263 A1 WO2018199263 A1 WO 2018199263A1 JP 2018017074 W JP2018017074 W JP 2018017074W WO 2018199263 A1 WO2018199263 A1 WO 2018199263A1
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WIPO (PCT)
Prior art keywords
blood vessel
fiber
inner layer
layer
measured
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PCT/JP2018/017074
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English (en)
Japanese (ja)
Inventor
明郎 萩原
Original Assignee
明郎 萩原
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Application filed by 明郎 萩原 filed Critical 明郎 萩原
Publication of WO2018199263A1 publication Critical patent/WO2018199263A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A61F2/06—Blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits

Definitions

  • 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.
  • non-bioabsorbable materials such as polyester, nylon, silk thread, etc.
  • biodegradable materials such as polylactic acid, caprolactone, PGA, gelatin, collagen, etc.
  • 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.
  • 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.
  • 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
  • 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).
  • 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).
  • 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.
  • 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.
  • a circulatory system such as blood vessels such as arteries and veins, heart, and lymphatic vessels because the outer layer has appropriate rigidity.
  • 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. 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
  • 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.
  • 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.
  • the medical base material of the present invention is used as an artificial blood vessel.
  • 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.
  • the medical base material 1 includes an outer layer 11 and an inner layer 12 disposed on the inner side.
  • the inner layer 12 may be integrated with the outer layer 11, or may be installed in multiple layers.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • the fiber constituting the outer layer 11 a single fiber may be used, or a plurality of fibers may be blended and used.
  • 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.
  • 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.
  • FIG. 2 is a diagram for explaining a method for determining the stiffness index a.
  • the artificial blood vessel and the rigidity index a of the blood vessel are determined by the following procedures 1) to 5).
  • the unit of the constant a obtained is millimeter of mercury (mmHg).
  • 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.
  • the fiber diameter is preferably 0.1 to 50 ⁇ m, more preferably 0.5 to 30 ⁇ m in terms of median value.
  • it is preferably 50 ⁇ m or more, more preferably 100 ⁇ m 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.
  • the median value is preferably 5 ⁇ m to 1000 ⁇ m, more preferably 15 ⁇ m to 500 ⁇ m. If it is smaller than 5 ⁇ m, 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.
  • the fiber spacing is preferably 15 ⁇ m to 2000 ⁇ m, more preferably 30 ⁇ m to 1500 ⁇ m.
  • the fiber spacing is in the range between 20 ⁇ m and 1/4 of the outer circumference of the blood vessel, preferably between 100 ⁇ m and 1/6 of the outer circumference of the blood vessel, and 250 ⁇ m to the outer circumference of the blood vessel. It is more preferable that the length is 1/8.
  • 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.).
  • 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.
  • 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.
  • interval The fiber space
  • 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).
  • 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.
  • the weave is a pseudo circle
  • this is regarded as a circle
  • the diameter of the circle is defined as the fiber interval of this circle.
  • the median of the fiber intervals of 30 randomly selected pseudo circles is set as the fiber interval of the cloth.
  • (B) Fiber interval The fiber interval of a nonwoven fabric is calculated
  • 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.
  • 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.
  • 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.
  • the weight ratio of the monomers constituting the bioabsorbable polymer is not particularly limited as long as the biocompatibility is satisfied.
  • 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.
  • the fiber length of the fibers constituting the inner layer 12 is easily biocompatible.
  • the fiber diameter is preferably 20 ⁇ m or less, more preferably 10 ⁇ m 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 ⁇ m or less, and more preferably 60 ⁇ m 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 ⁇ m or less, more preferably 100 ⁇ m 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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).
  • any known material can be used without particular limitation as long as the absorption condition is satisfied.
  • 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.
  • 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.
  • 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.
  • the fiber diameter of the fibers constituting the cloth constituting the intermediate layer 23 is preferably 50 ⁇ m or less, and more preferably 20 ⁇ m or less, as indicated by its median value.
  • the fiber spacing of the cloth constituting the intermediate layer 23 is preferably 3 to 300 ⁇ m, more preferably 5 to 100 ⁇ m, as indicated by its median value.
  • the median value is preferably 15 ⁇ m to 1000 ⁇ m, more preferably 30 ⁇ m to 300 ⁇ m.
  • 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.
  • 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.
  • the sheet-like medical base material is wound around an affected area and used for regeneration thereof.
  • 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.
  • 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.
  • 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.
  • a protective layer may be provided to protect the anastomosis when the medical substrate is anastomosed to the aorta.
  • the outer layer may be overlapped a plurality of times around the inner layer.
  • 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.
  • the cloth may be manufactured in advance by a manufacturing method such as electrospinning or a flat knitting machine.
  • mice 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.
  • 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.
  • 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 ⁇ m (because the mesh is irregular)
  • Middle layer PLLA / CL (75% / 25%) copolymer fiber electrospun non-woven fabric Fiber spacing: 32 ⁇ m (using spacers to extend the fiber spacing) Thickness: 200 (140 to 260, depending on the part) ⁇ m Number of fabric rolls: 3 times
  • Inner layer Polylactic acid electrospun nonwoven fiber spacing (average): 30 ⁇ m, Fiber diameter (average): 3.9 ⁇ m Thickness: 200 ⁇ m
  • 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: 16-20 ⁇ m, Number of monofilaments / twisted yarn: 78 Uses false twisted yarn Interval between twisted yarns: There is a width due to irregular stitches, but average 400-1000 ⁇ m 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: 32 ⁇ m (use spacer) Thickness: 200 (140 to 260, depending on the part) ⁇ m Number of fabric rolls: 3 times
  • Inner layer PLA / CL (50% / 50%) copolymer fiber electrospun nonwoven fabric Electrospun nonwoven fabric Fiber spacing: 11 ⁇ m Fiber diameter: 0.8 ⁇ m Thickness: about 200 ⁇ m
  • 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: 16-20 ⁇ m Number of monofilaments / twisted yarn: 42, Twist yarn interval: approx. Number of fabric turns: 3 times Stiffness index a: 8.5mmHg
  • Middle layer PLA / CL (75% / 25%) electrospun non-woven fabric of copolymer fiber Fiber spacing: 32 ⁇ m (use spacer) Thickness: 200 (140 to 260, depending on the part) ⁇ m Number of fabric rolls: 3 times
  • Inner layer PLA / CL (50% / 50%) electrospun nonwoven fabric of copolymer fibers Fiber spacing: 6.5 ⁇ m Fiber diameter: 0.8 ⁇ m Thickness: about 200 ⁇ m
  • Example 4 In the same manner as in Example 1, an artificial blood vessel (length 30 mm, inner diameter 6 mm) was produced.
  • Stereocomplex polylactic acid fiber knitted fabric plain
  • Stereocomplex polylactic acid molecular weight about 200,000
  • Monofilament diameter 16-20 ⁇ m
  • Middle layer PLA / CL (75% / 25%) electrospun non-woven fabric of copolymer fibers Fiber spacing: 32 ⁇ m (use spacer) Thickness: 200 (140 to 260, depending on the part) ⁇ m Number of fabric turns: 2
  • Inner layer PLA / CL (50% / 50%) copolymer fiber electrospun non-woven fabric Fiber spacing: 6.5 ⁇ m Fiber diameter: 0.8 ⁇ m Thickness: about 200 ⁇ m
  • 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 ⁇ m Number of rolls of fabric: 1 time Stiffness index a: 27mmHg
  • Inner layer PLA / CL (75% / 25%) copolymer fiber electrospun nonwoven fabric Fiber spacing: 32 ⁇ m Fiber diameter: 4.8 ⁇ m Thickness: 300-350 ⁇ m
  • 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: 7.0 ⁇ m or less Stiffness index a: 53mmHg
  • Inner layer PLA electrospun nonwoven fabric Fiber spacing: 30 ⁇ m Fiber diameter: 3.9 ⁇ m Thickness: 440 ⁇ m (use spacer)
  • 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 ⁇ m or less Stiffness index a: 147 mmHg
  • Inner layer PLA electrospun nonwoven fiber spacing: 30 ⁇ m Fiber diameter: 3.9 ⁇ m Thickness: 200 ⁇ m (use spacer)
  • 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.
  • the lumbar artery was ligated and disconnected.
  • the connective tissue around the artery was removed.
  • the aorta was grasped with two forceps.
  • the aorta was excised over a length of 10 mm between the two forceps.
  • 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.
  • this excised specimen 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 4 ⁇ m 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.
  • HE staining hematoxylin / eosin staining
  • Example 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.
  • Example 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.
  • Example 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.
  • Example 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.
  • Example 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.
  • the artificial blood vessel of the example 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.
  • 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. .
  • Table 1 summarizes the stiffness index a and its performance for the examples and comparative examples.
  • 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.
  • 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.
  • the ratio of the stiffness index a of the artificial blood vessel and the stiffness index a of the portion to be transplanted 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).
  • Example 1 (average 300 to 700 ⁇ m), Example 2 (average 400 to 1000 ⁇ m), Example 3 (about 100 to 200 ⁇ m), and Example 4 (700 to 1300 ⁇ m) have sufficiently large fiber intervals. ) Had a good evaluation.
  • Example 5 the evaluation result of Example 5 in which the fiber spacing was only 10.6 ⁇ m at the maximum was slightly good, and the evaluation result of Comparative Example 1 in which the maximum fiber spacing was only 7.0 ⁇ m was poor.
  • the large fiber spacing is also related to the favorable evaluation results.
  • 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.
  • the artificial blood vessels of the examples 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).
  • the aorta could be regenerated with a high probability by transplanting the artificial blood vessel of the present invention.
  • 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.

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  • Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Cardiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Anesthesiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pulmonology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Prostheses (AREA)
  • Materials For Medical Uses (AREA)

Abstract

La présente invention concerne un substrat médical adapté à la reproduction d'un système circulatoire, le substrat médical étant adapté à un vaisseau sanguin dans lequel un caillot se forme facilement, par exemple, un vaisseau sanguin artificiel relativement étroit qui a un diamètre de lumière de 6-8 mm ou moins et est exposé à une haute pression à partir de la lumière, tel qu'un vaisseau sanguin de système veineux ou une artère. Le substrat médical selon la présente invention est en forme de feuille, en forme de tube ou une combinaison de ces formes, et est transplanté dans un corps et utilisé pour reproduire un système circulatoire, le substrat médical ayant une structure multicouche comportant au moins une couche interne disposée sur un côté de la membrane interne d'un système circulatoire, et une couche externe disposée davantage vers un côté de la membrane externe du système circulatoire que la couche interne, la couche disposée davantage vers le côté de la membrane externe du système circulatoire que la couche interne étant façonnée sous une forme poreuse de telle sorte qu'un vaisseau sanguin d'alimentation atteigne la couche interne ou puisse pénétrer à proximité de la couche interne, et en ce qui concerne un indice de rigidité a déterminé par un procédé spécifique, le rapport de l'indice de rigidité a de la couche externe du substrat médical en forme de tube sur l'indice de rigidité a d'un vaisseau sanguin greffé est de 7,5 ou moins.
PCT/JP2018/017074 2017-04-28 2018-04-26 Substrat médical WO2018199263A1 (fr)

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WO2020147733A1 (fr) * 2019-01-16 2020-07-23 武汉杨森生物技术有限公司 Procédé de préparation de matériau pour vaisseau sanguin artificiel, vaisseau sanguin artificiel préparé par ce procédé et application correspondante
JP7498558B2 (ja) * 2019-12-23 2024-06-12 グンゼ株式会社 人工血管及び人工血管の製造方法
KR102546622B1 (ko) * 2022-10-06 2023-06-22 주식회사 티엠디랩 혈관 외벽 지지체의 인장강도 측정장치

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JP2011512201A (ja) * 2008-02-14 2011-04-21 テンジオン， インコーポレイテッド 組織工学足場
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