Artificial blood vessel, and artificial blood vessel production method

Abstract

To provide an artificial blood vessel capable of preventing excessive blood leakage, also to provide an artificial blood vessel production method that enables the same.SOLUTION: An artificial blood vessel includes a tubular porous body having interconnected pores and a biodegradable material contained within the pores, and has a porosity of 10% or less. Since the artificial blood vessel not only contains a biodegradable material in the interconnected pores of the porous tube but also maintains a porosity of 10% or less, excessive leakage of blood to the outside of the artificial blood vessel can be prevented. An artificial blood vessel production method includes immersing a pre-immersion artificial blood vessel in an aqueous solution containing a water-soluble biodegradable material in a pressure-reduced environment, increasing the ambient pressure of the aqueous solution in which the pre-immersion artificial blood vessel is immersed, and insolubilizing the water-soluble biodegradable material contained in the post-immersion artificial blood vessel.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to an artificial blood vessel and a method for producing the artificial blood vessel. [Background technology]

[0002] Hemodialysis patients undergo vascular access, such as a natural or synthetic intravascular shunt. Synthetic intravascular shunts are typically used when the creation of a natural intravascular shunt is difficult. To create a synthetic intravascular shunt, an artificial blood vessel is typically used to connect an artery to a vein (e.g., the cephalic or basilic vein).

[0003] Various technologies related to artificial blood vessels are known. For example, Patent Document 1 describes the production of an artificial blood vessel having a polyurethane porous tube with a pore size of 200 μm and a collagen gel filling the mesh structure of the polyurethane porous tube. Non-Patent Document 1 describes an artificial blood vessel having a tubular polyurethane porous body and a gelatin layer formed in the lumen of the tubular polyurethane porous body. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Laid-Open No. 2003-284767 [Non-patent literature]

[0005] [Non-Patent Document 1] Buddy Ratner. Vascular Grafts: Technology Success / Technology Failure. BME Front. 2023;4:0003.DOI:10.34133 / bmef.0003 Summary of the Invention [Problem to be solved by the invention]

[0006] Artificial blood vessels are sometimes required to have minimal leakage of blood flowing through them, specifically, minimal leakage from their surfaces. However, the artificial blood vessel described in Patent Document 1 may leak excessive blood from its surface when implanted in a living body. This is because the artificial blood vessel is fabricated by clamping one end of a porous polyurethane tube, injecting a collagen solution into the other end of the porous polyurethane tube, removing the clamp, inserting a mandrel into the porous polyurethane tube, and maintaining the tube at 37°C. This makes it unlikely that the collagen solution would penetrate the 200 μm pores. In other words, the mesh structure of this artificial blood vessel is not actually filled with collagen gel. Additionally, the porous polyurethane tube of this artificial blood vessel has interconnected pores.

[0007] An object of the present invention is to provide an artificial blood vessel capable of preventing excessive blood leakage, and a method for manufacturing the artificial blood vessel capable of preventing excessive blood leakage. [Means for solving the problem]

[0008] In order to solve this problem, the artificial blood vessel of the present invention has the following configuration [1]. [1] a tubular porous body having communicating holes; a biodegradable material contained in the communication hole, The porosity is 10% or less. Artificial blood vessel.

[0009] According to [1], the artificial blood vessel contains a biodegradable material in the pores of a tubular porous body (hereinafter sometimes referred to as a "porous tube"), and as the biodegradable material decomposes in the body, the number of vacant pores increases. Therefore, as the biodegradable material decomposes, tissues, capillaries, cells, etc. can penetrate into the pores.

[0010] Moreover, the artificial blood vessel not only contains a biodegradable material within the communicating pores of the porous tube, but also has a porosity of 10% or less, thereby preventing excessive blood leakage. Hereinafter, this will be explained. If the communicating pores of the porous tube were empty, the blood flowing through the artificial blood vessel would pass through the communicating pores, which could result in excessive blood leakage outside the artificial blood vessel. In contrast, the artificial blood vessel of [1] not only contains a biodegradable material within the communicating pores of the porous tube, but also has a porosity of 10% or less, thereby preventing excessive blood leakage outside the artificial blood vessel. In other words, excessive blood leakage can be prevented.

[0011] The artificial blood vessel of the present invention preferably further comprises the following components [2] to

[10] . [2] The artificial blood vessel according to [1], wherein the insoluble content of the biodegradable material is 40% or more. [3] The artificial blood vessel according to [1] or [2], wherein the porosity of the porous body itself is 30% or more. [4] The artificial blood vessel according to any one of [1] to [3], wherein the biodegradable material is at least one of a cross-linked gelatin gel and collagen. [5] The artificial blood vessel according to any one of [1] to [4], wherein the biodegradable material is a cross-linked gelatin gel. [6] The artificial blood vessel according to any one of [1] to [5], wherein the porous body contains a thermoplastic polyurethane elastomer. [7] the porous body includes a tubular first porous layer and a tubular second porous layer surrounding the first porous layer; the porosity of the first porous layer itself is smaller than the porosity of the second porous layer itself; The artificial blood vessel according to any one of [1] to [6]. [8] When water is passed through the artificial blood vessel at a water pressure of 16.0 kPa, the amount of water leaking from the outer surface of the artificial blood vessel is 1.0 mL / (cm 2The artificial blood vessel according to any one of [1] to [7], wherein the maximum operating time is 10 minutes or less. [9] The artificial blood vessel according to any one of [1] to [8], which has a simplified compliance of 1.3% / 100 mmHg to 1.8% / 100 mmHg.

[10] The artificial blood vessel according to any one of [1] to [9], which is used for creating a vascular access.

[0012] On the other hand, the method for producing an artificial blood vessel according to the present invention comprises the following constitution

[11] .

[11] A method for producing an artificial blood vessel according to any one of [1] to

[10] , a step of immersing the pre-immersion artificial blood vessel containing the porous body in an aqueous solution containing a water-soluble biodegradable material under a reduced pressure environment; increasing the atmospheric pressure of the aqueous solution in which the artificial blood vessel is immersed before immersion; and a step of insolubilizing the water-soluble biodegradable material contained in the artificial blood vessel after immersion. A method for manufacturing artificial blood vessels.

[12] The method for producing an artificial blood vessel according to

[11] , wherein the water-soluble biodegradable material is gelatin.

[13] The method for producing an artificial blood vessel according to

[11] or

[12] , wherein in the step of insolubilizing the water-soluble biodegradable material, the artificial blood vessel is irradiated with an electron beam after the immersion.

[14] The method for producing an artificial blood vessel according to any one of

[11] to

[13] , wherein the temperature of the aqueous solution is 40° C. or higher while the pre-immersion artificial blood vessel is immersed in the aqueous solution.

[0013] The present invention also preferably has the following configuration.

[15] An artificial blood vessel or a method for producing the same according to any one of the above configurations, wherein the porosity of the artificial blood vessel is 9% or less or 7% or less.

[16] An artificial blood vessel or a method for producing the same according to any one of the above configurations, wherein the porosity of the artificial blood vessel is 5% or less.

[17] The amount of water (i.e., the amount of water leaking from the outer surface of the artificial blood vessel when water is flowed through the artificial blood vessel at a water pressure of 16.0 kPa) is 0.5 mL / (cm 2 min) or less or 0.1 mL / (cm 2 1. An artificial blood vessel according to any one of the preceding configurations, or a method for producing the same, wherein the length of the artificial blood vessel is 100 mm or less.

[18] An artificial blood vessel or a method for producing the same according to any one of the above configurations, wherein the simplified compliance ratio of the artificial blood vessel is 2.6 to 3.7.

[19] An artificial blood vessel or a method for producing the same according to any one of the above configurations, wherein the thickness of the porous body is 0.5 mm or more or 1.0 mm or more.

[20] An artificial blood vessel or a method for producing the same according to any one of the above configurations, wherein the thickness of the porous body is 2.0 mm or less or 1.5 mm or less. [twenty one] An artificial blood vessel or a method for producing the same according to any one of the above configurations, wherein the porosity of the porous body itself is 35% or more or 40% or more. [twenty two] An artificial blood vessel or a method for producing the same according to any one of the above configurations, wherein the porosity of the porous body itself is 70% or less or 60% or less. [twenty three] An artificial blood vessel according to any of the above configurations, or a method for producing the same, wherein the porous body has, in a log differential pore volume distribution curve, at least one peak having an apex in the pore diameter range of more than 100 μm and not more than 1000 μm, and at least one peak having an apex in the pore diameter range of not more than 100 μm. [twenty four] An artificial blood vessel or a method for producing the same according to any of the above configurations, wherein the difference between the porosity of the second porous layer itself and the porosity of the first porous layer itself is 15% or more or 20% or more. [twenty five] An artificial blood vessel or a method for producing the same according to any one of the above configurations, wherein the porosity of the second porous layer itself is 40% or more or 45% or more.

[26] An artificial blood vessel or a method for producing the same according to any one of the above configurations, wherein the porosity of the second porous layer itself is 50% or more.

[27] An artificial blood vessel or a method for producing the same according to any one of the above configurations, wherein the porosity of the second porous layer itself is 70% or less or 60% or less.

[28] An artificial blood vessel or a method for manufacturing the same, according to any of the above configurations, wherein the thickness of the second porous layer is greater than the thickness of the first porous layer or is at least twice the thickness of the first porous layer.

[29] An artificial blood vessel or a method for producing the same according to any of the above configurations, wherein the thickness of the second porous layer is at least three times or at least four times the thickness of the first porous layer.

[30] An artificial blood vessel or a method for manufacturing the same, as described in any of the above configurations, wherein the total thickness of the first porous layer and the second porous layer is 90% or more or 95% or more of the 100% thickness of the porous body.

[31] An artificial blood vessel or a method for producing the same according to any of the above configurations, wherein the total thickness of the first porous layer and the second porous layer accounts for 100% of the total thickness of the porous body.

[32] An artificial blood vessel or a method for producing the same according to any one of the above configurations, wherein the content of the thermoplastic polyurethane elastomer in the porous body is 90% by mass or more, or 95% by mass or more.

[33] An artificial blood vessel or a method for producing the same according to any one of the above configurations, wherein the content of the thermoplastic polyurethane elastomer in the porous body is 98% by mass or more, or 98% by mass or more.

[34] An artificial blood vessel or a method for producing the same according to any one of the above configurations, wherein the content of the thermoplastic polyurethane elastomer in the porous body is 100% by mass.

[35] An artificial blood vessel or a method for producing the same according to any one of the above configurations, wherein the insoluble content of the biodegradable material is 45% or more or 50% or more.

[36] An artificial blood vessel or a method for producing the same according to any one of the above configurations, wherein the insoluble content of the biodegradable material is 70% or less or 60% or less.

[37] An artificial blood vessel according to any of the above configurations, or a method for manufacturing the same, wherein the artificial blood vessel further includes a first thread extending in a clockwise spiral from the first end to the second end of the porous body.

[38] An artificial blood vessel described in any of the above configurations, or a method for manufacturing the same, wherein the artificial blood vessel further includes a second thread extending spirally counterclockwise from the first end of the porous body toward the second end.

[39] The artificial blood vessel or the method for producing the same according to any one of the above configurations, wherein the content of the water-soluble biodegradable material in the aqueous solution is 5% by mass or more or 7% by mass or more.

[40] The method for producing an artificial blood vessel according to any one of the above aspects, wherein the content of the water-soluble biodegradable material in the aqueous solution is 15% by mass or less or 12% by mass or less.

[41] The method for producing an artificial blood vessel according to any one of the above configurations, wherein the reduced pressure environment is an environment of 25 kPa or less or 20 kPa or less.

[42] The method for producing an artificial blood vessel according to any one of the above configurations, wherein the reduced pressure environment is an environment of 15 kPa or less.

[43] The method for producing an artificial blood vessel according to any one of the above configurations, wherein the time for immersing the pre-immersion artificial blood vessel in the aqueous solution under the reduced pressure environment is 1 minute or more or 3 minutes or more.

[44] The method for producing an artificial blood vessel according to any one of the above configurations, wherein in the step of increasing the atmospheric pressure, the atmospheric pressure is increased to or above atmospheric pressure.

[45] The method for producing an artificial blood vessel according to any one of the above aspects further comprises the step of removing the artificial blood vessel from the aqueous solution after the immersion.

[46] The method for producing an artificial blood vessel according to any one of the above configurations, wherein in the step of insolubilizing the water-soluble biodegradable material, the artificial blood vessel after the immersion is irradiated with the electron beam at 20 kGy or more or 25 kGy.

[47] The method for producing an artificial blood vessel according to any one of the above configurations, wherein in the step of insolubilizing the water-soluble biodegradable material, the artificial blood vessel after the immersion is irradiated with the electron beam at 60 kGy or less or 45 kGy or less. [Effects of the Invention]

[0014] According to the present invention, it is possible to provide an artificial blood vessel capable of preventing excessive blood leakage and a method for manufacturing the same. [Brief explanation of the drawings]

[0015] [Figure 1] 1 is a photograph of an example of an artificial blood vessel according to the present embodiment taken obliquely from above. [Figure 2] 1 is a micrograph of a cross section perpendicular to the longitudinal direction of an example of an artificial blood vessel before immersion according to the present embodiment. [Figure 3A] This is a photograph of the device used to prepare the artificial blood vessel before immersion in Preparation Example 1. The device includes a cylindrical rod and mold A including an inner wall capable of forming a cylindrical cavity concentric with the rod. Mold A includes a pair of half-split frames. This photograph shows the device after assembly. [Figure 3B] 1 is a photograph of the device used to prepare the artificial blood vessel before immersion in Preparation Example 1. This photograph shows the device with a pair of halves of the frame separated. [Figure 4] On the left is shown an analysis area cut out from a micrograph of the cross section of the vascular prosthesis before immersion in order to determine the porosity of the vascular prosthesis before immersion in Preparation Example 1 (i.e., the porosity of the porous tube itself). On the right is shown a binary image of this analysis area. [Figure 5]On the left is shown an analysis area cut out from a micrograph of the cross section of the artificial blood vessel to determine the porosity of the artificial blood vessel of Example 1. On the right is shown a binary image of this analysis area. [Figure 6] On the left is shown an analysis range cut out from a micrograph of the cross section of the artificial blood vessel to determine the porosity of the artificial blood vessel of Comparative Example 1. On the right is shown a binary image of this analysis range. [Figure 7] On the left is shown an analysis range cut out from a micrograph of the cross section of the artificial blood vessel in order to determine the porosity of the artificial blood vessel of Comparative Example 2. On the right is shown a binary image of this analysis range. [Figure 8] On the left is shown an analysis area cut out from a micrograph of the cross section of the artificial blood vessel in order to determine the porosity of the artificial blood vessel of Example 2. On the right is shown a binary image of this analysis area. [Figure 9] On the left is shown an analysis area cut out from a micrograph of the cross section of the artificial blood vessel in order to determine the porosity of the artificial blood vessel of Example 4. On the right is shown a binary image of this analysis area. [Figure 10] 1 is a photograph of the surgical field during shunt construction in Example 5. The artificial blood vessel is in the area surrounded by the dotted line. [Figure 11] This is a photograph of the surgical field taken one month after shunt construction in Example 5. Although the artificial blood vessel is hidden by the surrounding tissue, it is in the area enclosed by the dotted line. [Figure 12] This is an HE-stained image taken one month after shunt construction in Example 5. This HE-stained image is an image of an HE-stained section including a cross section roughly perpendicular to the longitudinal direction of the artificial blood vessel. Note that because a blade was inserted along the longitudinal direction of the extracted artificial blood vessel, an opening can be seen in the HE-stained image. DETAILED DESCRIPTION OF THE INVENTION

[0016] Hereinafter, embodiments of the present invention will be described in detail.

[0017] <1.Artificial blood vessel> As shown in Figure 1, the artificial blood vessel of this embodiment comprises a tubular porous body (i.e., a porous tube) and a biodegradable material in the pores of the porous tube, specifically in the communicating pores. Because the artificial blood vessel of this embodiment comprises a biodegradable material in the communicating pores of the porous tube, the number of vacant communicating pores increases as the biodegradable material decomposes in the body. Therefore, as the decomposition of the biodegradable material progresses, tissues, capillaries, cells, or the like can penetrate into the communicating pores.

[0018] The artificial blood vessel may further include a first thread (hereinafter sometimes referred to as a "first reinforcing thread") extending helically in a clockwise direction from the first end to the second end of the porous tube. The artificial blood vessel may further include a second thread (hereinafter sometimes referred to as a "second reinforcing thread") extending helically in a counterclockwise direction from the first end to the second end of the porous tube.

[0019] The artificial blood vessel of this embodiment can be suitably used for creating vascular access, and in particular, can be more suitably used for creating vascular access for dialysis.

[0020] An artificial blood vessel has an inner lumen surface (hereinafter sometimes referred to as the "inner surface") and an outer surface. The artificial blood vessel may be, for example, a straight type, a tapered type, or a short taper type. Of these, the straight type is preferred. Here, the straight type means a shape in which the inner diameter is constant throughout the entire artificial blood vessel. Both ends of the artificial blood vessel are open.

[0021] The inner diameter of the artificial blood vessel is preferably 4 mm to 6 mm, more preferably 5 mm to 6 mm. When the inner diameter is 4 mm to 6 mm, the artificial blood vessel can be more suitably used for creating vascular access. In addition, when the artificial blood vessel is, for example, a tapered type or a short taper type, the inner diameter in this specification means the maximum inner diameter.

[0022] The thickness of the artificial blood vessel is preferably 0.5 mm or more, more preferably 1.0 mm or more, while the thickness of the artificial blood vessel is preferably 2.0 mm or less, more preferably 1.5 mm or less.

[0023] The length of the artificial blood vessel may be, for example, 50 mm or more, 100 mm or more, 200 mm or more, or 300 mm or more. The length of the artificial blood vessel may be 600 mm or less, or 500 mm or less. Note that the artificial blood vessel may be cut as necessary to adjust the length before placement, and in this paragraph, the length of the porous tube refers to the length before cutting.

[0024] The porosity of the artificial blood vessel is 10% or less. Since the artificial blood vessel contains a biodegradable material in the communicating pores of the porous tube and the porosity of the artificial blood vessel is 10% or less, excessive leakage of blood outside the artificial blood vessel can be prevented. In other words, excessive blood leakage can be prevented. The porosity is preferably 9% or less. The porosity may be, for example, 7% or less, or 5% or less.

[0025] The filling rate of the artificial blood vessel is preferably 60% or more, and more preferably 65% ​​or more. At 60% or more, excessive blood leakage can be further prevented. The filling rate of the artificial blood vessel may be, for example, 70% or more, or 80% or more.

[0026] The permeability of the artificial blood vessel (i.e., the amount of water leaking from the outer surface of the artificial blood vessel when water is passed through the artificial blood vessel at a water pressure of 16.0 kPa) is 1.0 mL / (cm 2 ·min) or less is preferable, and 0.5mL / (cm 2 ·min) or less is preferable, and 0.1mL / (cm 2 1.0 mL / (cm 2 If the blood flow rate is less than 1 / 2 min, excessive blood leakage can be further prevented.

[0027] The simplified compliance ratio of the artificial blood vessel is preferably 2.6 to 3.7. When the simplified compliance ratio is 2.6 to 3.7, the compliance of the artificial blood vessel is considered to be equal to or close to that of a vein, and therefore, when the artificial blood vessel is anastomosed to a vein, turbulence at the anastomosis site can be suppressed or reduced.

[0028] The simplified compliance of the artificial blood vessel is preferably 1.3% / 100mmHg to 1.8% / 100mmHg, because when the simplified compliance of the artificial blood vessel is in this range, the simplified compliance ratio of the artificial blood vessel is 2.6 to 3.7 (i.e., the preferred range).

[0029] <1.1.Porous pipe> The porous tube has an inner surface (hereinafter sometimes referred to as an "inner surface") and an outer surface, and both ends (i.e., the first end and the second end) of the porous tube are open.

[0030] The description of the inner diameter of the porous tube will be omitted because it overlaps with the description of the inner diameter of the artificial blood vessel. Therefore, the description of the inner diameter of the artificial blood vessel can also be used as the description of the inner diameter of the porous tube. However, the inner diameter of the porous tube and the inner diameter of the artificial blood vessel do not have to be the same. In other words, the inner diameter of the porous tube and the inner diameter of the artificial blood vessel may be the same or different. For example, the inner diameter of the porous tube may be larger than the inner diameter of the artificial blood vessel.

[0031] The description of the thickness of the porous tube will be omitted because it overlaps with the description of the thickness of the artificial blood vessel. Therefore, the description of the thickness of the artificial blood vessel can also be used as the description of the thickness of the porous tube. However, the thickness of the porous tube and the thickness of the artificial blood vessel do not have to be the same. In other words, the thickness of the porous tube and the thickness of the artificial blood vessel may be the same or different. For example, the thickness of the porous tube may be smaller than the thickness of the artificial blood vessel.

[0032] The explanation of the length of the porous tube is omitted here because it overlaps with the explanation of the length of the artificial blood vessel. Therefore, the explanation of the length of the artificial blood vessel can also be used as the explanation of the length of the porous tube.

[0033] A porous tube has interconnected pores. Specifically, the porous tube has interconnected pores extending from the inner surface of the porous tube to the outer surface of the porous tube. This allows tissues, capillaries, cells, and the like to invade the porous tube. This promotes their infiltration, which in turn promotes intimal formation.

[0034] The porosity of the porous tube itself is preferably 30% or more, more preferably 35% or more, and even more preferably 40% or more. This is because the higher the porosity, the greater the flexibility of the porous tube, and the compliance of the artificial blood vessel after the biodegradable material has decomposed tends to approach the compliance of a vein. On the other hand, the porosity of the porous tube itself may be, for example, 70% or less, 65% or less, or 60% or less.

[0035] It is preferable that the porous tube has at least one peak (hereinafter sometimes referred to as the "L peak") with a peak apex in the pore diameter range of more than 100 μm to 1000 μm in the log differential pore volume distribution curve, and at least one peak (hereinafter sometimes referred to as the "S peak") with a peak apex in the pore diameter range of 100 μm or less. When the porous tube has an L peak, i.e., relatively large pores, tissues, capillaries, cells, etc. can more easily penetrate the porous tube. When the porous tube has an S peak, i.e., small pores, it is possible to increase the frequency of contact between tissues, capillaries, cells, etc. and the artificial blood vessel when they enter the small pores, which may result in promoting tissue settlement.

[0036] The L peak may have a peak apex in the pore diameter range of 105 μm or more and 1000 μm or less, or may have a peak apex in the pore diameter range of 120 μm or more and 1000 μm or less.

[0037] The log differential pore volume of the L peak is preferably 3.0 mL / g or more, more preferably 4.0 mL / g or more, while the log differential pore volume of the L peak may be, for example, 8.0 mL / g or less, or 7.0 mL / g or less.

[0038] The S peak may have a peak apex in a pore diameter range of 60 μm or less, or may have a peak apex in a pore diameter range of 40 μm or less.

[0039] The log differential pore volume of the S peak is preferably 1.0 mL / g or more, while the log differential pore volume of the S peak may be, for example, 6.0 mL / g or less, or 5.0 mL / g or less.

[0040] The pore size distribution can be measured by mercury intrusion porosimetry. Specifically, the measurement can be performed using a pore size distribution measuring device, Autopore V9620, manufactured by Micromeritics, at an initial pressure of 1.5 kPa.

[0041] The porous tube may have a single-layer structure or a multi-layer structure, with the multi-layer structure being preferred.

[0042] As shown in Figure 2, the porous tube may include a tubular first porous layer and a tubular second porous layer surrounding the first porous layer. Note that Figure 2 is a micrograph of a cross section of an example of an artificial blood vessel before immersion (i.e., a porous tube with a monofilament). The first porous layer of the porous tube shown in Figure 2 has a thickness similar to the diameter of the monofilament, is located closer to the lumen surface than the second porous layer, and is denser than the second porous layer.

[0043] The porosity of the first porous layer itself is preferably smaller than that of the second porous layer itself. Because the porosity of the first porous layer itself is smaller than that of the second porous layer itself, the strength of the artificial blood vessel can be increased compared to when the porous tube is made only of the second porous layer. Therefore, when the artificial blood vessel is anastomosed to a blood vessel (e.g., a vein or an artery), rupture of the artificial blood vessel due to sutures can be prevented or reduced.

[0044] The difference between the porosity of the second porous layer itself and the porosity of the first porous layer itself (i.e., the porosity of the second porous layer itself - the porosity of the first porous layer itself) is preferably 15% or more, more preferably 20% or more, which further prevents or reduces rupture of the artificial blood vessel by the suture.

[0045] The porosity of the second porous layer itself is preferably 40% or more, more preferably 45% or more, and even more preferably 50% or more. On the other hand, the porosity of the second porous layer itself may be, for example, 70% or less, 65% or less, or 60% or less. Of course, the porosity of the second porous layer itself may be, for example, 40% or less, 35% or less, or 30% or less.

[0046] The thickness of the second porous layer is preferably greater than the thickness of the first porous layer, and may be at least two times, at least three times, or at least four times the thickness of the first porous layer.

[0047] The total thickness of the first porous layer and the second porous layer is preferably 90% or more, more preferably 95% or more, and even more preferably 100% of the total thickness of the porous tube.

[0048] The porous pipe preferably contains a thermoplastic elastomer. When the porous pipe contains a thermoplastic elastomer, the porous pipe is easy to manufacture. The porous pipe may further contain components other than the thermoplastic elastomer (for example, additives).

[0049] An example of a thermoplastic elastomer is a thermoplastic polyurethane elastomer. When a porous tube contains a thermoplastic polyurethane elastomer, the porous tube is easy to manufacture. Moreover, in this case, it is possible to impart entropy elasticity to the porous tube, thereby providing an artificial blood vessel that is easy to place.

[0050] Examples of thermoplastic polyurethane elastomers include Pellethane (registered trademark), ChronoFlex (registered trademark), ChronoThane (registered trademark), and HydroThane (registered trademark), which are preferred because medical grade products are commercially available.

[0051] The thermoplastic elastomer preferably has entropy elasticity at least at 30° C. to 42° C. When the porous tube has entropy elasticity, an artificial blood vessel that can be easily placed can be provided.

[0052] The content of the thermoplastic elastomer in the porous pipe is preferably 90% by mass or more, more preferably 95% by mass or more, even more preferably 97% by mass or more, and even more preferably 98% by mass or more. The content of the thermoplastic elastomer in the porous pipe may be 100% by mass.

[0053] <1.1.1. Manufacturing method of porous pipe> As an example of a method for producing a porous pipe, a preferred method for producing a porous body containing a thermoplastic polyurethane elastomer will be described.

[0054] The method for producing a porous pipe may include the steps of preparing a porous polyurethane stock solution containing a thermoplastic polyurethane elastomer, dimethyl sulfoxide, and a pore-forming agent that is insoluble in dimethyl sulfoxide and water-soluble (hereinafter referred to as the "preparation step"); solidifying the porous polyurethane stock solution by cooling it while it is in a tubular state (hereinafter referred to as the "solidification step"); and washing the tubular solid product of the solidified porous polyurethane stock solution with water (hereinafter referred to as the "washing step"). This production method can produce a porous pipe having pores derived from the pore-forming agent and pores derived from dimethyl sulfoxide crystals. The method for producing a porous pipe may further include the step of drying the porous pipe obtained in the washing step.

[0055] <1.1.1.1.Preparation process> In this step, a stock solution of porous polyurethane is prepared. For example, the stock solution of porous polyurethane can be prepared by mixing and stirring a thermoplastic polyurethane elastomer and dimethyl sulfoxide, and then adding a pore-forming agent and stirring the mixture, or by mixing a thermoplastic polyurethane elastomer and a pore-forming agent with dimethyl sulfoxide and stirring the mixture. The former is preferred.

[0056] The temperature of dimethyl sulfoxide mixed with at least the thermoplastic polyurethane elastomer is preferably 70°C or higher. At 70°C or higher, the thermoplastic polyurethane elastomer can be easily dissolved in dimethyl sulfoxide. The temperature of dimethyl sulfoxide may be, for example, 80°C or higher, or 90°C or higher. The temperature of dimethyl sulfoxide may be, for example, 150°C or lower, or 120°C or lower.

[0057] The pore-forming agent is a particle that is insoluble in dimethyl sulfoxide and water-soluble. The particle size of the pore-forming agent can be adjusted using a mortar, a sieve, etc. An example of the pore-forming agent is sodium chloride.

[0058] The content of the thermoplastic polyurethane elastomer is preferably 3% by mass or more, more preferably 4% by mass or more, and even more preferably 5% by mass or more, based on 100% by mass of the polyurethane porous material liquid. On the other hand, the content of the thermoplastic polyurethane elastomer is preferably 7% by mass or less, more preferably 6% by mass or less, and even more preferably 5.5% by mass or less, based on 100% by mass of the polyurethane porous material liquid. The lower the content of the thermoplastic polyurethane elastomer, the higher the porosity of the porous pipe can be.

[0059] The content of the pore-forming agent is preferably 10% by mass or more, more preferably 20% by mass or more, and even more preferably 30% by mass or more, based on 100% by mass of the polyurethane porous material stock solution, while the content of the pore-forming agent is preferably 60% by mass or less, more preferably 55% by mass or less, and even more preferably 50% by mass or less, based on 100% by mass of the polyurethane porous material stock solution.

[0060] The total content of the thermoplastic polyurethane elastomer, dimethyl sulfoxide, and pore-forming agent is preferably 90% by mass or more, more preferably 95% by mass or more, even more preferably 98% by mass or more, and even more preferably 100% by mass, based on 100% by mass of the polyurethane porous material solution.

[0061] <1.1.1.2. Solidification process> In this step, the porous polyurethane liquid is solidified by cooling it while it is in a tubular state. To create a tubular state of the porous polyurethane liquid, it is preferable to prepare a cylindrical rod and a mold including an inner wall capable of forming a cylindrical cavity concentric with the rod, and fill the space between the rod and the inner wall (i.e., the tubular space) with the porous polyurethane liquid.

[0062] To solidify the porous polyurethane liquid, the porous polyurethane liquid is cooled to a temperature below the freezing point of dimethyl sulfoxide, for example, 10°C or below, 0°C or below, or -10°C or below.

[0063] <1.1.1.3. Cleaning process> In this step, the tubular solid formed by solidifying the polyurethane porous material stock solution is washed with water. Because both dimethyl sulfoxide and the pore-forming agent are soluble in water, washing the tubular solid with water can remove the dimethyl sulfoxide and pore-forming agent from the tubular solid. Therefore, a porous tube can be obtained by washing the tubular solid with water. For example, tap water, ion-exchanged water, distilled water, or ultrapure water can be used to wash the tubular solid. Note that water washing may be performed multiple times. For example, the tubular solid may be washed with water below the freezing point of dimethyl sulfoxide (e.g., ice-cold water), and then further washed with warm water at 50°C to 70°C. After washing with water, the porous tube may be dried.

[0064] <1.1.1.4. Other processes> The porous tube may be cut to adjust its length.

[0065] <1.2. Biodegradable materials> Examples of biodegradable materials include cross-linked gelatin gel and collagen. These are preferred because they have cell adhesive properties. Among these, cross-linked gelatin gel is preferred because its dissolution rate in blood is slower than that of gelatin or cross-linked gelatin sol, and therefore the cross-linked gelatin gel can extend the time during which excessive blood leakage can be prevented. Note that cross-linked gelatin gel refers to cross-linked gelatin that forms a gel at 40°C.

[0066] The insoluble fraction of the biodegradable material is preferably 40% or more. This is because the higher the insoluble fraction of the biodegradable material, the slower the biodegradable material dissolves in blood, and therefore the higher the insoluble fraction, the longer the period of time that excessive blood leakage can be prevented. The insoluble fraction may be, for example, 45% or more, or 50% or more. On the other hand, the insoluble fraction may be, for example, 70% or less, or 60% or less.

[0067] <1.3. First reinforcing thread> The first reinforcing thread can extend in a clockwise spiral from the first end to the second end of the porous tube, and the first reinforcing thread can prevent or reduce kinking (i.e., closure of the lumen of the vascular graft due to excessive bending of the vascular graft).

[0068] The first reinforcing yarns may extend spirally on the outer surface of the porous pipe, or may extend spirally inside the porous pipe, but it is particularly preferable that the first reinforcing yarns extend spirally inside the porous pipe.

[0069] The pitch of the first reinforcing threads may be, for example, 1 mm or more, or 2 mm or more, while the pitch of the first reinforcing threads may be, for example, 10 mm or less, or 5 mm or less.

[0070] The diameter of the first reinforcing yarns may be, for example, 100 μm or more, or 120 μm or more, while the diameter of the first reinforcing yarns may be, for example, 200 μm or less, or 180 μm or less.

[0071] Examples of the first reinforcing yarn include filament yarn and spun yarn. Examples of the filament yarn include monofilament and multifilament. Of these, monofilament is preferred. Examples of the monofilament include polyester monofilament, nylon monofilament, and polypropylene monofilament. Of these, polyester monofilament is preferred.

[0072] <1.4. Second reinforcing thread> The second reinforcing yarn may extend counterclockwise in a spiral pattern from the first end to the second end of the porous tube. The second reinforcing yarn may further prevent or reduce kinking.

[0073] The explanation of the second reinforcing threads will be omitted because it overlaps with the explanation of the first reinforcing threads. Therefore, the explanation of the first reinforcing threads can also be used as an explanation of the second reinforcing threads.

[0074] <1.5.Other> The artificial blood vessel may further include a layer (hereinafter sometimes referred to as a "coating layer") that covers the outer surface of the porous tube. The coating layer may contain a biodegradable material. A description of the biodegradable material of the coating layer will be omitted here, as it overlaps with the description of the biodegradable material in the communicating holes. Therefore, the description of the biodegradable material in the communicating holes can also be used as a description of the biodegradable material of the coating layer.

[0075] On the other hand, the artificial blood vessel may further include a layer covering the inner surface of the porous tube.The artificial blood vessel may also include components other than the biodegradable material (for example, additives) in the communicating pores of the porous tube.

[0076] 2. Method of manufacturing artificial blood vessels The method for producing an artificial blood vessel in this embodiment includes the steps of immersing a pre-immersion artificial blood vessel in an aqueous solution containing a water-soluble biodegradable material under reduced pressure (hereinafter sometimes referred to as the "immersion step"), increasing the atmospheric pressure of the aqueous solution in which the pre-immersion artificial blood vessel is immersed (hereinafter sometimes referred to as the "pressurization step"), removing the post-immersion artificial blood vessel from the aqueous solution (hereinafter sometimes referred to as the "removal step"), and insolubilizing the water-soluble biodegradable material contained in the post-immersion artificial blood vessel (hereinafter sometimes referred to as the "insolubilization step"). The method for producing an artificial blood vessel in this embodiment may further include the step of preparing a pre-immersion artificial blood vessel (hereinafter sometimes referred to as the "preparation step") prior to the immersion step.

[0077] <2.1. Preparation process> In this step, a pre-immersion artificial blood vessel is prepared. The pre-immersion artificial blood vessel may be the same as the artificial blood vessel of this embodiment except that the porous tube does not contain a biodegradable material in the communicating pores. The pre-immersion artificial blood vessel includes a porous tube. The pre-immersion artificial blood vessel may further include a first reinforcing thread. The pre-immersion artificial blood vessel may further include a second reinforcing thread.

[0078] <2.2. Soaking process> In this process, the artificial blood vessel before immersion is immersed in an aqueous solution containing a water-soluble biodegradable material under reduced pressure. For example, the artificial blood vessel before immersion, with the mandrel inserted, is immersed (i.e., placed) in the aqueous solution in a container, and then the container and the artificial blood vessel before immersion are placed in a desiccator, the pressure in the desiccator is reduced, and the reduced pressure state is maintained. The diameter of the mandrel is preferably 0.9 to 1.1 times the inner diameter of the porous tube, and more preferably equal to the inner diameter of the porous tube.

[0079] Gelatin is preferred as the water-soluble biodegradable material. The content of the water-soluble biodegradable material in the aqueous solution is preferably 5% by mass or more, more preferably 7% by mass or more. If it is 5% by mass or more, the gel strength is high and the pressure resistance is high. On the other hand, the content of the water-soluble biodegradable material in the aqueous solution is preferably 15% by mass or less, more preferably 12% by mass or less. If it is 12% by mass or less, the viscosity of the aqueous solution is low, making it easier to fill the porous tube.

[0080] The reduced pressure environment is an environment below atmospheric pressure. The reduced pressure environment is preferably an environment of 25 kPa or less, more preferably an environment of 20 kPa or less, and even more preferably an environment of 15 kPa or less. This can reduce the porosity of the artificial blood vessel.

[0081] While the artificial blood vessel is immersed in the aqueous solution under reduced pressure, the temperature of the aqueous solution is preferably 35° C. or higher, more preferably 40° C. or higher, which can reduce the porosity of the artificial blood vessel.

[0082] The time for which the artificial blood vessel is immersed in the aqueous solution under reduced pressure before immersion, that is, the immersion time under reduced pressure, is preferably 1 minute or more, more preferably 3 minutes or more, and even more preferably 5 minutes or more.

[0083] <2.3. Pressurization process> In this step, the atmospheric pressure of the aqueous solution in which the artificial blood vessel is immersed is increased, preferably to a pressure higher than atmospheric pressure, and more preferably to atmospheric pressure.

[0084] <2.4. Removal process> In this step, the artificial blood vessel is taken out of the aqueous solution after immersion, and if necessary, the aqueous solution adhering to the surface of the porous tube of the artificial blood vessel after immersion is removed.

[0085] <2.5. Insolubilization step> In this step, the water-soluble biodegradable material contained in the artificial blood vessel after immersion is insolubilized. For insolubilization, it is preferable to irradiate the artificial blood vessel with an electron beam after immersion. When the water-soluble biodegradable material is gelatin, this allows the gelatin to be crosslinked without using a crosslinking agent that may affect the body. When crosslinking gelatin with an electron beam, the dose of the electron beam is preferably 20 kGy or more, more preferably 25 kGy or more. At 20 kGy or more, the gelatin aqueous solution can be effectively gelled and the insoluble content can be increased. On the other hand, the dose of the electron beam may be, for example, 80 kGy or less, 60 kGy or less, 50 kGy or less, or 45 kGy or less. Among these, 45 kGy or less is preferred from the viewpoint of preventing excessive yellowing of the porous tube.

[0086] <3. Various modifications can be made to the above-described embodiment> The above-described embodiment can be modified in various ways. For example, the above-described embodiment can be modified by selecting one or more of the following modifications.

[0087] In the above-described embodiment, the artificial blood vessel is used for creating a vascular access. However, the present embodiment is not limited to this configuration. For example, the artificial blood vessel may be used for revascularization.

[0088] In the above-described embodiment, the artificial blood vessel is manufactured by a method including a step of removing the artificial blood vessel from the aqueous solution after immersion (i.e., a removal step) between the pressurizing step and the insolubilizing step. However, the present embodiment is not limited to this configuration. For example, the removal step may be omitted. [Example]

[0089] The present invention will be described in more detail below with reference to examples and comparative examples. Unless otherwise specified, "parts" means "parts by mass" and "%" means "% by mass".

[0090] <1. Evaluation method> <1.1.Filling rate> Before immersion, the dimensions of the artificial blood vessel (specifically, the length and outer diameter) were measured using a ruler bearing the Japanese Industrial Standards (JIS) mark. Meanwhile, the thickness of the wall of the artificial blood vessel before immersion was measured using the following method. A 76 razor (specifically, a 76 razor manufactured by Nissin EM Co., Ltd.) was pressed against the artificial blood vessel before immersion in a direction perpendicular to the longitudinal direction of the artificial blood vessel before immersion, and then the artificial blood vessel before immersion was pressed through. This resulted in a sample having a cross section perpendicular to the longitudinal direction of the artificial blood vessel before immersion. The sample was fixed on the sample stage of a scanning electron microscope (SEM, specifically, an IT-200 manufactured by JEOL Ltd.) with the cross section facing upward. The cross section of the sample was observed under the following conditions. High Vacuum Mode Detector: Secondary electron detector (SED) Accelerating voltage: 5 kV Irradiation current: 30μA From the observed images, the thickness of the wall of the artificial blood vessel before immersion was determined. The apparent volume of the artificial blood vessel before immersion was calculated from the lengthwise dimension, outer diameter, and thickness of the artificial blood vessel before immersion. Apparent volume and polyurethane (Lubrizol, Pellethan 2363-80AE, density 1.05 g / cm 3 The void ratio in the artificial blood vessel before immersion was calculated from the density of the vascular graft. Void ratio = Weight of artificial blood vessel before immersion / Apparent volume of artificial blood vessel before immersion / Density of polyurethane × 100 In this formula, the weight of the artificial blood vessel before immersion is substituted in g. In this formula, the apparent volume of the artificial blood vessel before immersion is substituted in cm. 3 In this formula, the density of polyurethane is in g / cm 3 The unit value is substituted. Meanwhile, the net volume of the artificial blood vessel before immersion was calculated as defined by the following formula: Net volume = Weight of artificial blood vessel before immersion / Density of polyurethane / (100 - void ratio) / 100 In this formula, the weight of the vascular prosthesis before immersion is substituted in mg. In this formula, the density of polyurethane is expressed in mg / cm. 3 The unit value is substituted. After immersion, the weight of the gelatin aqueous solution (specifically, a 10% by mass gelatin aqueous solution described below) in the artificial blood vessel was calculated using the following formula. Weight of gelatin solution = Weight of artificial blood vessel after immersion - Weight of artificial blood vessel before immersion In this formula, values ​​in mg are substituted for the weight of the artificial blood vessel after immersion and the weight of the artificial blood vessel before immersion. Assuming that all of the pores of the artificial blood vessel after immersion were filled with the gelatin aqueous solution, the weight of the gelatin aqueous solution in the artificial blood vessel after immersion (hereinafter sometimes referred to as the "theoretical weight of the gelatin aqueous solution") was calculated using the following formula. Theoretical weight of gelatin solution = Net volume x void ratio / 100 x density of gelatin solution In this formula, the net volume is in cm 3 In this formula, the density of a 10% gelatin solution is expressed in mg / cm 3 The unit value is substituted. Finally, the filling rate of the gelatin aqueous solution was calculated using the following formula: Filling rate of gelatin aqueous solution = weight of gelatin aqueous solution / theoretical weight of gelatin aqueous solution x 100 In this formula, values ​​in mg are substituted for the weight of the gelatin aqueous solution and the theoretical weight of the gelatin aqueous solution.

[0091] <1.2. Porosity> <1.2.1.SEM> A 76 razor (specifically, a 76 razor manufactured by Nisshin EM Co., Ltd.) was pressed against the artificial blood vessel in a direction perpendicular to the longitudinal direction of the artificial blood vessel, and then the artificial blood vessel was pushed through. This resulted in an artificial blood vessel for observation, with a cross section perpendicular to the longitudinal direction of the artificial blood vessel. The artificial blood vessel for observation was fixed on the sample stage of a scanning electron microscope (SEM, specifically, an IT-200 manufactured by JEOL Ltd.) with the cross section facing upward. The cross section of the artificial blood vessel for observation was observed under the following conditions. Low vacuum mode: 30Pa Detector: Backscattered electron detector BED Accelerating voltage: 10 kV Irradiation current: 60μA 1.2.2. Calculation of porosity The observed image was opened in image processing software called ImageJ, and the analysis range was cut out using a rectangular frame. The rectangular frame used to cut out the analysis range included the first, second, third, and fourth sides. The first side of the rectangular frame was a line segment extending in the thickness direction of the porous body on the observed image. The second side was a line segment passing through the intersection of the first side and the inner surface of the porous body and perpendicular to the first side. The third side was a line segment extending parallel to the first side at an interval of 0.5 mm. The fourth side was a line segment passing through the intersection of the first side and the outer surface of the porous body and perpendicular to the first side. The analysis range was binarized into pores and non-pores using ImageJ. The porosity was then calculated using ImageJ. The porosity was calculated using the following formula: Porosity = Pore area in the analysis range / Area of ​​the analysis range × 100 A total of two analysis ranges were cut out from one observation image, and the porosity of each analysis range was calculated. The two analysis ranges were the first analysis range and the second analysis range located opposite each other across the lumen of the artificial blood vessel. When selecting the two analysis ranges, care was taken to avoid including reinforcing threads in either analysis range. The average values ​​of these porosities are shown in Table 2 below. The porosity of the artificial blood vessel before immersion was also measured in the same manner as the porosity of the artificial blood vessel.

[0092] <1.3.Water permeability> A first tube was attached to the first end of the artificial blood vessel. A second tube was attached to the second end of the artificial blood vessel. Water was allowed to flow through the artificial blood vessel for one minute at a water pressure of 16.0 kPa via the first tube, and the amount of water leaking from the outer surface of the artificial blood vessel, i.e., the amount of water leakage, was measured. During this time, the water flowing through the artificial blood vessel was discharged through the second tube. Water permeability = Water leakage / (Area of ​​the outer surface of the artificial blood vessel x Time) In this formula, the leakage volume is substituted in mL. In this formula, the outer surface area of ​​the artificial blood vessel is substituted in cm. 2 In this formula, time is substituted with a value in minutes (min).

[0093] <1.4. Simple Compliance Test> <1.4.1.Preparation> Before the simple compliance test, the inner diameter of the artificial blood vessel (hereinafter referred to as "D inside The outer diameter of the artificial blood vessel (hereinafter referred to as "D") was measured using a cylindrical taper gauge (Niigata Seiki Co., Ltd. CGTPG710A). outer The thickness of the artificial blood vessel wall (hereinafter sometimes referred to as "t") was calculated using the following formula: t=(D outer -D inside ) / 2 A first tube was attached to a first end of the vascular graft for a simple compliance test, and a second tube was attached to a second end of the vascular graft.

[0094] 1.4.2. Low Pressure Compliance The outer diameter of the artificial blood vessel (hereinafter referred to as "D 7.0 The outer diameter of the artificial blood vessel (hereinafter referred to as "D") was measured using a laser displacement meter. During this time, the water flowing into the artificial blood vessel was discharged from the second tube. Next, the outer diameter of the artificial blood vessel (hereinafter referred to as "D") was measured while water was flowing into the artificial blood vessel through the first tube at a water pressure of 12.0 kPa (90.0 mmHg) ± 0.3 kPa (2.3 mmHg). 12.0The outer diameter was measured using a laser displacement meter. The outer diameter of the central part of the artificial blood vessel was measured using a laser displacement meter. During this time, the water flowing through the artificial blood vessel was discharged through the second tube.The radius of the lumen of the artificial blood vessel (hereinafter sometimes referred to as the "inner radius") under each water pressure was then calculated using the following formula. R 7.0 =D 7.0 / 2-t R 12.0 =D 12.0 / 2-t where R 7.0 is the inner radius under 7.0 kPa. R 12.0 is the inner radius under 12.0 kPa. The low pressure compliance was calculated using the following formula: Low pressure compliance = (R 12.0 -R 7.0 ) / R 7.0 / (90.0-52.5)×10 4 In this formula, R 12.0 and R 7.0 is substituted with a value in mm.

[0095] <1.4.3. Medium Pressure Compliance> The outer diameter of the artificial blood vessel (hereinafter referred to as "D 10.7 The outer diameter of the artificial blood vessel (hereinafter referred to as "D") was measured using a laser displacement meter. During this time, the water flowing into the artificial blood vessel was discharged from the second tube. Next, the outer diameter of the artificial blood vessel (hereinafter referred to as "D") was measured while water was flowing into the artificial blood vessel through the first tube at a water pressure of 16.0 kPa (120.0 mmHg) ± 0.3 kPa (2.3 mmHg). 16.0 The outer diameter was measured using a laser displacement meter. The outer diameter of the central part of the artificial blood vessel was measured using a laser displacement meter. During this time, the water flowing through the artificial blood vessel was discharged from the second tube. 10.7"), and the inner radius under 16.0 kPa (hereinafter referred to as "R 16.0 ") was calculated using the same formula as low-pressure compliance. The medium pressure compliance was calculated using the following formula: Medium pressure compliance = (R 16.0 -R 10.7 ) / R 10.7 / (120.0-80.3)×10 4 In this formula, R 16.0 and R 10.7 is substituted with a value in mm.

[0096] 1.4.4. High-Pressure Compliance The outer diameter of the artificial blood vessel (hereinafter referred to as "D 14.7 The outer diameter of the artificial blood vessel (hereinafter referred to as "D") was measured using a laser displacement meter. During this time, the water flowing into the artificial blood vessel was discharged from the second tube. Next, the outer diameter of the artificial blood vessel (hereinafter referred to as "D") was measured while water was flowing into the artificial blood vessel through the first tube at a water pressure of 20.0 kPa (150.0 mmHg) ± 0.3 kPa (2.3 mmHg). 20.0 The outer diameter was measured using a laser displacement meter. The outer diameter of the central part of the artificial blood vessel was measured using a laser displacement meter. During this time, the water flowing through the artificial blood vessel was discharged from the second tube. 14.7 "), and the inner radius under 20.0 kPa (hereinafter referred to as "R 20.0 ") was calculated using the same formula as low-pressure compliance. High pressure compliance was calculated using the following formula: High pressure compliance = (R 20.0 -R 14.7 ) / R 14.7 / (150.0-110.3)×10 4 In this formula, R 20.0 and R 14.7is substituted with a value in mm.

[0097] <1.4.5. Simplified Compliance> Simplified compliance was calculated using the following formula: Simplified compliance = (low pressure compliance + medium pressure compliance + high pressure compliance) / 3

[0098] <1.4.6. Simplified Compliance Ratio> A Vectra vascular graft (5.0 mm inner diameter, 50 cm total length, densely reinforced central portion) manufactured by Goodman Co., Ltd. has, from the first end to the second end in the longitudinal direction, a first loosely reinforced portion, a densely reinforced portion, and a second loosely reinforced portion. The simplified compliance of the first loosely reinforced portion of the Vectra vascular graft was measured using the method described above. The simplified compliance was 0.5% / 100 mmHg. The simplified compliance ratio, defined by the following formula, was calculated using the simplified compliance of the Vectra vascular graft. Simplified compliance ratio = Simplified compliance of artificial blood vessels prepared in Examples or Comparative Examples / Simplified compliance of Vectra artificial blood vessels In this formula, a value in % / 100 mmHg is substituted for the simplified compliance of the artificial blood vessels prepared in the Examples or Comparative Examples. In this formula, the simplified compliance of the Vectra vascular graft is substituted with a value in % / 100mmHg. 1.5. Consideration of target values ​​for simplified compliance ratio When considering anastomosis of a vascular prosthesis to a vein, it is desirable that the compliance of the vascular prosthesis be equal to or close to that of the vein in order to avoid compliance mismatch. The compliance of the vein (strictly speaking, the compliance of the saphenous vein) is known to be 4.4±0.8% / 100mmHg. 1) . By obtaining the compliance of the Vectra vascular graft, the ratio of the vein's compliance to the Vectra vascular graft (i.e., vein's compliance / Vectra vascular graft's compliance) (hereinafter sometimes referred to as the "compliance ratio") can be determined. The compliance ratio can be viewed as a target value for the simplified compliance ratio. Based on this idea, we commissioned an external organization to conduct a compliance test to determine the compliance of Vectra vascular graft (inner diameter 5.0 mm, total length 50 cm, central dense reinforcement type) manufactured by Goodman Co., Ltd. The compliance test was conducted in accordance with ISO7198:2016 using the following procedure and measurement conditions. (Procedure and measurement conditions) The Vectra artificial blood vessel was immersed in distilled water at 37±2°C for 5 minutes to remove air bubbles from the artificial blood vessel wall. Distilled water at 37±2°C was flowed through the sample while applying a tensile load of 45±5 g in the longitudinal direction of the Vectra artificial blood vessel. The outer diameter of the first roughly reinforced portion was measured with a laser displacement meter while the water pressure was varied within a range of 7.0 kPa (52.5 mmHg) to 12.0 kPa (90.0 mmHg) at a frequency of 1 Hz (60 beats per minute). Regarding the location of the outer diameter, the first roughly reinforced portion was divided into four equal parts in the longitudinal direction, and the outer diameter at the position of the line dividing the first roughly reinforced portion was measured with the laser displacement meter. Based on this, the compliance at 7.0 kPa to 12.0 kPa (hereinafter sometimes referred to as "first compliance") was calculated using the following formula. First Compliance = (D P2 -D P1 ) / D P1 / (P2-P1)×10 4 In this formula, P1 is the minimum water pressure (52.5 mmHg) in the water pressure fluctuation range. P2 is the maximum water pressure (90.0 mmHg) in the water pressure fluctuation range. D P1 is the outer diameter under minimum water pressure. D P2 is the outer diameter under maximum water pressure. Compliance under 10.7 kPa to 16.0 kPa (hereinafter sometimes referred to as "second compliance") was determined in the same manner as for the first compliance, except that the water pressure was varied in the range of 10.7 kPa to 16.0 kPa at a frequency of 1 Hz. Compliance under 14.7 kPa to 20.0 kPa (hereinafter sometimes referred to as "third compliance") was determined in the same manner as for the first compliance, except that the water pressure was varied in the range of 14.7 kPa to 20.0 kPa at a frequency of 1 Hz. The compliance of the Vectra vascular graft was calculated from the first, second, and third compliances using the following formula: Compliance = (1st compliance + 2nd compliance + 3rd compliance) / 3 Compliance was 1.4% / 100mmHg. As described above, the venous compliance is 4.4±0.8% / 100 mmHg. In other words, the venous compliance is 3.6% / 100 mmHg to 5.2% / 100 mmHg. On the other hand, the compliance of the Vectra vascular artificial blood vessel is 1.4% / 100 mmHg. Therefore, the compliance ratio (i.e., venous compliance / Vectra vascular artificial blood vessel compliance) is 2.6 (= 3.6 / 1.4) to 3.7 (= 5.2 / 1.4). Although the methods for measuring venous compliance and Vectra vascular artificial blood vessel compliance are not identical, they share commonalities, and therefore, a target value of 2.6 to 3.7 for the simplified compliance ratio is not necessarily unreasonable. Therefore, in this example, the desired range of the simplified compliance ratio was set to 2.6 to 3.7.

[0099] <2. Gelatin insolubilization study> <2.1.Electron beam crosslinking> A 10% by mass aqueous solution of gelatin (LET-NP250 manufactured by Nitta Gelatin Co., Ltd.) was placed in a sealed container. The sealed container containing the 10% by mass aqueous solution of gelatin was irradiated with electron beams at 10 kGy, 20 kGy, 40 kGy, or 60 kGy using an electron beam irradiation device manufactured by Sumiju Atex Co., Ltd. Crosslinked gelatin was thus obtained.

[0100] <2.2. Insoluble matter> Two grams of a sample (specifically, cross-linked gelatin or a 10% by mass aqueous solution of gelatin) was placed in a screw tube, and pure water was added to the screw tube. The resulting 2% by mass solution of the sample (hereinafter sometimes referred to as the "sample solution") was allowed to stand for two hours and then stirred at 40°C for 30 minutes. The sample solution was suction filtered using a polytetrafluoroethylene (PTFE) membrane filter (Merck, Omnipore) with a pore size of 10 μm. The screw tube was washed with pure water at 40°C, and the post-wash solution was recovered. This membrane filter was also used for suction filtering of the post-wash solution. The residue remaining on the membrane filter was washed with pure water at 40°C. The post-wash residue was heated at 110°C for 16 hours, and the weight of the residue (i.e., dry weight) was measured. The dry weight of 2 g of the sample (specifically, cross-linked gelatin or a 10% by mass aqueous solution of gelatin) was also measured. That is, 2 g of the sample was heated at 110°C for 16 hours and then weighed. The insoluble content was calculated using the following formula from the dry weight of the sample and the dry weight of the residue. Insoluble matter = (dry weight of residue / dry weight of sample) x 100 In this formula, the dry weight of the residue is substituted in grams. In this formula, the dry weight of the sample is also substituted in grams. The table below shows the results of the insoluble matter measurement. In addition, the samples (specifically, cross-linked gelatin or 10% by mass aqueous solution of gelatin) were also evaluated as to whether they were in a sol or gel state at 40°C, i.e., whether they had fluidity at 40°C, and the results of this evaluation are also shown in this table. [Table 1] By irradiation with 20kGy, 40kGy or 60kGy of electron beam, crosslinked gelatin which became gel at 40℃ and had an insoluble content of about 40% or more could be obtained.

[0101] 3. Preparation of pore-forming agent Commercially available reagent sodium chloride (NaCl) was pulverized in an agate mortar. From this pulverized material, the component that passed through a stainless steel sieve with a mesh size of 106 μm but did not pass through a sieve with a mesh size of 45 μm was collected as pore-forming agent A. In the same manner, the component that passed through a sieve with a mesh size of 212 μm but did not pass through a sieve with a mesh size of 106 μm was collected as pore-forming agent B.

[0102] <4. Preparation of polyurethane stock solution> Polyurethane (Lubrizol, Pellethan 2363-80AE, density 1.05 g / cm 3 10 parts by mass of the polyurethane foam and 90 parts by mass of dimethyl sulfoxide (DMSO) were mixed and dissolved at 90° C. This gave a polyurethane stock solution containing 10% by mass of polyurethane.

[0103] <5. Preparation of polyurethane porous material stock solution> To 100 parts by mass of the polyurethane stock solution, 100 parts by mass of pore-forming agent A was added and thoroughly stirred to obtain a polyurethane porous material stock solution A. To 100 parts by mass of the polyurethane stock solution, 100 parts by mass of pore-forming agent B was added and thoroughly stirred to obtain a polyurethane porous material stock solution B.

[0104] <6. Preparation of artificial blood vessels before immersion> <6.1. Preparation Example 1> As shown in Figures 3A and 3B, a cylindrical rod with a diameter of 5.0 mm and a mold A including an inner wall capable of forming a cylindrical cavity with a diameter of 7 mm concentric with the rod were prepared. The space between the rod and the inner wall (i.e., the tubular space) was filled with polyurethane concentrate. This was then cooled overnight in a -20°C freezer. After cooling, only mold A was removed. The tubular coagulated material formed around the rod (i.e., the cylindrical rod with a diameter of 5.0 mm) was immersed in ice-cold water and then washed with warm water at 60°C. It was then air-dried. This resulted in a tubular polyurethane porous body formed around the rod (hereinafter sometimes referred to as the "porous tube for the inner layer"). The reinforcing thread was spirally wound around the porous tube for the inner layer at intervals of 2.5 mm. Specifically, a polyester monofilament with a diameter of 150 μm was wound as the reinforcing thread around the outer surface of the porous tube for the inner layer clockwise from the first end to the second end of the porous tube for the inner layer at a pitch of 2.5 mm. Next, the reinforcing thread (specifically, a polyester monofilament with a diameter of 150 μm) was further wound around the outer surface of the porous tube for the inner layer at a pitch of 2.5 mm in the counterclockwise direction from the first end to the second end of the porous tube for the inner layer. To form an outer layer around the porous tube for the inner layer reinforced with two reinforcing threads, mold B was prepared. Specifically, mold B included an inner wall capable of forming a cylindrical cavity with a diameter of 9 mm concentric with a rod (i.e., a cylindrical rod with a diameter of 5.0 mm). The porous tube for the inner layer reinforced with two reinforcing threads was placed inside mold B, and the space between the inner wall of mold B and the porous tube for the inner layer (i.e., the tubular space) was filled with polyurethane porous material stock solution A. This was cooled overnight in a freezer at -20°C. After cooling, the rod and mold B were removed, and the tubular coagulated product was immersed in ice-cold water and then washed with warm water at 60°C. It was then dried under reduced pressure. This resulted in a pre-immersion artificial blood vessel comprising a tubular polyurethane porous body including inner and outer layers and two reinforcing threads reinforcing the polyurethane porous body. The pre-immersion artificial blood vessel had an inner diameter of 5.0 mm and a length of 70 mm. The porosity of the pre-immersion artificial blood vessel was 51%. The porosity of the inner layer was 34%. The porosity of the outer layer was 54%. The porosity of each layer was calculated using the following formula. Porosity of inner layer = Pore area of ​​inner layer within analysis range / Area of ​​inner layer within analysis range × 100 Porosity of outer layer = Pore area of ​​outer layer within analysis range / Area of ​​outer layer within analysis range × 100

[0105] <6.2. Preparation Example 2> Pre-immersion artificial blood vessels were prepared in the same manner as in Preparation Example 1, except that the pitch of each reinforcing thread was changed from 2.5 mm to 10 mm.

[0106] <6.3. Preparation Example 3> Pre-immersion artificial blood vessels were prepared in the same manner as in Preparation Example 1, except that the pitch of each reinforcing thread was changed from 2.5 mm to 1.0 mm.

[0107] <6.4. Preparation Example 4> A cylindrical rod with a diameter of 5.0 mm and mold B (i.e., mold B including an inner wall capable of forming a cylindrical cavity with a diameter of 9 mm concentric with the 5.0 mm cylindrical rod) were prepared, and the space between the rod and the inner wall (i.e., the tubular space) was filled with polyurethane porous material stock solution B. This was cooled overnight in a freezer at -20°C. After cooling, the rod and mold B were removed, and the tubular coagulated material was immersed in ice-cold water and then washed with warm water at 60°C. It was then dried under reduced pressure. This resulted in a tubular polyurethane porous material with a single-layer structure as a pre-immersion artificial blood vessel. The pre-immersion artificial blood vessel had an inner diameter of 5.0 mm and a length of 70 mm. The porosity of the pre-immersion artificial blood vessel was 54%.

[0108] 7. Fabrication of artificial blood vessels 7.1 Example 1 A cylindrical stainless steel (SUS) mandrel with a diameter of 5.0 mm and a length of 100 mm was inserted into the lumen of the pre-immersion artificial blood vessel prepared in Preparation Example 1. The pre-immersion artificial blood vessel, together with the mandrel, was immersed in a 10% by weight aqueous solution of gelatin (LET-NP250, manufactured by Nitta Gelatin Co., Ltd.) in a container. The vessel was placed in a desiccator (specifically, in a metal water bath within the desiccator, as described below), and the pressure in the desiccator was reduced to 11.3 kPa absolute and maintained at 11.3 kPa for 10 minutes. During this time, the 10% by weight aqueous solution of gelatin was maintained at 50°C using a hot plate within the desiccator and a metal water bath placed on the hot plate. The pressure in the desiccator was then returned to normal pressure, i.e., 101.3 kPa absolute, and the post-immersion artificial blood vessel, together with the mandrel, was removed from the container. After immersion, the artificial blood vessel was rotated while a doctor blade was applied to the surface of the artificial blood vessel, thereby removing the 10% by mass aqueous solution of gelatin adhering to the surface of the artificial blood vessel after immersion. Subsequently, the immersed artificial blood vessel was sealed in a sealed container, and the sealed container containing the immersed artificial blood vessel was irradiated with electron beams at 30 kGy using an electron beam irradiation device manufactured by Sumiju Atex Co., Ltd. This resulted in the production of an artificial blood vessel.

[0109] 7.2. Comparative Example 1 An artificial blood vessel was produced in the same manner as in Example 1, except that instead of leaving it to stand for 10 minutes at 11.3 kPa, it was left to stand for 10 minutes at normal pressure. That is, an artificial blood vessel was produced in the same manner as in Example 1, except that the artificial blood vessel together with the mandrel before immersion was immersed in a 10% by mass aqueous solution of gelatin in a container, and then left to stand at normal pressure at 50°C for 10 minutes, and after immersion, the artificial blood vessel together with the mandrel was removed from the container.

[0110] 7.3 Comparative Example 2 An artificial blood vessel was produced in the same manner as in Example 1, except that instead of leaving it to stand at 11.3 kPa for 10 minutes, it was left to stand at 31.3 kPa for 10 minutes. That is, an artificial blood vessel was produced in the same manner as in Example 1, except that the pressure inside the desiccator was reduced to an absolute pressure of 31.3 kPa and maintained at 31.3 kPa at 50°C for 10 minutes.

[0111] 7.4 Example 2 An artificial blood vessel was produced in the same manner as in Example 1, except that the pre-immersion artificial blood vessel produced in Preparation Example 2 was used instead of the pre-immersion artificial blood vessel produced in Preparation Example 1.

[0112] 7.5. Example 3 An artificial blood vessel was produced in the same manner as in Example 1, except that the pre-immersion artificial blood vessel produced in Preparation Example 3 was used instead of the pre-immersion artificial blood vessel produced in Preparation Example 1.

[0113] 7.6 Example 4 An artificial blood vessel was produced in the same manner as in Example 1, except that the pre-immersion artificial blood vessel produced in Preparation Example 4 was used instead of the pre-immersion artificial blood vessel produced in Preparation Example 1.

[0114] <8.Results> The results are summarized in the table below. [Table 2] In this table, "absolute pressure" is the absolute pressure inside the desiccator at the time of immersion.

[0115] Immersing the pre-immersion artificial blood vessel in a 10% by mass aqueous solution of gelatin at normal pressure did not reduce the porosity, i.e., the 10% by mass aqueous solution of gelatin did not penetrate into the pores (see Preparation Example 1 and Comparative Example 1), but immersing the pre-immersion artificial blood vessel in a 10% by mass aqueous solution of gelatin under reduced pressure allowed the 10% by mass aqueous solution of gelatin to penetrate into the pores (see, for example, Example 1 and Comparative Example 2).In particular, immersing the pre-immersion artificial blood vessel in a 10% by mass aqueous solution of gelatin at 11.3 kPa allowed the 10% by mass aqueous solution of gelatin to effectively penetrate into the pores (see Example 1).

[0116] Artificial blood vessels with a porosity of 9% or less have a water permeability of 0.0 mL / (cm 2 ·min) (see Examples 1, 2 and 4). The artificial blood vessel with a porosity of 10% had a water permeability of 0.3 mL / (cm 2 1·min) (see Example 3). Therefore, these artificial blood vessels can prevent excessive leakage of blood out of the artificial blood vessels until some of the cross-linked gelatin is decomposed in the living body.

[0117] The simplified compliance ratio of the artificial blood vessel with a porosity of 7% was 3.4, which was within the desired range (specifically, 2.6 to 3.7) (see Example 1). On the other hand, the simplified compliance ratio of the artificial blood vessel with a porosity of 12% was 11.8, which was outside the desired range (see Comparative Example 2).

[0118] <9. Example 5 - Shunt Construction Test> <9.1. Introduction> A shunt was created in a domestic pig using an artificial blood vessel prepared in exactly the same manner as in Example 1. One month after the shunt creation, the artificial blood vessel was removed, and HE-stained sections were prepared and observed. A detailed description is given below.

[0119] 9.2. Anesthesia A mixture of medetomidine hydrochloride and midazolam (1:5) was intramuscularly administered at 0.08 mL / kg to domestic pigs (LWD, conventional, male, implantation weight 56.2-59.2 kg, SPF Koganeya Agricultural Cooperative). A tracheal cannula was then inserted into the airway, and artificial ventilation was performed using an animal ventilator. The mixed gas was set to a 3:0.5 ratio of air to oxygen. The ventilator was controlled with a maximum circuit pressure of 14 mmHg and a respiratory rate of 12 or 14 breaths / min. A constant depth of anesthesia was maintained by inhaling 2.5% isoflurane. As an antibiotic, cefovecin sodium (Convenia® Injection, Zoetis Japan Inc.) was administered subcutaneously at 8 mg / kg, followed by intramuscular administration of butorphanol tartrate (Betorfal 5 mg, Meiji Animal Health Co., Ltd.) at 0.2 mg / kg.

[0120] <9.3. Implantation> The right neck of an anesthetized domestic pig was incised, exposing the carotid artery and jugular vein. Heparin (heparin sodium injection 50,000 units / 50 mL "AY", AY Pharmaceuticals Co., Ltd.) was administered intravenously at 200 IU / kg. The carotid artery was clamped with forceps and then incised 6 mm. A vascular graft was anastomosed end-to-side to the carotid artery at a 45° angle using 7-0 polypropylene sutures, followed by an end-to-side anastomosis to the jugular vein at a 45° angle (see Figure 10). Both ends of the vascular graft were cut prior to anastomosis to allow for end-to-side anastomosis.

[0121] <9.4. Removal and Preparation of HE-Stained Sections> After the shunt was placed, the domestic pig was anesthetized as described above, the axillary artery was severed, and the pig was euthanized by exsanguination. The right neck was incised, and the adipose tissue surrounding the graft (i.e., the artificial vascular graft) was trimmed (see Figure 11). The artificial vascular graft was perfused with saline and then subjected to pressure perfusion with formalin. The artificial vascular graft, along with the carotid artery, jugular vein, and surrounding tissue, was then excised and fixed in 10% neutral buffered formalin for at least 24 hours. The resulting specimen was then incised from the anastomosis between the artificial vascular graft and the carotid artery to just before the anastomosis between the artificial vascular graft and the jugular vein. The artificial vascular graft was then cut just before the anastomosis between the artificial vascular graft and the jugular vein, specifically, 5 mm before the anastomosis. The resulting artificial vascular graft specimen was then embedded in paraffin and sliced ​​into approximately 5 μm-thick sections. The sections were stained with hematoxylin and eosin (HE) and the virtual slides were saved.

[0122] <9.5.Results> When the shunt was constructed, no blood leakage from the surface of the artificial blood vessel was observed (see Figure 10). During the rearing period after shunt placement, the domestic pigs received approximately 1000 g of feed (solid feed NS, Nichiken Co., Ltd.) per day. In other words, no leftover feed was observed. No notable findings were observed during the rearing period after shunt placement. One month after shunt placement, no blood leakage was observed in or around the shunt (see Figure 11).

[0123] One month after the shunt was created, tissue infiltration and angiogenesis into the artificial blood vessel were evident, and only a small amount of cross-linked gelatin remained (see Figure 12). This confirmed that the cross-linked gelatin had decomposed in vivo, and tissue, capillaries, cells, etc. had infiltrated into the pores.

[0124] Note 1) Raphael Walden, MD; Gilbert J. L'Italien; Joseph Megerman, PhD; William M. Abbott, MD. Matched Elastic Properties and Successful Arterial Grafting. Archives of Surgery 115(10)1980_1166-1169

Claims

1. a tubular porous body having communicating holes; a biodegradable material contained in the communication hole; The porosity is 10% or less. Artificial blood vessel.

2. 2. The artificial blood vessel according to claim 1, wherein the insoluble content of said biodegradable material is 40% or more.

3. 2. The artificial blood vessel according to claim 1, wherein the porous body itself has a porosity of 30% or more.

4. The artificial blood vessel according to claim 1, wherein the biodegradable material is at least one of a cross-linked gelatin gel and a collagen.

5. The artificial blood vessel according to claim 1 , wherein the biodegradable material is a cross-linked gelatin gel.

6. The artificial blood vessel according to claim 1, wherein the porous body contains a thermoplastic polyurethane elastomer.

7. the porous body includes a tubular first porous layer and a tubular second porous layer surrounding the first porous layer; the porosity of the first porous layer itself is smaller than the porosity of the second porous layer itself; The artificial blood vessel according to claim 1.

8. When water is passed through the artificial blood vessel at a water pressure of 16.0 kPa, the amount of water leaking from the outer surface of the artificial blood vessel is 1.0 mL / (cm ２ 2. The artificial blood vessel according to claim 1, wherein the elongation of the blood vessel is 0.05 mm or less.

9. 2. The artificial blood vessel according to claim 1, which has a simple compliance of 1.3% / 100 mmHg to 1.8% / 100 mmHg.

10. The artificial blood vessel according to claim 1, which is used for creating vascular access.

11. A method for producing the artificial blood vessel according to any one of claims 1 to 10, comprising the steps of: a step of immersing the pre-immersion artificial blood vessel containing the porous body in an aqueous solution containing a water-soluble biodegradable material under a reduced pressure environment; increasing the atmospheric pressure of the aqueous solution in which the artificial blood vessel is immersed before immersion; and a step of insolubilizing the water-soluble biodegradable material contained in the artificial blood vessel after immersion. A method for manufacturing artificial blood vessels.

12. The method for producing an artificial blood vessel according to claim 11, wherein the water-soluble biodegradable material is gelatin.

13. The method for producing an artificial blood vessel according to claim 11, wherein the step of insolubilizing the water-soluble biodegradable material comprises irradiating the artificial blood vessel with an electron beam after the immersion.

14. The method for producing an artificial blood vessel according to claim 11, wherein the temperature of the aqueous solution is 40°C or higher while the pre-immersion artificial blood vessel is immersed in the aqueous solution.

Images