Valved Graft Formation Substrate

Abstract

To provide a valved graft forming substrate by which a vessel can be formed with a desired thickness.SOLUTION: A valve leaflet formation surface 9 on a body side is set on a columnar substrate body 6. A valve leaflet formation surface 10 on an auxiliary side is set on an auxiliary substrate 7. The auxiliary substrate 7 is freely detachably installed on the end of the substrate body 6. A space between the valve leaflet formation surface 9 on the body side and the valve leaflet formation surface 10 on the auxiliary side is defined as a valve leaflet formation space 12. On the outer peripheral side of the substrate body 6 and the auxiliary substrate 7, there is installed a cylindrical cover substrate 8. A space between the outer peripheral surface of the substrate body 6 as well as of the auxiliary substrate 7 and the inner peripheral surface of the cover substrate 8 is defined as a vessel formation space 13. By installing in an environment in which a biological tissue material exists, a connective tissue is formed on the substrate surface, with a valved graft formed.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a valved graft forming substrate that is placed in an environment where biological tissue material is present to form connective tissue on the surface of the substrate and form a valved graft having multiple valve leaflets that bulge radially inward from a conduit. [Background technology]

[0002] There is a great deal of research being conducted into regenerative medicine, which aims to revive cells, tissues, and organs lost due to illness or accident using artificial materials and cells.

[0003] Normally, the body has a self-defense mechanism, and when a foreign object such as a thorn penetrates shallowly within the body, it attempts to expel it. It is also known that when a foreign object penetrates deep within the body, fibroblasts gradually gather around the object, forming a capsule of connective tissue composed mainly of fibroblasts and collagen to cover the foreign object and isolate it within the body. As a technique for forming tissue derived from living cells using this latter self-defense mechanism, several techniques have been reported in which a foreign object is embedded in a living body to form a connective tissue (see Patent Documents 1 to 3).

[0004] Furthermore, Patent Document 4 discloses an artificial valve formation substrate for forming an artificial valve having multiple valve leaflets that bulge radially inward from an outer tube portion by placing the substrate inside a living body or the like and forming connective tissue on the surface of the substrate. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Application Laid-Open No. 2007-312821 [Patent Document 2] Japanese Patent Application Laid-Open No. 2008-237896 [Patent Document 3] Japanese Patent Application Laid-Open No. 2010-094476 [Patent Document 4] WO2016 / 098877A1 (Claim 1) Summary of the Invention [Problem to be solved by the invention]

[0006] However, although the substrate described in Patent Document 4 can form valve leaflets (valve cusps) of the desired shape and thickness in the valve leaflet formation space, the connective tissue formed around the substrate body and the cover member is used as the outer tube portion (conduit), and the outer tube portion (conduit) cannot be formed to the desired thickness.

[0007] SUMMARY OF THE INVENTION An object of the present invention is to provide a valved graft formation substrate that allows for the formation of a conduit of a desired thickness. [Means for solving the problem]

[0008] To achieve the above object, the valved graft formation substrate of the present invention is for being placed in an environment where biological tissue material is present to form connective tissue on the substrate surface and form a valved graft having a plurality of valve leaflets bulging radially inward from a conduit, and comprises a columnar substrate main body and an auxiliary substrate detachably attached to an end of the substrate main body. Furthermore, the substrate main body and the auxiliary substrate are provided with a main body-side valve leaflet formation surface and an auxiliary-side valve leaflet formation surface, respectively, facing each other with a gap corresponding to the thickness of the valve leaflets, and the space between the main body-side valve leaflet formation surface and the auxiliary-side valve leaflet formation surface is defined as a valve leaflet formation space where connective tissue infiltrates through intrusion openings at the outer edges to form the valve leaflets of the valved graft. Furthermore, a cylindrical cover substrate is provided on the outer periphery of the substrate main body and the auxiliary substrate, and the outer periphery of the substrate main body and the auxiliary substrate are opposed to the inner periphery of the cover substrate with a gap corresponding to the thickness of the conduit, and the space between the outer periphery of the substrate main body and the auxiliary substrate and the inner periphery of the cover substrate is defined as a conduit formation space where connective tissue infiltrates to form the conduit of the valved graft.

[0009] According to the above-described configuration, a cylindrical cover substrate is provided on the outer periphery of the base material body and auxiliary substrate to form a conduit-forming space, and connective tissue can penetrate into this conduit-forming space to form a conduit of a desired thickness. Moreover, because the conduit is formed between the base material body and auxiliary substrate and the cover substrate, the quality, such as strength, of the conduit can be improved compared to when the conduit is simply formed on the outer periphery of the base material body and auxiliary substrate.

[0010] Furthermore, since the base material body and the auxiliary base material are provided with a main body side valve leaflet formation surface and an auxiliary side valve leaflet formation surface, the valve leaflet formation space formed between these two surfaces can be formed by allowing connective tissue to infiltrate through an entry port on the outer edge, and a connection between the conduit and the end of the valve leaflet can be formed at the entry port.

[0011] This allows the creation of a valved graft in which the ends of the valve leaflets are supported by high-quality conduits of the desired thickness, and the leaflets can open and close the flow path by bending radially under fluid pressure.

[0012] Here, "connective tissue" generally refers to a tissue whose main component is collagen and which is formed in the body. However, in the present specification and claims, the concept also includes tissues equivalent to connective tissue formed in the body when formed in an ex vivo environment.

[0013] Furthermore, "biological tissue materials" refer to substances necessary for forming desired biological tissues, and examples include animal cells such as fibroblasts, smooth muscle cells, endothelial cells, stem cells, ES cells, and iPS cells, various proteins (collagen, elastin), sugars such as hyaluronic acid, and various physiologically active substances present in the body, such as cell growth factors and cytokines. This "biological tissue material" includes those derived from mammals such as humans, dogs, cows, pigs, goats, and sheep, birds, fish, and other animals, as well as equivalent artificial materials.

[0014] Furthermore, the term "environment in which a biological tissue material exists" refers to an artificial environment containing a biological tissue material inside the body of an animal (such as a mammal, such as a human, dog, cow, pig, goat, or sheep, a bird, fish, or other animal) (for example, implanted subcutaneously in the limbs, shoulder, back, or abdomen, or in the abdominal cavity) or outside the body of an animal.

[0015] Furthermore, the auxiliary base material may be formed with a valve tip hole that connects a portion of the valve leaflet formation space corresponding to the tip of the valve leaflet with the outside of the base material.

[0016] According to this configuration, the leaflet formation space is connected to the outside of the base material via the valve tip hole, so that not only can connective tissue invade from the outside of the base material into the leaflet formation space via the conduit formation space and the intrusion port, but also connective tissue can invade from the outside of the base material directly into the leaflet formation space via the valve tip hole, thereby shortening the time required to form the valve leaflets.

[0017] In other words, because the cover base material is provided on the outer periphery of the base material body and auxiliary base material, the connective tissue must invade the conduit formation space inside the cover base material and then invade the valve leaflet formation space through the intrusion opening, which tends to increase the time required for valve leaflet formation.In contrast, by forming a valve tip hole in the auxiliary base material to connect the valve leaflet formation space to the outside of the base material, the connective tissue can invade through the valve tip hole as well, preventing delays in valve leaflet formation.

[0018] Furthermore, the valve leaflet formation space may be set to the shape of the valve leaflets in the closed state, and a common valve tip hole may be formed that connects the areas corresponding to the tips of the multiple valve leaflets with the outside of the base material.

[0019] With this configuration, the leaflet formation spaces are set to the shape of the valve leaflets in the closed state, so the tips of the multiple leaflet formation spaces can be brought close to each other, and the tip holes formed at the tips of the leaflet formation spaces can be integrated and made common. This allows the opening of the tip holes to be larger toward the outside of the base material, making it easier for connective tissue to penetrate into the tip holes from outside the base material, more reliably forming high-quality valve leaflets and shortening the time required to form the valve leaflets.

[0020] Furthermore, by setting the leaflet formation space to the shape of the valve leaflets in their closed state, the valve leaflets can be formed in a closed state, which reduces the possibility of backflow occurring in a valved graft implanted in the body due to delayed closure of the valve leaflets, compared to when the valve leaflets are formed in an open state.

[0021] Furthermore, a promotion hole may be formed in the auxiliary base material to connect the valve leaflet formation space with the conduit formation space and promote the infiltration of connective tissue into the valve leaflet formation space, and a cutting slit may be formed in the range from the end face of the auxiliary base material to the promotion hole to cut the connective tissue formed inside the promotion hole.

[0022] According to this configuration, the formation of promotion holes in the auxiliary base material can promote the infiltration of connective tissue from the conduit formation space outside the auxiliary base material to the valve leaflet formation space inside the auxiliary base material. In this case, the connective tissue formed inside the promotion holes connects the conduit and valve leaflets of the valved graft across the auxiliary base material, but the formation of cutting slits in the auxiliary base material makes it easy to cut the connective tissue formed inside the promotion holes. This allows the valved graft to be efficiently formed and removed from the valved graft formation base material without damage. [Effects of the Invention]

[0023] As described above, according to the present invention, a tubular cover substrate is provided on the outer periphery of the substrate body and auxiliary substrate to form a conduit formation space, and connective tissue is allowed to infiltrate into this conduit formation space to form a conduit. This makes it possible to form the conduit of the valved graft to a desired thickness and to improve its quality, such as its strength.

[0024] Furthermore, by allowing connective tissue to invade from the conduit formation space through the intrusion opening at the outer edge into the leaflet formation space between the main body side leaflet formation surface and the auxiliary side leaflet formation surface, it is possible to form the leaflets of the valved graft in the leaflet formation space while forming a connection between the conduit and the end of the leaflet at the intrusion opening. [Brief explanation of the drawings]

[0025] [Figure 1] 1 is a perspective view of a valved graft forming substrate according to the present invention; [Figure 2] 1 is a perspective view of a base body and an auxiliary base material with a cover base material removed; [Figure 3] A perspective view of Figure 2 from the opposite side [Figure 4] A perspective view of the base body [Figure 5] (a) is a plan view of the substrate body, and (b) is an AA cross section. [Figure 6] FIG. 1 is a diagram illustrating a procedure for forming a valved graft using a valved graft formation substrate. [Figure 7] Perspective view of a valved graft, (a) showing the closed state and (b) showing the open state. DETAILED DESCRIPTION OF THE INVENTION

[0026] Hereinafter, embodiments for carrying out a valved graft forming substrate according to the present invention will be described with reference to the drawings.

[0027] As shown in Figures 1 to 5, the valved graft formation substrate 1 is placed in an environment where biological tissue material is present to form connective tissue 2 on the substrate surface and form a valved graft 5 to be used, for example, as a heart valve graft, having multiple valve cusps 4 bulging radially inward from a conduit 3. The substrate 1 comprises a columnar substrate main body 6, an auxiliary substrate 7 that can be detachably attached to the end of the substrate main body 6, and a tubular cover substrate 8 that is provided on the outer periphery of the substrate main body 6 and the auxiliary substrate 7.

[0028] Furthermore, the base material main body 6 and the auxiliary base material 7 are each provided with a main body-side leaflet formation surface 9 and an auxiliary side leaflet formation surface 10 that face each other with a gap corresponding to the thickness of the valve leaflet, and the space between the two leaflet formation surfaces 9, 10 forms a leaflet formation space 12 where connective tissue 2 invades from an intrusion port 11 on the outer edge to form the leaflets 4 of the valved graft 5, and the outer surfaces of the base material main body 6 and the auxiliary base material 7 face the inner surface of the cover base material 8 with a gap corresponding to the thickness of the conduit, and the space between these two surfaces forms a conduit formation space 13 where connective tissue 2 invades to form the conduit 3 of the valved graft 5.

[0029] The base body 6 is cylindrical and made of a polymeric material such as acrylic resin, and at its ends are formed three body-side cusp-forming surfaces 9 separated by a central Y-shaped partition wall 14. Each body-side cusp-forming surface 9 consists of a wall surface of the partition wall 14 and a curved surface that slopes from its lower edge toward the central axis of the base body and spreads radially outward, and is set in a shape that corresponds to the upstream surface of the valve cusp 4 in the closed state.

[0030] The body-side leaflet-forming surface 9 can be set by interpolation using five variables, for example, the valve diameter (D), valve closure angle (θ), valve center length (L), commissure height (H), and commissure-to-commissure distance (a), using what is called non-uniform rational B-spline (NURBS) interpolation. Here, the valve diameter (D) corresponds to the outer diameter of the base material 6, the valve closure angle (θ) is, for example, 20° and corresponds to the inclination angle of the outer edge of the body-side leaflet-forming surface 9 relative to the cross section of the base material, the valve center length (L) is, for example, 13.5 mm and corresponds to the length from the lower edge of the partition wall 14 to the outer edge of the body-side leaflet-forming surface 9, the commissure height (H) is, for example, 14.2 mm and corresponds to the height in the axial direction of the base material from the outer edge of the body-side leaflet-forming surface 9 to the tip of the partition wall 14, and the commissure-to-commissure distance (a) corresponds to the thickness of the partition wall 14.

[0031] A notch 15 is formed on the radially outer edge of the partition wall 14, connecting adjacent leaflet formation spaces 12 with a space of sufficient thickness to form a commissure portion 16 in the valved graft 5 with sufficient thickness and predetermined strength.

[0032] Auxiliary base material 7 is cylindrical and made of a polymer material such as acrylic resin, and the inner surface of a Y-shaped slit 18 formed in the area from the end face on the central side of the base material to an end plate 17 on the outer end side of the base material, and the end face on the central side of the base material divided into three by slit 18, form auxiliary-side leaflet-forming surface 10. By inserting partition wall 14 into slit 18 and fitting its wall tip 19 into fitting groove 20 formed in end plate 17, auxiliary base material 7 is attached to the end of base material main body 6, and auxiliary-side leaflet-forming surface 10 faces main body-side leaflet-forming surface 9 to form leaflet-forming space 12.

[0033] The distance of the auxiliary side leaflet forming surface 10 from the main body side leaflet forming surface 9 is set to a range of, for example, 0.2 mm to 2.0 mm for each position on the surface, so that the leaflets 4 are formed to have the desired leaflet thickness distribution, taking into consideration, for example, the resistance to blood pressure and hemodynamics.

[0034] The width of the slit 18 is equal to the sum of the thickness of each side end of the two adjacent leaflet formation spaces 12 and the thickness of the partition wall 14, and the width of the commissure portion 16 of the valved graft 5 is set to a sufficient size corresponding to the width of this slit 18, so that the commissure portion 16 is formed with a predetermined strength.

[0035] A Y-shaped valve tip hole 21 is formed in the end plate 17 of the auxiliary base material 7, exposing the central portion of the wall tip portion 19 of the partition wall 14. This valve tip hole 21 is set to a width of, for example, 0.5 mm or more, so that the portions of the valve tip formation space 12 corresponding to the tips of the multiple valve leaflets 4 communicate with the outside of the base material via the common valve tip hole 21.

[0036] Promotion holes 22 that communicate between the valve cusp formation space 12 and the conduit formation space 13 are formed on the peripheral surface of the auxiliary base material 7, promoting the infiltration of connective tissue 2 from the conduit formation space 13 into the valve cusp formation space 12. Furthermore, cutting slits 23 are formed in the area that opens into the end plate 17 and reaches the promotion holes 22, so that when the valved graft 5 is removed, a scalpel or the like is inserted into the cutting slit 23 to cut the connective tissue 2 that has formed inside the promotion holes 22 and connects the inside and outside of the auxiliary base material 7.

[0037] Cover substrate 8 is cylindrical and made of a polymeric material such as acrylic resin, and is attached to the outer periphery of substrate body 6 and auxiliary substrate 7 at a fixed interval of, for example, about 2 mm by fitting protrusions 25 protruding radially outward from end plate 17 of auxiliary substrate 7 into recesses 24 formed at its end, thereby forming conduit-forming space 13 between cover substrate 8 and the outer periphery of substrate body 6 and auxiliary substrate 7. Intrusion holes 26 are formed in cover substrate 8 so as to extend over almost the entire surface, allowing connective tissue 2 to easily infiltrate conduit-forming space 13 from outside the substrate.

[0038] Here, the material for the valved graft forming substrate 1 is preferably a resin that has the strength (hardness) to prevent significant deformation when implanted in a living body, is chemically stable, can withstand stresses such as sterilization, and has no or little elution that irritates the living body, such as acrylic resin, as mentioned above, but is not limited to this.

[0039] Next, a method for producing a valved graft 5 using the above-described valved graft-forming substrate 1 will be described.

[0040] As shown in Figure 6, this production method consists of an "installation process" in which a valved graft-forming substrate 1 is installed in an environment where biological tissue material is present; a "formation process" in which connective tissue 2 is formed around the valved graft-forming substrate 1 and the connective tissue 2 is allowed to invade the valve leaflet formation space 12 and the conduit formation space 13; a "removal process" in which the valved graft-forming substrate 1 coated with connective tissue 2 is removed from the environment; and a "separation process" in which the connective tissue 2 is separated from the valved graft-forming substrate as a valved graft 5 including a conduit 3 and a valve leaflet 4.

[0041] <Installation process> After attaching the auxiliary substrate 7 to the end of the substrate body 6, the cover substrate 8 is attached to the outer periphery of the substrate body 6 and the auxiliary substrate 7 so as to fit onto the protrusions 25, thereby assembling the valved graft-forming substrate 1. Furthermore, the assembled valved graft-forming substrate 1 is placed in an environment where biological tissue material is present, such as under the skin of a goat (FIG. 6(a)).

[0042] The environment in which the biological tissue material exists can be an environment inside an animal's body (for example, implanted subcutaneously or intraperitoneally), or an artificial environment such as a solution in which the biological tissue material is suspended outside the animal's body. When the valved graft-forming substrate 1 is placed in an artificial environment, cell culture can be performed according to known methods in a clean environment under various culture conditions. The biological tissue material can be derived from mammals such as goats, dogs, cows, pigs, rabbits, sheep, and humans, or from birds, fish, and other animals, or it can also be an artificial material.

[0043] <Formation process> After the installation step, by allowing a predetermined time, for example about three months, to pass, connective tissue 2 is formed around the valved graft-forming substrate 1, and the connective tissue 2 invades the conduit formation space 13 through the end opening of the conduit formation space 13 and the intrusion holes 26 of the cover substrate 8. Furthermore, the connective tissue 2 that has invaded the conduit formation space 13 invades the valve cusp formation space 12 through the intrusion opening 11, the slit 18, and the promotion hole 22, and the connective tissue 2 outside the substrate invades directly into the valve cusp formation space 12 through the valve tip hole 21 (Fig. 6(b)).

[0044] In this formation process, by providing the valve tip hole 21, connective tissue 2 is directly invaded from the outside of the base material in addition to invading via the conduit formation space 13, and as a result, connective tissue 2 is formed in the valve cusp formation space 12 in a relatively short time. In particular, since multiple valve cusp formation spaces 12 are connected to the outside of the base material by the common valve tip hole 21, and the valve tip hole 21 is made larger, the invading of connective tissue 2 into the valve cusp formation space 12 is further promoted. The connective tissue 2 is composed of fibroblasts and extracellular matrix such as collagen.

[0045] <Removal process> After the formation process has been carried out for a predetermined period of time, and the connective tissue 2 has been sufficiently formed in the valve leaflet formation space 12 and the conduit formation space 13, a removal process is carried out in which the valved graft forming substrate 1 coated with the connective tissue 2 is removed from the environment in which the biological tissue material is present.

[0046] <Separation process> The connective tissue 2 covering the outer surface of the cover substrate 8 is removed while cutting with a scalpel or the like between the connective tissue 2 formed inside the entry holes 26 of the cover substrate 8, and the connective tissue 2 at both ends of the valved graft-forming substrate 1 is also removed. Furthermore, the connective tissue 2 in the conduit formation space 13 is deformed and peeled off with tweezers or the like so as to remain on the substrate main body 6 and auxiliary substrate 7, and then the cover substrate 8 is removed (Fig. 6(c)).

[0047] Here, by removing the cover substrate 8, the connective tissue 2 that constitutes the conduit 3 is revealed, and the connective tissue 2 formed inside the entry hole 26 of the cover substrate 8 remains on its surface in the form of protrusions. However, even if there are protrusions on the outer surface of the conduit 3, they do not affect blood flow, etc., so there is no particular need to remove them.

[0048] A scalpel or the like is inserted into the cutting slit 23 covered with connective tissue 2, and the connective tissue 2 formed inside the promotion holes 22 of the auxiliary base material 7 is cut to separate the connective tissue 2 inside and outside the auxiliary base material 7 that constitutes the conduit 3 and the valve cusp 4. Furthermore, the auxiliary base material 7 is removed while peeling the connective tissue 2 from the outer peripheral surface and the auxiliary side valve cusp forming surface 10, and then the connective tissue 2 covering the wall tip 19 of the partition wall 14 of the base material main body 6 is removed, and the connective tissue 2 inside the promotion holes 22 that remains as protrusions on the conduit 3 and the valve cusp 4 is excised (Fig. 6(d)).

[0049] The connective tissue 2 is separated from the base material body 6 so as to be peeled off from the outer peripheral surface of the base material body 6 and the body-side valve leaflet forming surface 9, thereby obtaining a valved graft 5 (FIG. 6(e)).

[0050] As shown in Figure 7, the valved graft 5 produced using the valved graft-forming substrate 1 is a cardiac valve graft that is implanted into a blood vessel such as the aorta emerging from the heart to impart valve function. The pressure of the fluid flowing inside causes multiple valve leaflets 4 that bulge radially inward from the conduit 3 to displace inward and outward, thereby opening and closing the flow path inside the conduit 3.

[0051] The valve leaflets 4 are connected to the conduit 3 through the slits 18 and the commissures 16 formed at the entry ports 11 in the valved graft-forming substrate 1 and the valve base, and when the flow direction in the flow channel is from the distal end to the proximal end, the pressure of the fluid trying to enter between the valve leaflets 4 and the conduit 3 causes the valve leaflets 4 to bend radially inward, closing the flow channel (Fig. 7(a)). On the other hand, when the flow direction in the flow channel is from the proximal end to the distal end, the valve leaflets 4 bend radially outward due to the flow, opening the flow channel (Fig. 7(b)).

[0052] The valved graft 5 produced using the valved graft forming substrate 1 has its valve leaflets 4 formed in a closed state shape, so that the free state is a closed state, thereby reducing the risk of backflow due to delayed closure.

[0053] The present invention is not limited to the above-described embodiment, and appropriate modifications can be made within the scope of the present invention. For example, while the above embodiment has been described using a tricuspid valve as an example, the valve may have any number of cusps, such as a bicuspid valve or a quadricuspid valve. Furthermore, the entry holes 26 in the cover substrate 8 and the promotion holes 22 and cutting slits 23 in the auxiliary substrate 7 can be omitted as appropriate. Furthermore, the valve leaflet holes do not have to be common, and each valve leaflet formation space may have one valve leaflet hole, and the valve leaflet holes can also be omitted. [Explanation of symbols]

[0054] 1. Valved graft formation substrate 2 Connective tissue 3 Conduit 4 leaflets 5. Valved Graft 6 Base material 7 Auxiliary base material 8 Cover substrate 9 Main body side leaflet formation surface 10 Auxiliary leaflet formation surface 11 Entry Point 12 Leaflet formation space 13 Conduit formation space 14 Partition Wall 15 Notch 16 Commissures 17 End plate 18 Slit 19 Wall tip 20 Fitting groove 21 Leaflet foramen 22 Promotion hole 23 Cutting slit 24 recess 25 Protrusion 26 Penetration hole D Valve diameter θ Valve closing angle L Valve central length H Commissure height a Intercommissural distance

Claims

1. A valved graft forming substrate for forming a valved graft having a plurality of valve leaflets bulging radially inward from a conduit by placing the substrate in an environment where a biological tissue material is present to form connective tissue on the surface of the substrate, the valved graft forming substrate comprising: The device comprises a columnar substrate body and an auxiliary substrate detachably attached to an end of the substrate body, a main body-side leaflet forming surface and an auxiliary-side leaflet forming surface are respectively set on the base body and the auxiliary base material, the main body-side leaflet forming surface facing each other with a gap corresponding to the thickness of the valve leaflet, and a leaflet forming space is defined between the main body-side leaflet forming surface and the auxiliary-side leaflet forming surface, where connective tissue is allowed to invade from an intrusion port on the outer edge to form the leaflets of the valved graft; a cylindrical cover substrate is provided on the outer peripheral sides of the substrate body and auxiliary substrate, the outer peripheral surfaces of the substrate body and auxiliary substrate face the inner peripheral surface of the cover substrate at a distance corresponding to the thickness of the conduit, and the space between the outer peripheral surfaces of the substrate body and auxiliary substrate and the inner peripheral surface of the cover substrate forms a conduit formation space into which connective tissue is allowed to infiltrate to form the conduit of the valved graft; A valved graft formation substrate characterized in that the auxiliary substrate has a valve tip hole formed therein, which connects a portion of the valve leaflet formation space corresponding to the tip of the valve leaflet with the outside of the substrate.

2. 2. The valved graft formation substrate according to claim 1, characterized in that the valve leaflet formation space is set to the shape of the valve leaflet in a closed state, and a common valve tip hole is formed that connects the areas corresponding to the tips of multiple valve leaflets with the outside of the substrate.

3. 3. A valved graft formation substrate according to claim 1, characterized in that the auxiliary substrate has a promotion hole formed therein that connects the valve leaflet formation space with the conduit formation space and promotes the infiltration of connective tissue into the valve leaflet formation space, and a cutting slit is formed in the range from the end face of the auxiliary substrate to the promotion hole for cutting the connective tissue formed inside the promotion hole.

4. A valved graft-forming substrate for forming a valved graft having a plurality of valve leaflets bulging radially inward from a conduit by being placed in an environment where a biological tissue material is present to form connective tissue on the surface of the substrate, comprising: The device comprises a columnar substrate body and an auxiliary substrate detachably attached to an end of the substrate body, a main body-side leaflet forming surface and an auxiliary-side leaflet forming surface are respectively set on the base body and the auxiliary base material, the main body-side leaflet forming surface facing each other with a gap corresponding to the thickness of the valve leaflet, and a leaflet forming space is defined between the main body-side leaflet forming surface and the auxiliary-side leaflet forming surface, where connective tissue is allowed to invade from an intrusion port on the outer edge to form the leaflets of the valved graft; a cylindrical cover substrate is provided on the outer peripheral sides of the substrate body and auxiliary substrate, the outer peripheral surfaces of the substrate body and auxiliary substrate face the inner peripheral surface of the cover substrate at a distance corresponding to the thickness of the conduit, and the space between the outer peripheral surfaces of the substrate body and auxiliary substrate and the inner peripheral surface of the cover substrate forms a conduit formation space into which connective tissue is allowed to infiltrate to form the conduit of the valved graft; A valved graft formation substrate characterized in that the auxiliary substrate has formed therein promotion holes that connect the valve cusp formation space with the conduit formation space and promote the infiltration of connective tissue into the valve cusp formation space, and a cutting slit is formed in the range from the end face of the auxiliary substrate to the promotion hole for cutting the connective tissue formed inside the promotion hole.

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