WO2013128718A1

WO2013128718A1 - Method for producing biological lumen graft

Info

Publication number: WO2013128718A1
Application number: PCT/JP2012/079148
Authority: WO
Inventors: あや斉藤; 和佳谷
Original assignee: テルモ株式会社
Priority date: 2012-02-27
Filing date: 2012-11-09
Publication date: 2013-09-06
Also published as: JP2015091279A

Abstract

The purpose of the present invention is to provide a thinned biological lumen graft having ample strength. The present invention pertains to a method for producing a biological lumen graft, the method comprising: dissolving a polyester (B-1) into a solvent (B-2) to prepare a polyester (B) solution; and spray-atomizing the polyester (B) solution onto at least one surface of a polyester (A) woven fabric and filling the polyester (A) woven fabric under such conditions that the solvent (B-2) evaporates immediately after the polyester (B) solution arrives at the polyester (A) woven fabric; wherein the increase in thickness of the polyester (A) woven fabric after the spray atomization is 3 μm or less.

Description

Method for producing graft for living body lumen

The present invention relates to a graft for living body lumen and a method for manufacturing the graft for living body lumen.

An aortic aneurysm is a state in which a part of the aorta is swollen like an aneurysm, and is mainly divided into an abdominal aortic aneurysm and a thoracic aortic aneurysm depending on the site where the aneurysm is formed. The aortic wall usually has a three-layer structure of the intima, media and adventitia, and the structure of the blood vessel wall at the site where the aortic aneurysm is formed confirms the normal aortic wall structure on the aneurysm wall. It is divided into a true aneurysm, a dissecting aneurysm formed by dissection of the aortic wall, and a pseudoaneurysm in which the wall structure of the aorta is not confirmed on the aneurysm wall. Among these, a true aneurysm or a pseudoaneurysm usually has no remarkable symptoms unless it ruptures, so that early treatment is difficult. On the other hand, a dissecting aneurysm (aortic dissection) is easy to detect because it involves severe pain in the chest and back, but due to organ blood flow disorders, various organ complications may be caused by the site of dissociation Since various symptoms (for example, heart failure, myocardial infarction, disturbance of consciousness, abdominal pain, lower limb pain, etc.) appear, it is difficult to treat aortic dissection. In addition, in any case of the aortic aneurysm, if left untreated, the aneurysm may rupture and there is a risk of causing fatal major bleeding, so treatment is necessary.

The main treatment method for an aortic aneurysm is a surgical bypass operation in which the aneurysm is replaced with an artificial blood vessel. However, it requires laparotomy or thoracotomy, and is invasive to the patient. Moreover, extracorporeal circulation (artificial cardiopulmonary), hypothermia, organ cooling, etc. are performed as appropriate, but these methods are complicated and enter into specialized fields, causing complications related to the brain (brain disorders) and spinal cord (lower body paralysis). May cause.

Therefore, in recent years, instead of artificial blood vessel replacement by surgical bypass surgery, aortic aneurysms can be treated by folding a stent graft (stented artificial blood vessel) into small pieces and inserting it into the affected area through a catheter (stent graft). Treatment) has become widespread. The stent graft is an artificial blood vessel in which a spring-like metal called a stent is attached to an artificial blood vessel, and is used while being compressed and housed in a thin catheter. The catheter is advanced to the site where the aneurysm is present, and the stored stent graft is released and expanded from the catheter and is placed in the site where the aneurysm is present. For this reason, in the treatment by the stent graft, the incision portion by the operation can be made small, and the burden on the patient's body is extremely small, and this is a treatment method with a small invasion to the patient. In addition, according to this method, the aneurysm is capped with a stent graft, and there is no blood flow in the aneurysm, which gradually becomes smaller or even when the aneurysm does not become smaller, the enlargement of the aneurysm can be prevented and the risk of rupture can be reduced. .

In order to perform such a stent graft treatment in a less invasive manner, it is desirable to make the catheter thinner. For this purpose, it is necessary to reduce the bulk of the stent graft to be inserted. For this reason, a technique has been reported in which the artificial blood vessel portion of the stent graft is composed of 5 to 50 denier yarn, thereby reducing the thickness and enabling transplantation into a small diameter blood vessel (for example, WO 2006/014592 A1). reference).

However, as described in WO 2006/014592 A1, a stent graft produced using a fine yarn has a small thickness, but has insufficient strength, and the opening area of the weave is large when the weave density is maintained. There is a problem that it becomes large and causes blood leakage from the stent graft base material (artificial blood vessel portion).

Therefore, the present invention has been made in view of the above circumstances, and an object thereof is to provide a thinned living body lumen graft having sufficient strength.

Another object of the present invention is to provide a thinned biological lumen graft having low water permeability.

As a result of intensive studies to solve the above problems, the present inventors applied the polyester solution to the substrate under specific conditions such that the solvent evaporates immediately after the polyester solution arrives on the substrate. As a result, the present inventors have found that the above problems can be solved, and have completed the present invention.

That is, the above-mentioned purposes are to prepare polyester (B) solution by dissolving polyester (B-1) in solvent (B-2), and immediately after the polyester (B) solution arrives on the polyester (A) woven fabric. The polyester (A) woven fabric is spray-sprayed on at least one surface of the polyester (A) woven fabric under conditions such that the solvent (B-2) evaporates on the polyester (A). A method for producing a graft for a living body lumen having a stopping, wherein the increase in thickness of the polyester (A) woven fabric before and after spraying is 3 μm or less is achieved. .

The above-mentioned objects include a polyester (A) woven fabric and a polyester (B-1) film formed by fusing on the surface of the polyester (A) woven fabric. Is also achieved by a graft for living body lumens, which seals the polyester (A) woven fabric.

1A is an electron micrograph of the surface of the graft substrate 1 of Example 1, and FIG. 1B is an electron micrograph of a cross section of the graft substrate 1 of Example 1. FIG. FIG. 2 is an electron micrograph of the surface of the graft substrate 4 of Comparative Example 2. 3A is an electron micrograph of the surface of the graft substrate 5 of Comparative Example 3, and FIG. 3B is an electron micrograph of a cross section of the graft substrate 5 of Comparative Example 3. 4A is an electron micrograph of the surface of the graft substrate 6 of Comparative Example 4, and FIG. 4B is an electron micrograph of the back surface of the graft substrate 6 of Comparative Example 4. FIG. 5 is an electron micrograph of the surface of the graft substrate 7 of Comparative Example 5. FIG. 6 is a schematic view showing a water permeability measuring device. FIG. 7 is a diagram for explaining the measurement of the adaptive sheath size. FIG. 8 is a diagram for explaining the measurement of burst intensity.

The method for producing a graft for living body lumen according to the present invention comprises (i) preparing a polyester (B) solution by dissolving polyester (B-1) in a solvent (B-2) (coating liquid preparation step (i) Ii); (ii) The polyester (B) solution is added to the polyester (A) under conditions such that the solvent (B-2) evaporates immediately after the polyester (B) solution arrives on the polyester (A) woven fabric. Spraying onto at least one surface of the woven fabric to seal the polyester (A) woven fabric (application step (ii)), the thickness of the polyester (A) woven fabric before and after spraying The increase is 3 μm or less. The method of the present invention is characterized in that the polyester solution is applied to the substrate under specific conditions such that the solvent evaporates immediately after the polyester solution arrives at the polyester (A) woven fabric as the substrate.

Further, the graft for living body lumen of the present invention has a polyester (A) woven fabric and a polyester (B-1) film formed by fusing on the surface of the polyester (A) woven fabric. B-1) The membrane is a graft for living body lumens that seals the polyester (A) woven fabric.

As described above, in order to perform treatment with a stent graft in a less invasive manner, it is desirable to make the catheter thinner. For this purpose, it is necessary to reduce the bulk of the stent graft to be inserted. Stent grafts are made by attaching a stent skeleton using a super elastic metal or the like to an artificial blood vessel such as a polyester woven fabric or ePTFE. It is particularly effective to reduce the bulk of the artificial blood vessel portion to make the catheter thinner. It is. In addition, in order to reduce the bulk of artificial blood vessels such as polyester woven fabrics, it is important not only to reduce the thickness of the fabric but also to maintain the softness of the woven fabric.

Here, as a method of reducing the bulk of the stent graft base (artificial blood vessel portion), there is a method of thinning the yarn constituting the woven fabric. However, if the yarn constituting the woven density is thinned, the opening area of the weave increases and blood leakage from the stent-graft base material (artificial blood vessel) occurs. For this reason, it is necessary to weave as close as possible without causing blood leakage from the stent-graft substrate. On the other hand, in order to increase the weaving density, it is necessary to increase the number of yarns, but it is difficult to converge warps (warp yarns) to the target weaving width. Further, since the strength of the yarn itself decreases as the yarn becomes thinner, the yarn is likely to break due to friction between the yarn and the loom in the weaving process or between the yarns, and it is difficult to increase the weave density from this viewpoint. .

In order to solve the above-mentioned problem, at least one surface of a thin stent graft base material (for example, polyester woven fabric) having a large opening in the weave is coated with a film such as a thin polymer material, a porous film, or a nonwoven fabric. A way to stop is also conceivable. However, as the coating thickness increases, not only does the bulk increase, but the stent graft base material becomes hard, making it difficult to fold it small, making it difficult to reduce the diameter of the applied catheter. Further, in this method, when the coating material is peeled off, there is a risk that blood leaks from the opening of the weave of the stent graft base material and the function as the stent graft cannot be maintained. For this reason, it is necessary to firmly adhere the coating material to the stent graft substrate.

In order to solve this problem, a method using an adhesive between the coating material and the substrate may be considered. However, a stent graft, like an artificial blood vessel, is placed in the body for a long time (permanently in some cases). is there. For this reason, from the viewpoint of safety (toxicity) and stability in long-term implantation, the adhesive is preferably the same polyester as the base material, and a method of welding using a solvent capable of dissolving the polyester is preferable. ,Conceivable. However, since the base material is also the same polyester base material, the base material itself may be dissolved depending on the welding conditions, leading to a decrease in strength.

Also, a coating method such as a method of forming a film on a substrate or a method of laminating a separately prepared film is conceivable. However, in a method in which a film having a uniform thickness or a porous film is bonded to a substrate, it is difficult to cover the substrate uniformly because a film having a thickness of about 1 μm is very thin and difficult to handle. Further, since the film does not enter the openings of the base material, there is a problem that the contact area between the base material and the film becomes small and the film is easily peeled by contact / rubbing with the cartel lumen.

Therefore, there has been a strong demand for a thin stent graft base material having sufficient strength and flexibility and low water permeability, but it has not been realized.

On the other hand, the method of the present invention uses a polyester woven fabric as the graft substrate, and the polyester before and after spraying under specific conditions such that the solvent of the polyester solution evaporates immediately after the polyester solution arrives on the substrate. (A) A biological lumen graft is produced by applying a polyester solution to a base material (polyester (A) woven fabric) so that the increase in thickness of the woven fabric is 3 μm or less. According to this method, by using the same polyester as the base material for the coating liquid (coating film), the coating film is firmly formed on the base material and is difficult to peel off. For this reason, even if the graft base material (artificial blood vessel portion) has a large opening area (opening size) with a fine thread, the opening can be firmly covered (sealed). For this reason, the water permeability of the graft for living body lumen can be reduced. Moreover, since the adhesiveness between the substrate and the coating film is good, even if a coating film that is thin enough to cover (seal) the opening is formed on the substrate, peeling does not easily occur. Therefore, the increase in the thickness of the polyester (A) woven fabric before and after spraying can be made 3 μm or less, and the graft for living body lumen can be made thin while maintaining strength and flexibility. Therefore, the graft for living body lumen according to the present invention can be accommodated in a small-diameter catheter, has low water permeability, and can suppress / prevent blood leakage from the graft. Even when implanted for a long period of time, since the coating film is integrated (adhered) with the base material, a part of the coating film does not deviate into the blood vessel, and the stability is high. Further, since the solvent constituting the polyester solution evaporates immediately after reaching the graft substrate, the solvent hardly dissolves the polyester substrate. Therefore, since the graft base material can maintain the original strength, the graft according to the present invention has high strength and flexibility.

As described above, the graft for living body lumen of the present invention has sufficient strength and low water permeability even if it is thin. For this reason, the graft for living body lumen of the present invention can be inserted into a thin catheter, and the treatment with the stent graft can be performed with less invasiveness.

Hereinafter, embodiments of the present invention will be described.

(I) Preparation Step of Coating Solution In this step, polyester (B-1) is dissolved in solvent (B-2) to prepare a polyester (B) solution.

Here, the polyester (B-1) is not particularly limited, and polyesters used for known medical devices can be used in the same manner. Specific examples include polyethylene terephthalate (PET) and polybutylene terephthalate (PBT). Polyethylene terephthalate is also known as Dacron (registered trademark). The polyester may be synthesized or commercially available. In the latter case, Lumirror (registered trademark) series (all manufactured by Toray Industries, Inc.) such as Lumirror (registered trademark) S10, T60, H10, F65, F53, F57S15, S105, etc., Teijin Tetron Film (manufactured by Teijin DuPont Films, Ltd.) ) Etc. can be used.

The solvent (B-2) is not particularly limited as long as it can dissolve the polyester (B-1). Specific examples include 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), trifluoroacetic acid (TFA), and the like. Of these, HFIP is preferred.

The concentration of polyester (B-1) in the polyester (B) solution is such that the opening (openings) of the polyester (A) woven fabric can be sufficiently covered (sealed) in the next step (ii). If there is no particular limitation. Specifically, the concentration of the polyester (B-1) in the polyester (B) solution is preferably 0.5 to 20% by weight, and more preferably 3 to 10% by weight. If it is such a density | concentration, the opening part (opening) of a polyester (A) woven fabric can fully be covered (sealed). In the next step, the solvent (B-2) can be quickly evaporated immediately after the polyester (B) solution arrives at the polyester (A) woven fabric.

The polyester (B) solution is usually prepared by dissolving the polyester (B-1) in the solvent (B-2) to a predetermined concentration. At this time, if necessary, heat treatment, stirring Processing may be performed.

(Ii) Coating step In this step, the polyester (A) woven fabric is sprayed by spraying the polyester (B) solution prepared in the above step (i) onto at least one surface of the polyester (A) woven fabric. (Coating) The spraying is performed under such a condition that the solvent (B-2) evaporates immediately after the polyester (B) solution arrives on the polyester (A) woven fabric. By such an operation, the dissolution of the polyester (A) woven fabric by the solvent (B-2) can be suppressed / prevented, so that the obtained graft for living body lumen has high strength and flexibility inherent in the polyester (A) woven fabric. The ability to demonstrate. Further, since a sufficient amount of polyester (B-1) is applied to the opening (opening) of the polyester (A) woven fabric by spraying the polyester (B) solution, the polyester (A) woven fabric is substantially Can be completely sealed (coated). Here, “the polyester (A) woven fabric is substantially completely sealed (covered)” means that the opening (opening) of the polyester (A) woven fabric is substantially completely polyester (B- It means the state filled in 1). Specifically, 90 to 100% of the surface of the polyester (A) woven fabric is preferably sealed (coated) with the polyester (B-1), and 95 to 100% of the surface of the polyester (A) woven fabric is polyester. More preferably, it is sealed (coated) with (B-1). With such a sealing rate (covering rate), water permeability can be suppressed and blood leakage from the graft can be suppressed / prevented.

On the other hand, after the polyester (B) solution is applied to the polyester (A) woven fabric, a coating film is formed (that is, after the polyester (B) solution arrives on the polyester (A) woven fabric, the solvent (B-2 ) Is evaporated), a large amount of the solvent (B-2) comes into contact with the polyester (A) woven fabric to dissolve the polyester (A) woven fabric, so that the strength of the biological lumen graft is reduced. End up. On the other hand, when the solvent (B-2) evaporates before the polyester (B) solution arrives on the polyester (A) woven fabric, the polyester (B-1) coating surface becomes rough, and the polyester (B-1 ) Cannot sufficiently seal (cover) the polyester (A) woven fabric. For this reason, the water permeability of the obtained graft for living body lumen cannot be sufficiently reduced, and blood leakage from the graft cannot be prevented. In addition, since a sufficient amount of polyester (B-1) does not enter the opening (opening) of the polyester (A) woven fabric, the polyester (B-1) coating film is easily peeled off from the polyester (A) woven fabric. Therefore, it is not preferable for safety.

In this step (ii), the increase in the thickness of the polyester (A) woven fabric before and after spraying is 3 μm or less. With such an increase in thickness, the obtained graft for living body lumen is sufficiently thin and flexible enough to be folded into a small diameter (for example, an inner diameter of 11 Fr or less) and easily stored in a thin catheter. Can be inserted from blood vessels. For this reason, the graft for living body lumen according to the present invention can be applied to a patient with a thin blood vessel (for example, a child or an elderly person). The increase in the thickness of the polyester (A) woven fabric before and after spraying is preferably 0 to 3 μm, more preferably more than 0 μm and 3 μm or less, and particularly preferably 0.5 to 2 μm. The “increase in the thickness of the polyester (A) woven fabric before and after spraying” is the difference between the thickness of the polyester (A) woven fabric after spraying and the thickness of the polyester (A) woven fabric before spraying (μm ) [= (The thickness of the polyester (A) woven fabric after spraying (μm)) − (the thickness of the woven fabric of polyester (A) before spraying (μm))]]. In addition, “the increase in the thickness of the polyester (A) woven fabric before and after spraying is 0 μm” means that the polyester (B) penetrates only into the openings of the polyester (A) woven fabric, and the polyester (A) It means that the thickness of the woven fabric itself does not change. In this specification, the thickness of the polyester (A) woven fabric before and after spraying is a value measured by the method described in the following examples.

Here, the polyester (A) woven fabric is a fabric that constitutes the base material of the graft for living body lumen of the present invention and is composed of a polyester fiber fabric. The fabric structure is not particularly limited, and the same structure as that usually used as a graft base material, such as a knitted fabric and a nonwoven fabric, can be similarly applied. Also, the structure of the woven fabric is not particularly limited, and a structure usually used as a base material for grafts can be similarly applied. Specific examples include plain weave, twill weave, satin weave, and double weave. Of these, plain weave is preferred in terms of strength and thinness. The form of the fabric is also not particularly limited, and may be a form woven in a cylindrical shape other than a general plane fabric. Further, the surface of the polyester (A) woven fabric may be raised or not raised, but is preferably not raised from the viewpoint of the thickness and strength of the woven fabric. By making the polyester (A) woven fabric smooth as described above, the polyester (A) woven fabric can be easily folded and inserted into the catheter lumen.

The polyester (A) woven fabric is formed by interweaving yarns made of polyester (A) filaments (fibers) as warps and wefts. Here, the yarn may be a monofilament or a multifilament, but is preferably a multifilament. The polyester (A) woven fabric made of multifilaments can flexibly respond to external forces, and can exhibit softness and wear resistance by shifting each monofilament (single yarn). Therefore, the polyester (A) woven fabric produced from the multifilament is excellent in wear resistance and flexibility. The multifilament may be either a non-twisted yarn or a real twisted yarn, or may be a false twisted yarn to which crimps are imparted.

The polyester (A) constituting the polyester (A) filament (fiber) is not particularly limited, and polyesters used for known medical devices can be used in the same manner. Specific examples include polyethylene terephthalate (PET) and polybutylene terephthalate (PBT). Here, the polyester constituting the polyester (A) woven fabric and the polyester (B-1) may be the same or different, but the polyester (A) and the polyester (B-1) Are preferably the same. As a result, the adhesion between the polyester (A) woven fabric and the sealing (coating film) of the polyester (B-1) can be enhanced, and the polyester (B-1) film is peeled off from the polyester (A) woven fabric. Can be effectively suppressed / prevented. Therefore, a thin polyester (A) woven fabric having a large weave opening can be used as a graft substrate, and the graft can be made thin. Therefore, the graft for living body lumen according to the present invention can be housed in a small-diameter catheter, has low water permeability, and can suppress / prevent blood leakage from the graft. Moreover, even if it is a case where it is embedded for a long period of time, since the coating film is integrated (adhered) with the base material, a part of the coating film does not peel off to the blood vessel, and the stability is high.

When monofilament fiber is used for the polyester (A) woven fabric, the diameter of the filament (fiber) [polyester (A) fiber] is not particularly limited, but is preferably 10 to 50 μm, more preferably 20 to 40 μm. . With such a diameter, sufficient thinness, flexibility and strength can be achieved. Moreover, the cross section of the monofilament (single yarn) constituting the filament (fiber) used in the polyester (A) woven fabric is not particularly limited, and may be any of a circular cross section, a triangular cross section, a flat cross section, a hollow cross section, and the like. However, from the viewpoints of flexibility and low water permeability, a circular cross section and a flat cross section are preferable.

When multifilament fibers are used for the polyester (A) woven fabric, the total fineness of the filaments (fibers) is not particularly limited, but is preferably 20 to 100 dtex, more preferably 30 to 50 dtex. With such a total fineness, sufficient thinness, strength and flexibility can be achieved.

The production (spinning) method of the polyester (A) fiber is not particularly limited, and may be obtained by direct spinning, or may be obtained by direct spinning or complex spinning using a sea-island-type or split-split-type composite die to obtain a woven fabric. May be obtained.

The opening size of the polyester (A) woven fabric is not particularly limited, but is preferably 5 to 150 μm, more preferably 5 to 30 μm. Alternatively, the opening size of the polyester (A) woven fabric may be defined by the yarn density. Here, the yarn density is not particularly limited, but is preferably 70 to 700 yarns / inch, more preferably 400 to 600 yarns / inch. With such an opening size or yarn density, the polyester (A) woven fabric can be made sufficiently thin. The thickness of the polyester (A) woven fabric is not particularly limited, but is preferably thin. Specifically, the thickness of the polyester (A) woven fabric is preferably 20 to 80 μm, and more preferably 30 to 60 μm. With such a thickness, for example, even a graft for living body lumen after applying polyester (B-1) to a woven fabric of polyester (A) is folded and inserted into a thin catheter having an inner diameter of 11 Fr or less. Is easy. The graft for living body lumen has sufficient strength and flexibility, and polyester (B-1) also firmly seals (covers) the polyester (A) woven fabric (base material). Therefore, even if the catheter lumen and the biological lumen graft are rubbed, the polyester (B-1) membrane is not peeled off from the graft.

The method for producing the polyester (A) woven fabric is not particularly limited, and a known method can be used. For example, a method of plain weaving polyester (A) fibers so that one to four wefts are arranged for every one warp can be used. The apparatus used for producing the polyester (A) woven fabric is not particularly limited, and a known apparatus can be used in the same manner. For example, a shuttleless loom such as a water jet loom, an air jet loom, and a needle loom, a fly shuttle loom, a tappet loom, a dobby loom, a jacquard loom, and the like can be used. The woven fabric may be scoured and relaxed as necessary, and heat set with a tenter or the like. The obtained polyester (A) woven fabric may be further pressed with a calendar or the like. At this time, the surface of the calendar or the like is preferably heated at a temperature equal to or higher than the glass transition point or softening point of the polymer constituting the fiber. By such heat treatment, the cross-sectional shape of the fiber on the surface in contact with the calendar or the like can be deformed substantially parallel to the surface. Here, the heating temperature is not particularly limited, but for example, it is preferable to heat the calender or the like to about 120 to 180 ° C. for treatment.

The polyester (A) woven fabric may be produced as described above or a commercially available product may be used. Here, the commercially available product is not particularly limited, but Tetron Mesh T-No. 508T, T-No. 420T, T-No. 380T, T-No. 355T, T-No. 330T, T-No. 305T, T-No. 280T, T-No. 255T, T-No. 230T, T-No. 200T, T-No. 180T, T-No. 150T, T-No. 135T, T-No. 120T, T-No. 100T, T-No. 90T, T-No. 80T, TB-70, TB-60, TB-50, TB-40 (all manufactured by Tokyo Screen Co., Ltd., material: polyester PET), PETEX PET10, PET11-HC (all manufactured by SEFAR), and the like.

ポリエステル Spray the polyester (A) solution onto the polyester (A) woven fabric as described above. Here, the polyester (B) solution may be sprayed on at least one surface of the polyester (A) woven fabric. In consideration of thinning (reducing diameter), flexibility, etc., it is preferable to spray spray the polyester (B) solution on one surface of the polyester (A) woven fabric. Here, spray spraying is performed under conditions such that the solvent (B-2) evaporates immediately after the polyester (B) solution arrives on the polyester (A) woven fabric. In the present specification, “the solvent (B-2) evaporates immediately after the polyester (B) solution arrives on the polyester (A) woven fabric” means that the polyester (A) woven with the solvent (B-2). It means that the solvent (B-2) evaporates before the cloth dissolves. Specifically, the conditions are preferably such that the solvent (B-2) evaporates 1 to 15 seconds after the polyester (B) solution arrives on the polyester (A) woven fabric. More preferably, the polyester (A) is woven on the polyester (A) woven fabric under conditions such that the solvent (B-2) evaporates 2 to 10 seconds after the polyester (B) solution arrives. ) Spray the solution. Further, “solvent (B-2) evaporates” means that substantially the entire amount of solvent (B-2) evaporates. Specifically, it is contained in the sprayed polyester (B) solution. It is preferable that 90 to 100% by volume of the solvent (B-2) is evaporated. Here, the confirmation of whether or not the solvent (B-2) has evaporated immediately after the polyester (B) solution arrives on the polyester (A) woven fabric may be carried out by any method. The polyester (A) woven fabric after spraying is held under a light source, and it can be confirmed by visually observing the color tone that changes due to light refraction by the residual solvent. Alternatively, the confirmation of whether or not the solvent (B-2) has evaporated immediately after the polyester (B) solution arrives on the polyester (A) woven fabric is more specific because the dissolution of the polyethylene terephthalate fiber is not observed. Can be confirmed by the fact that the melted area of the polyester (A) woven fabric after spraying is less than 5% of the surface of the polyester (A) woven fabric.

The method for evaporating the solvent (B-2) immediately after the polyester (B) solution arrives on the polyester (A) woven fabric is not particularly limited. For example, (a) a method for adjusting the spraying speed; (b) a method for adjusting the spraying pressure; (c) a method in which the polyester (A) woven fabric is preheated and then sprayed with the polyester (B) solution. (D) There may be a method of adjusting the spraying distance. Among these, in (a) above, the spray spraying speed is not particularly limited as long as the solvent (B-2) evaporates immediately after the polyester (B) solution arrives at the polyester (A) woven fabric. . Specifically, the polyester (B) solution, preferably 0.005 ~ 0.3mL / cm ^2, more preferably sprayed in an amount of 0.007 ~ 0.015mL / cm ^2. If the polyester (B) solution is sprayed in such an amount, the solvent (B-2) in the polyester (B) solution evaporates immediately before or after it reaches the polyester (A) woven fabric. Then, the polyester (A) woven fabric is sealed (coated) with the polyester (B). In addition, the solvent (B-2) can be effectively suppressed and prevented from dissolving the polyester (A) woven fabric.

In the above (b), the spraying pressure is not particularly limited as long as the solvent (B-2) evaporates immediately after the polyester (B) solution arrives on the polyester (A) woven fabric. Specifically, the polyester (B) solution is sprayed at an air pressure of 10 to 80 kPa, more preferably 30 to 60 kPa. If the polyester (B) solution is sprayed at such an air pressure, the solvent (B-2) in the polyester (B) solution evaporates immediately before or after it arrives at the polyester (A) woven fabric. Then, the polyester (A) woven fabric is sealed (coated) with the polyester (B-1). In addition, the solvent (B-2) can be effectively suppressed and prevented from dissolving the polyester (A) woven fabric.

In the above (c), the heating condition of the polyester (A) woven fabric is such that the solvent (B-2) evaporates immediately after the polyester (B) solution arrives at the polyester (A) woven fabric. There is no particular limitation. Specifically, the heating temperature of the polyester (A) woven fabric is preferably 20 to 80 ° C., more preferably 50 to 70 ° C. Further, the heating time of the polyester (A) woven fabric is not particularly limited as long as it is a preferable temperature as described above, but is usually preferably 1 minute or more, more preferably about 2 to 3 minutes. is there. If the polyester (B) solution is spray-sprayed on the polyester (A) woven fabric at such a temperature, the solvent (B-2) in the polyester (B) solution is promptly received after reaching the polyester (A) woven fabric. By evaporation, the polyester (A) woven fabric is sealed (coated) with the polyester (B-1). In addition, the solvent (B-2) can be effectively suppressed and prevented from dissolving the polyester (A) woven fabric.

In the above (d), the spray spray distance is not particularly limited as long as the solvent (B-2) evaporates immediately after the polyester (B) solution arrives on the polyester (A) woven fabric. Specifically, the spraying is performed with the distance between the nozzle for spraying the polyester (B) solution and the polyester (A) woven fabric being 50 to 150 mm, more preferably 100 to 130 mm. If the polyester (B) solution is sprayed from such a distance, the solvent (B-2) in the polyester (B) solution evaporates immediately before or after it reaches the polyester (A) woven fabric. Then, the polyester (A) woven fabric is sealed (coated) with the polyester (B-1). In addition, the solvent (B-2) can be effectively suppressed and prevented from dissolving the polyester (A) woven fabric. Of these, the methods (a), (b), (c), and (d) are preferably used. In addition, the said method may be used independently or may be used in combination of 2 or more types as appropriate.

The conditions for applying (sealing) polyester (B-1) to the polyester (A) woven fabric are as long as the increase in the thickness of the polyester (A) woven fabric before and after spraying is 3 μm or less. There is no particular limitation. Specifically, the polyester (B) solution is sprayed on the surface of the polyester (A) woven fabric using at least one of the operations (a) to (d). In addition, the said process (ii) may be performed once or may be performed twice or more. In the latter case, the application conditions in each operation may be the same or different. Considering the flexibility of the graft and the ease of operation, the step (ii) is preferably performed once.

The graft for living body lumen thus obtained has a polyester (A) woven fabric and a polyester (B-1) membrane formed by fusing on the surface of the polyester (A) woven fabric. B-1) The membrane has a structure for closing the polyester (A) woven fabric. In the graft for living body lumen of the present invention, the polyester (A) woven fabric has an opening (opening) in addition to the polyester (A) fiber surface constituting the polyester (A) woven fabric. It has a woven-membrane composite structure formed by coating (sealing).

The graft for living body lumen of the present invention is thinned while ensuring strength and flexibility. Specifically, it is preferable that the thickness of the graft for living body lumen is twice the diameter (μm) of the polyester (A) fiber + 3 μm or less. Here, “2 times the diameter (μm) of the polyester (A) fiber + 3 μm or less” means that it is twice the diameter (μm) of the polyester (A) fiber ± 3 μm. The thickness of the graft for living body lumen is more preferably 2 ± 2 μm of the diameter (μm) of the polyester (A) fiber, and 2 ± 1 μm of the diameter (μm) of the polyester (A) fiber. Particularly preferred. Such a thin graft for a living body lumen is rich in flexibility, so it can be folded into a small size and easily stored in a catheter having a small diameter (for example, an inner diameter of 11 Fr or less), and can be inserted even from a thin blood vessel. For this reason, the graft for living body lumen according to the present invention can be applied to a patient with a thin blood vessel (for example, a child or an elderly person). In addition, in the above, the thickness of the graft for living body lumens is less (minus) than twice the diameter (μm) of the polyester (A) fiber. A) This is a case where the diameter is less than twice the fiber diameter (μm). Here, the thickness of the graft for living body lumens is smaller than twice the fiber diameter when the woven fabric itself is subjected to a crushing process such as a calendering process. It is because it becomes smaller than twice.

Moreover, the graft for living body lumen of the present invention has low water permeability. Specifically, the biological lumen graft of the present invention is preferably 0 to 300 mL / min / cm ² , more preferably 0 to 200 mL / min / cm ² , more preferably 0 to 10 mL / min / cm ² , Particularly preferably, it has a water permeability of 0 to 5 mL / min / cm ² . With such a water permeability, blood leakage from the graft substrate can be effectively suppressed / prevented. In addition, “water permeability” in the present specification means a value defined by the following examples.

The biological lumen graft of the present invention has high strength. Specifically, the biological lumen graft of the present invention preferably has a burst strength of 50 to 250 N, more preferably 70 to 200 N. With this strength, after placement (fixation) in the aneurysm, the biological lumen graft sufficiently seals the aneurysm and reduces blood pressure in the aneurysm, resulting in a larger aneurysm size. The thickness can be reduced. “Burst intensity” in this specification means a value defined by the following examples.

The graft for living body lumen of the present invention can be used for, for example, a graft substrate (artificial blood vessel portion) of a stent graft, an artificial blood vessel, an artificial trachea, an artificial bronchus, an artificial esophagus, and the like. It can be suitably used for artificial blood vessels. The biological lumen graft of the present invention can also be used for medical purposes other than those described above. Among the above uses, the graft for living body lumen of the present invention can be applied to an artificial blood vessel as it is. Moreover, although preferable embodiment at the time of applying the graft for biological lumens of this invention to the graft base material (artificial blood vessel part) of a stent graft below is described, this invention is not limited to the following.

A stent graft is a type of artificial blood vessel in which a spring-like metal (stent part), called a stent, is attached to an artificial blood vessel. The stent graft is compressed and stored in a thin catheter. The graft for living body lumen of the present invention can be used for an artificial blood vessel portion (graft base material) of a stent graft. The stent portion may be a self-expanding stent, a balloon-expandable stent, or a combination of these (ie, a combination of a balloon-expandable portion and a self-expandable portion). The stent material is not particularly limited, and is stainless steel such as SUS304, SUS316L, SUS420J2, SUS630, gold, platinum, silver, copper, nickel, cobalt, titanium, iron, aluminum, tin and nickel-titanium alloy, cobalt-chromium. Metal materials such as alloys, zinc-tungsten alloys, and the like can be preferably used. In the stent graft of the present invention, at least one stent is fixed to the biological lumen graft of the present invention with a suture or the like.

Also, the graft for living body lumen of the present invention can be applied in place of a known graft substrate (artificial blood vessel portion) of a stent graft. For example, the graft fabric disclosed in JP-T-2008-505713, the annular thin film / thin-film tube disclosed in JP-T-2008-514309, the tubular graft material main body disclosed in JP-A-2010-269161, and the lumen disclosed in JP-A-2007-125415. It may be applied as a graft.

In addition, the application method to a patient when the graft for living body lumen of the present invention is used for a stent graft is not particularly limited, and known methods can be similarly applied. For example, the stent graft is folded into a small size and stored in a catheter. Here, the thickness of the catheter is not particularly limited, but is preferably 11 Fr (3 Fr = 1 mm) or less in inner diameter. Invasion to patients can be reduced. The catheter is then incised 4-5 cm at the base of the patient's leg to expose the femoral artery, inserted into the femoral artery, and introduced to the site of the aneurysm under fluoroscopy. When it is confirmed that the stent graft exists so as to sandwich the site where the aneurysm is located, the stent graft housed from the catheter is released and expanded, and placed (fixed) at the site where the aneurysm is located. After confirming that the stent graft has been properly placed (fixed) at the site of the aneurysm, the catheter is removed and the incision in the femoral artery is closed. By this method, the aneurysm is sealed with a stent graft, reducing the blood pressure into the aneurysm and consequently reducing the size of the aneurysm. In addition, the above method does not require an abdominal / thoracotomy operation and is a minimally invasive procedure with very little burden on the patient's body because the incision is small.

The effect of the present invention will be described using the following examples and comparative examples. However, the technical scope of the present invention is not limited only to the following examples.

Example 1
Tetoron mesh (Tokyo Screen Co., Ltd .: T-No. 508T; thickness = 50 μm; yarn density = 508 pieces / inch; PET woven fabric) was used as a polyester (A) woven fabric. The polyester (A) woven fabric is formed of polyester single fibers having a diameter of 27 μm. Separately, a polyester (B) solution was prepared by dissolving polyester (Toray Industries, Inc .: Lumirror (registered trademark) S10 # 188) in hexafluoroisopropanol (HFIP) to a concentration of 5% by weight. Moreover, the said polyester (A) woven fabric was installed in the to-be-coated member of the spray apparatus (Nordson Co., Ltd.:DR2404N), and the temperature around the apparatus was set to about 25 ° C.

Next, on the one side of the polyester (A) woven fabric, the polyester (B) solution prepared above from the spray nozzle is set at a distance of 120 mm from the polyester (A) woven fabric and sprayed at an air pressure of 50 kPa. Spray spraying was performed once so that the amount was 0.01 mL / cm ^2, and the polyester (A) woven fabric was sealed to prepare the graft substrate 1. Under the present circumstances, when the increase in the thickness of the said polyester (A) woven fabric before and after spraying of the obtained graft base material 1 was measured according to the method described in <Thickness Measurement> below, the polyester ( A) The increase in the thickness of the woven fabric was 1 μm. Here, the HFIP evaporated in 5 to 10 seconds after the polyester (B) solution arrived at the polyester (A) woven fabric. Further, when the cross section of the polyester (A) woven fabric after spraying was observed with an electron microscope at 1000 times magnification, as shown in FIG. 1, the polyester (B-1) coating film was found to have a polyester (A) woven fabric. The melted area of the polyester (A) woven fabric after spray spraying was less than 5% of the surface of the polyester (A) woven fabric, and dissolution of polyethylene terephthalate fibers was not observed. Further, as shown in FIG. 1, the polyester (B-1) coating film was formed over an area of 95% or more of the polyester (A) woven fabric surface (95% or more of the polyester (A) woven fabric surface was polyester. (B-1) was observed (coated).

Example 2
The graft spraying operation of Example 1 was repeated 3 times, and the graft base material 2 was produced. Under the present circumstances, when the increase in the thickness of the said polyester (A) woven fabric before and after spraying of the obtained graft base material 2 was measured according to the method described in <Thickness measurement> below, the polyester ( A) The increase in the thickness of the woven fabric was 3 μm. Further, when the cross section of the polyester (A) woven fabric after spray spraying was observed with an electron microscope at a magnification of 1000 times, the dissolved area of the polyester (A) woven fabric after spray spraying was 5 on the surface of the polyester (A) woven fabric. %, And dissolution of polyethylene terephthalate fiber was not observed. Further, the polyester (B-1) coating film was formed over an area of 95% or more of the surface of the polyester (A) woven fabric (95% or more of the surface of the polyester (A) woven fabric was sealed with the polyester (B-1). (Coated) was observed.

Comparative Example 1
The spraying operation of Example 1 was repeated 5 times to produce a graft substrate 3. Under the present circumstances, when the increase in the thickness of the said polyester (A) woven fabric before and behind spraying of the obtained graft base material 3 was measured according to the method as described in the following <thickness measurement>, it was 5 micrometers. Further, when the cross section of the polyester (A) woven fabric after spray spraying was observed with an electron microscope at a magnification of 1000 times, the dissolved area of the polyester (A) woven fabric after spray spraying was 5 on the surface of the polyester (A) woven fabric. %, And dissolution of polyethylene terephthalate fiber was not observed.

Comparative Example 2
In Example 1, the polyester (A) woven fabric was not sealed. That is, the polyester (A) woven fabric (thickness: 50 μm) used in Example 1 was used as the graft substrate 4. When the surface of the graft substrate 4 [polyester (A) woven fabric] was observed with an electron microscope at a magnification of 1000 times, as shown in FIG. Open) was observed.

Comparative Example 3
A polyester woven fabric (thickness: 120 μm; yarn density = 140 yarns / inch), which has a proven record as a graft base material for stent grafts, was used as the graft base material 5. In addition, this polyester woven fabric is formed with a thread in which 55 polyester fibers having a diameter of about 12 μm are bundled. When the surface of the graft substrate 5 was observed with an electron microscope at 1000 times magnification, it was observed that the graft was composed of many fibers and had a considerable thickness as shown in FIG. .

[Graft performance evaluation]
The graft substrates 1 to 5 obtained above were evaluated as follows, and the results are shown in Table 1 below.

<Thickness measurement>
The total thickness in the longitudinal direction of each graft substrate before and after application of the polyester (B) solution was measured with a thickness gauge, and the maximum thickness before application (T ₀ (μm)) and the maximum value after application (T ₁ (μm)) is recorded. The difference between these values (T ₁ -T ₀ (μm)) is calculated, and this difference is defined as the increase (μm) in the thickness of the polyester (A) woven fabric before and after spraying.

<Water permeability>
The water permeability of the graft substrate is measured according to ISO 7198. Specifically, each graft substrate is cut into a size of about 2 cm × 2 cm to prepare a sample. Next, the sample is sandwiched and set in the sample installation part (hole) 11 in the water permeability measuring device 10 shown in FIG. 6, and the water 12 is flowed while checking the water pressure with the pressure gauge 13, and the water pressure of 120 mmHg When water is applied, the amount of water oozing out from this sample per minute is measured and expressed as water permeability (mL / min / cm ² ).

<Applicable sheath size (adaptive sheath diameter)>
The adaptive sheath size of the graft substrate is measured according to the following method. That is, as shown in FIG. 7A, each graft base material is sewn into a cylindrical shape (diameter: 26 mm, length: 32 mm) to produce the graft 2. Next, five graft-shaped nickel-titanium stents 3 having a diameter of 28 mm are sewn to the graft 2 at intervals of 8 mm. Moreover, the thread | yarn 4 for making the inside of a tube slide is attached to the terminal of this cylindrical base material (FIG. 7B). Using a SUS wire 5 having a diameter of 1.5 mm as a shaft, it is placed in PTFE tubes (sheaths) 6 having various diameters, and sliding force is measured. Here, the diameter of the thinnest PTFE tube (sheath) at which the sliding force is 40 N or less is confirmed and set as an adaptive sheath size. In this test, the sliding force sets a PTFE tube (sheath) in a tensile tester, pulls the graft substrate through the yarn at a speed of 200 mm / min in the PTFE tube, and measures the load. The average value of the load applied for 3 to 5 seconds from the beginning of tension is calculated, and this is defined as the sliding force (N).

<Peeling of coating>
After measuring the adaptive sheath size obtained above, the graft is taken out from the PTFE tube (sheath), and the portion of the graft having many wrinkles is magnified 1000 times with an electron microscope and observed.

Comparative Example 4
In Example 1, the polyester (B) solution prepared above was sprayed on one side of a woven fabric of polyester (A) in an amount of 0.5 mL / cm ² at an air pressure of 10 kPa from a spray nozzle. (A) A graft substrate 6 was produced by repeating the operation of Example 1 except that the woven fabric was sealed. Under the present circumstances, when the increase of the thickness of the said polyester (A) woven fabric before and after spraying of the obtained graft base material 6 was measured according to the method as described in the above <thickness measurement>, it was 1 micrometer. At this time, HFIP remained without evaporating for 30 seconds to 1 minute after the polyester (B) solution arrived at the polyester (A) woven fabric. Further, when the cross section of the polyester (A) woven fabric after spray spraying was observed with an electron microscope at 1000 times magnification, it was observed that polyethylene terephthalate fibers were considerably dissolved as shown in FIG.

Comparative Example 5
In Example 1, the polyester (B) solution prepared above was sprayed on one side of a polyester (A) woven fabric from a spray nozzle at an air pressure of 100 kPa so as to have an amount of 0.01 mL / cm ^2. A graft substrate 7 was prepared by repeating the operation of Example 1 except for sealing the polyester (A) woven fabric. Under the present circumstances, when the increase in the thickness of the said polyester (A) woven fabric before and after spraying of the obtained graft base material 7 was measured according to the method as described in the above <thickness measurement>, it was 3 micrometers. At this time, the HFIP had evaporated before the polyester (B) solution arrived at the polyester (A) woven fabric. Further, when the cross section of the polyester (A) woven fabric after spray spraying was observed with an electron microscope at 1000 times magnification, as shown in FIG. 5, the polyester (B-1) coating film was polyester like a non-woven fabric. (A) Covering the surface of the woven fabric, it was observed that they were not fused to the polyester (A) woven fabric.

[Graft performance evaluation]
The graft bases 6 and 7 obtained above were evaluated in the same manner as described above for water permeability and peeling of the coating, and the results are shown in Table 2 below.

Also, the following evaluations were performed on the

graft substrates

1, 4, 6, and 7 obtained above, and the results are shown in Table 2 below.

<Burst intensity>
The burst strength of the graft substrate is measured according to ISO 7198. Specifically, each graft substrate is cut into a size of about 3 cm × 3 cm to prepare a sample. As shown in FIG. 8, each graft base material (sample) is set by being sandwiched in a sample installation portion (hole) 21 having a diameter of 11.3 mm of the measuring device 20. A pusher (diameter: 11.3 mm) 22 having a spherical tip is pushed into this sample at a speed of 125 mm / min, and a load (N) when the graft base material is broken is measured.

Furthermore, this application is based on Japanese Patent Application No. 2012-040552 filed on February 27, 2012, the disclosure of which is incorporated by reference in its entirety.

Claims

The polyester (B-1) is dissolved in the solvent (B-2) to prepare a polyester (B) solution, and immediately after the polyester (B) solution arrives on the polyester (A) woven fabric, the solvent (B-2) And spraying the polyester (B) solution on at least one surface of the polyester (A) woven fabric under the conditions such that the polyester (A) woven fabric is sealed. A method for producing a graft for a living body, wherein the increase in thickness of the polyester (A) woven fabric before and after spraying is 3 μm or less.
The method according to claim 1, wherein the concentration of the polyester (B-1) in the polyester (B) solution is 0.5 to 20% by weight.
3. The method according to claim 1, wherein the polyester (A) woven fabric has an opening size of 5 to 150 μm and a yarn density of 70 to 700 yarns / inch.
The method according to any one of claims 1 to 3, wherein the polyester (B) solution is sprayed in an amount of 0.005 to 0.3 mL / cm 2 .
The method according to any one of claims 1 to 4, wherein the polyester (B) solution is sprayed at an air pressure of 10 to 80 kPa.
The method according to any one of claims 1 to 5, wherein the polyester (A) woven fabric is preheated and then sprayed with the polyester (B) solution.
A polyester (A) woven fabric and a polyester (B-1) film formed by fusing on the surface of the polyester (A) woven fabric, the polyester (B-1) film being a woven fabric of the polyester (A) A graft for living body lumens that seals cloth.
The living body lumen according to claim 7, wherein the polyester (A) woven fabric is formed of a polyester (A) monofilament fiber having a diameter of 10 to 50 µm or a polyester (A) multifilament fiber having a total fineness of 20 to 100 dtex. Graft.
The graft for living body lumen according to claim 7 or 8, wherein the polyester (A) woven fabric has an opening size of 5 to 150 µm and a yarn density of 70 to 700 yarns / inch.
10. The graft for living body lumen according to any one of claims 7 to 9, wherein the thickness of the graft for living body lumen is twice the diameter (μm) of the polyester (A) fiber + 3 μm or less.