Vascular graft with double-layer structure and application thereof

Abstract

The invention provides a blood vessel graft with a double-layer structure, and particularly relates to application of the blood vessel graft to preparation of an artificial blood vessel. The vascular graft comprises a terylene inner layer of a woven structure and a compact polyurethane outer layer. The blood vessel graft is implanted in a to-be-repaired and / or to-be-replaced blood vessel position or a to-be-bypass-transplanted position in a subject, the original blood vessel can be replaced, and after a period of time, a layer of elastic outer membrane with excellent mechanical properties is formed on the outer surface of the compact polyurethane outer layer, so that the blood vessel graft can be used for repairing and / or replacing the blood vessel. The obtained artificial blood vessel has the property similar to that of an autologous blood vessel. The blood vessel graft and the artificial blood vessel prepared from the blood vessel graft can be made into various calibers so as to meet different clinical requirements.

Description

Technical Field

[0001] The invention relates to the fields of medical devices and vascular surgery, and in particular to a double-layer structured vascular graft and use thereof in preparing an artificial blood vessel. Background Art

[0002] Artificial blood vessels are mainly used to repair and / or replace natural blood vessels damaged by disease or injury to maintain the normal flow of blood. At present, the commonly used artificial blood vessel materials mainly include polyester, expanded polytetrafluoroethylene (Teflon) and polyurethane. However, there are still some problems in the biocompatibility and mechanical properties of artificial blood vessels made of these materials, which limits their clinical application. For example, the high porosity of polyester can cause serious bleeding in artificial blood vessels. For another example, the biocompatibility of polyester and expanded polytetrafluoroethylene is poor. After being implanted in the body, human tissue will produce an inflammatory reaction to wrap it and invade the implanted body, so that the artificial blood vessel loses its elasticity and is seriously adhered to the surrounding tissue. For another example, polyurethane artificial blood vessels can make the endothelial cells in the inner layer of the blood vessel fall off easily, especially in large-caliber artificial blood vessels. After the polyurethane artificial blood vessel is implanted, the endothelial cells in the inner layer are easily caused to fall off due to blood flow impact, causing distal embolism.

[0003] The existing solutions are mainly to improve the biocompatibility and mechanical properties of artificial blood vessels by improving the materials and structures. For example, the prior art such as CN112402690A designs a braided reinforced biodegradable polyurethane elastomer artificial blood vessel. The inner layer of the artificial blood vessel uses activated H2N-PEG-COOH, heparin and (Mpa)-GGGGGREDV polypeptide to treat the C-PEEUU-NH2 electrospun nanofiber tubular scaffold to obtain a C-PEEUU-PEG-Hep / REDV tubular scaffold, the middle layer uses one or more of the masterbatch of PLGA, PDO, PGA and silk protein dissolved and mixed according to the mass ratio to braid the nanofiber yarn braided reinforcement layer, and the outer layer is a macroporous layer prepared by thermal phase separation. Coupling heparin on the surface of the artificial blood vessel material can improve the anticoagulant activity of the artificial blood vessel, but whether heparin can maintain long-term biological activity still needs further study. For another example, the prior art CN116672505A discloses a self-healing artificial blood vessel with a hollow circular tube multilayer structure, the inner and outer layers of which are three-dimensional nanofiber structures, and there is a dense layer between the inner and outer layers, thereby enhancing the anti-leakage effect of the artificial blood vessel and improving the mechanical properties. However, such a design is more intended to provide an artificial blood vessel that can be punctured multiple times, and still cannot solve the problem of adhesion and inelasticity of the artificial blood vessel to the surrounding tissue.

[0004] Therefore, the art still needs a new vascular graft design to solve the above problems. Summary of the invention

[0005] The inventors designed and manufactured a two-layer vascular graft, in which the inner layer was a polyester layer with a porous structure and the outer layer was a dense polyurethane layer. Surprisingly, it was found that by replacing the aorta of an animal with the two-layer vascular graft, samples were taken 6 months later and it was found that a tightly attached inner membrane was formed on the surface of the polyester inner layer, while a layer of elastic outer membrane with excellent mechanical properties was formed on the surface of the polyurethane outer layer, thereby realizing the present invention.

[0006] In a first aspect of the present invention, there is provided a use of a vascular graft in preparing an artificial blood vessel for repairing and / or replacing a damaged blood vessel, wherein the vascular graft comprises an inner layer of polyester and an outer layer of polyurethane, and the vascular graft is implanted in a subject's body at a location of a blood vessel to be repaired and / or replaced for a period of time to form an artificial blood vessel for repairing and / or replacing a damaged blood vessel.

[0007] In a second aspect, a use of a vascular graft in preparing an artificial blood vessel for bypass transplantation is provided, wherein the vascular graft comprises a polyester inner layer and a polyurethane outer layer, and the vascular graft is implanted in a subject's body at a site to be bypassed for a period of time to form an artificial blood vessel for bypass transplantation.

[0008] The present invention aims to provide an artificial blood vessel with similar properties to autologous blood vessels. To this end, the inventor first provides a two-layer vascular graft with a simple structure, which includes a polyester inner layer with a woven structure and a dense polyurethane outer layer. The inventor found that after the two-layer vascular graft of the present invention is placed in an animal body for several months, a layer of outer membrane with elasticity and excellent mechanical properties will be formed by vascular adventitial cells on the outer surface of the polyurethane outer layer, thereby obtaining the artificial blood vessel of the present invention. Due to its good biocompatibility and density, the polyurethane outer layer can prevent human tissue cells from wrapping and invading the vascular graft, thereby preventing the vascular graft from adhering to the surrounding tissue. Therefore, there is no adhesion between the adventitia and the polyurethane outer layer, but there is a gap, which allows the adventitia to maintain the elasticity of the blood vessel while also avoiding the adhesion of the blood vessel to the surrounding tissue, thereby improving the effect of clinical application.

[0009] The inventors have also found that in the artificial blood vessel prepared by the vascular graft of the present invention, a layer of tightly attached inner membrane appears on the inner surface of the polyester inner layer of the braided structure, and the inner membrane is formed by vascular endothelial cells. The braided structure of the polyester inner layer allows endothelial cells to grow closely attached to the polyester inner surface, which avoids the problem of easy shedding of vascular endothelial cells, especially in large-caliber artificial blood vessels, and can effectively prevent distal embolism caused by shedding of endothelial cells.

[0010] The artificial blood vessels thus obtained by the present invention, which are composed of the inner membrane, the polyester inner layer, the polyurethane outer layer and the outer membrane, have biocompatibility, elasticity and other related properties similar to those of autologous blood vessels, can be implanted in subjects in need for a long time, and can be made into a variety of calibers to meet different clinical needs. For example, medium-caliber and large-caliber artificial blood vessels of more than 6 mm can be made for aortic replacement or bypass, peripheral vascular bypass grafting, vascular trauma repair, hemodialysis vascular access, coronary artery bypass grafting, etc. For another example, small-caliber artificial blood vessels of less than 6 mm can be made for peripheral vascular replacement, arteriovenous fistula establishment, and heart bypass grafting, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] In order to more clearly illustrate the specific implementation of the present invention or the technical solution in the prior art, the drawings required for use in the specific implementation or the description of the prior art will be briefly introduced below.

[0012] Figure 1 A schematic diagram of the polyurethane outer layer and outer membrane of an artificial blood vessel obtained according to one embodiment of the present invention is shown.

[0013] Figure 2 A schematic diagram of the inner membrane, polyester inner layer, polyurethane outer layer and outer membrane of an artificial blood vessel obtained according to one embodiment of the present invention is shown.

[0014] Figure 3 A schematic diagram of the longitudinal stretching of the outer membrane of an artificial blood vessel obtained according to one embodiment of the present invention is shown.

[0015] Figure 4 A schematic diagram of the circumferential stretching of the outer membrane of an artificial blood vessel obtained according to one embodiment of the present invention is shown. DETAILED DESCRIPTION

[0016] The following detailed description is merely exemplary and is in no way intended to limit the disclosure or its application or uses.

[0017] Although the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values ​​set forth in the specific examples are as precise as possible. However, any numerical value inherently contains certain errors necessarily resulting from the standard variation found in their respective testing measurements.

[0018] The terms "approximately" and "substantially" as used herein refer to measurable values ​​and ranges due to expected variations known to those skilled in the art (such as limitations and variability of measurements). The term "approximately" also means that the numerical value allows for some slight imprecision (the numerical value has some approach to precision; approximately or reasonably close to the numerical value; close). If the imprecision provided by the term "approximately" is not understood in the art as this ordinary meaning, then the term "approximately" as used herein at least represents the variations that may occur due to ordinary methods of measuring and using such parameters. In addition, the disclosed range includes the disclosure of all values ​​and further ranges within the entire range.

[0019] As used herein, the terms "include", "comprising" and similar terms, together with their grammatical variations, are synonymous with the term "comprises" and its grammatical variations. The term "includes" and its grammatical variations are open-ended and should be understood in the context of the present invention to include not only the specified elements, materials, components or method steps, but also other unspecified elements, materials, components or method steps.

[0020] As used herein, the term "consisting of" and its grammatical variants are to be understood in the context of the present invention as excluding any unspecified elements, ingredients, or method steps. As used herein, the term "consisting essentially of" and its grammatical variants are to be understood in the context of the present invention as including the specified elements, materials, ingredients, or method steps, as well as those elements, materials, ingredients, or method steps that have no substantial effect on the basic and novel characteristics described. It should be understood that when the term "comprising" and its grammatical variants are used, if other elements, materials, ingredients, or method steps that may have a substantial effect on the "basic and novel characteristics" of the content are not included, the term "consisting of" or "consisting primarily of" and its grammatical variants may be used instead of the term "comprising".

[0021] When describing the specific aspects of the present invention in detail, those skilled in the art will appreciate that various modifications and substitutions may be made to these details based on the overall teachings of the present invention. Therefore, the specific arrangements disclosed are only for illustration, rather than for limiting the scope of disclosure, which should include the full scope of the attached claims and any and all equivalents thereof.

[0022] As mentioned above, the present invention aims to provide an artificial blood vessel. To this end, the inventors designed and manufactured a two-layer vascular graft, wherein the inner layer is a polyester layer with a porous structure, and the outer layer is a dense polyurethane layer. The inventors found that by replacing the aorta of an animal with the two-layer vascular graft, it was found that a layer of tightly attached inner membrane was formed on the surface of the polyester inner layer, and a layer of elastic outer membrane with excellent mechanical properties was formed on the surface of the polyurethane outer layer, thereby realizing the present invention.

[0023] In a first aspect of the present invention, there is provided a use of a vascular graft in preparing an artificial blood vessel for repairing and / or replacing a damaged blood vessel, wherein the vascular graft comprises an inner layer of polyester and an outer layer of polyurethane, and the vascular graft is implanted in a subject's body at a location of a blood vessel to be repaired and / or replaced for a period of time to form an artificial blood vessel for repairing and / or replacing a damaged blood vessel.

[0024] In a specific embodiment, the vascular graft is implanted in a subject's body at a site of a blood vessel to be repaired and / or replaced for at least 1 month (eg, at least 3 months) to form an artificial blood vessel for repairing and / or replacing the blood vessel.

[0025] In a preferred embodiment, the vascular graft is implanted in a subject's body at a site of a blood vessel to be repaired and / or replaced for at least 6 months to form an artificial blood vessel for repairing and / or replacing the blood vessel.

[0026] In a specific embodiment, the artificial blood vessel includes a polyester inner layer, a polyurethane outer layer, and an outer membrane located on the outer surface of the polyurethane outer layer.

[0027] In another specific embodiment, the outer membrane is attached to the polyurethane outer layer, but not adhered to each other. The outer membrane is differentiated from fibroblasts to form loose connective tissue, which contains spiral or longitudinally distributed elastic fibers and collagen fibers. The outer membrane can maintain the elasticity of the artificial blood vessel while avoiding adhesion of the blood vessel to surrounding tissues.

[0028] In another specific embodiment, the polyurethane can be selected from polyether polyurethane, polycarbonate polyurethane, polyorganosiloxane modified polycarbonate polyurethane, fluoride modified polycarbonate, but not limited thereto. In the context of the present invention, the polyurethane outer layer can be prepared by methods well known in the art, such as pulling, dipping, spraying, electrostatic spinning, etc., but not limited thereto.

[0029] In another specific embodiment, the polyurethane outer layer is a dense structure. The dense structure can prevent human tissue cells from wrapping and invading the vascular graft, thereby preventing the vascular graft from adhering to surrounding tissues. This is also the reason why there is no adhesion between the polyurethane outer layer and the outer membrane formed thereon.

[0030] In a preferred embodiment, the porosity of the polyurethane outer layer may be 5%-50%.

[0031] In a more preferred embodiment, the porosity of the polyurethane outer layer may be 5%-35%, or even lower than 10%.

[0032] In yet another specific embodiment, the thickness of the polyurethane outer layer may be 0.1 mm to 0.5 mm.

[0033] In a preferred embodiment, the thickness of the polyurethane outer layer may be 0.2 mm.

[0034] In yet another specific embodiment, the artificial blood vessel further comprises an inner membrane located on the inner surface of the polyester inner layer.

[0035] In a preferred embodiment, the inner membrane is closely attached to the polyester inner layer. Those skilled in the art will know that the inner membrane closely attached to the inner surface of the polyester inner layer is mainly formed by endothelial cells of blood vessels.

[0036] In another specific embodiment, the polyester inner layer is a loose porous structure. The loose porous structure of the polyester inner layer is the reason why endothelial cells can grow closely attached to the inner surface of the polyester, which avoids the problem of easy shedding of vascular endothelial cells, especially in large-caliber artificial blood vessels, and can effectively prevent distal embolism caused by shedding of endothelial cells. In the context of the present invention, the loose porous polyester inner layer can be prepared by methods well known in the art, such as knitting or weaving processes, but is not limited thereto.

[0037] In a further specific embodiment, the pore size of the polyester inner layer is 0.5 mm to 4 mm. In a preferred embodiment, the pore size of the polyester inner layer is 1.0 mm to 2.0 mm.

[0038] In another specific embodiment, the polyester inner layer can be woven from 2-0 to 10-0 polyester sutures. In a preferred embodiment, the polyester inner layer can be woven from 5-0 to 6-0 polyester sutures. According to the published standard YY0167-2005 "Non-absorbable surgical sutures", the diameter range of 2-0 sutures is 0.250mm-0.299mm, the diameter range of 5-0 sutures is 0.100mm-0.149mm, the diameter range of 6-0 sutures is 0.070mm-0.099mm, and the diameter range of 10-0 sutures is 0.020mm-0.029mm. In this case, the pore size of polyester can also be understood as the pitch range of weaving.

[0039] In the context of the present invention, the vascular graft can be prepared by methods well known in the art. For example, a polyester inner layer can be first obtained by knitting or weaving, and then a polyurethane coating solution is coated on the polyester inner layer by pulling or dipping to form a polyurethane outer layer.

[0040] In a second aspect, a use of a vascular graft in preparing an artificial blood vessel for bypass transplantation is provided, wherein the vascular graft comprises a polyester inner layer and a polyurethane outer layer, and the vascular graft is implanted in a subject's body at a site to be bypassed for a period of time to form an artificial blood vessel for bypass transplantation.

[0041] In a specific embodiment, the vascular graft is implanted in a subject's body at a site to be bypassed for at least 1 month (eg, at least 3 months) to form an artificial blood vessel for bypass grafting.

[0042] In a preferred embodiment, the vascular graft is implanted in a subject's body at a site to be bypassed for at least 6 months to form an artificial blood vessel for bypass grafting.

[0043] In a specific embodiment, the artificial blood vessel includes a polyester inner layer, a polyurethane outer layer, and an outer membrane located on the outer surface of the polyurethane outer layer.

[0044] In yet another specific embodiment, the inner film is closely attached to the polyester inner layer.

[0045] In yet another specific embodiment, the outer film and the polyurethane outer layer are attached together but not to each other.

[0046] In yet another specific embodiment, the polyurethane may be selected from polycarbonate polyurethane, polyorganosiloxane-modified polycarbonate polyurethane, and fluoride-modified polycarbonate, but is not limited thereto.

[0047] In yet another specific embodiment, the polyurethane outer layer is a dense structure, and its porosity may be 5%-50%.

[0048] In a more preferred embodiment, the porosity of the polyurethane outer layer may be 5%-35%, or even lower than 10%.

[0049] In yet another specific embodiment, the thickness of the polyurethane outer layer may be 0.1 mm to 0.5 mm, preferably 0.2 mm.

[0050] In yet another specific embodiment, the artificial blood vessel further comprises an inner membrane located on the inner surface of the polyester inner layer.

[0051] In a preferred embodiment, the inner film is closely attached to the polyester inner layer.

[0052] In another specific embodiment, the polyester inner layer is a loose porous structure, and its pore size can be 0.5mm to 4mm. In a preferred embodiment, the pore size of the polyester inner layer can be 1.0mm to 2.0mm.

[0053] In another specific embodiment, the polyester inner layer is woven from 2-0 to 10-0 polyester sutures. In a preferred embodiment, the polyester inner layer can be woven from 5-0 to 6-0 polyester sutures.

[0054] Example

[0055] In the following examples, the preparation of thermoplastic starch compositions of the present invention and the characterization of related properties thereof are shown. Unless otherwise specified, the test method wherein adopted is a conventional method, and unless otherwise specified, the test material used in the following examples is purchased from a conventional reagent store. Unless otherwise defined, all technical and scientific terms used herein are identical with the meaning generally understood by the technician belonging to the technical field of the present invention.

[0056] It should be noted that the terms used in the specification of the present invention are only for the purpose of describing specific embodiments, and are not intended to limit the present invention. The above summary of the invention, the specific embodiments and the following examples are only for the purpose of specifically explaining the present invention, and are not intended to limit the present invention in any way. Without departing from the spirit and purpose of the present invention, the scope of the present invention is determined by the attached claims.

[0057] Example 1: Preparation of vascular graft

[0058] A vascular graft for use in porcine aorta was prepared according to the following steps:

[0059] Step 1, preparing a polyester inner layer, according to the required caliber, selecting a tubular fabric knitting machine with the same diameter to knit a tubular polyester layer, using a polyester suture thread number 6-0, and controlling the knitting pitch range of the prepared polyester inner layer to be 1.0 mm to 2.0 mm;

[0060] Step 2: prepare a casting solution. Mix polycarbonate polyurethane (ASB CF AR-LT) with N,N-dimethylformamide solvent, and rapidly stir at 80° C. for 4 hours to obtain a uniform casting solution with a concentration of 30% w / w.

[0061] Step three, outer layer preparation, use the pulling method to apply the casting liquid obtained in step two on the inner layer, immediately transfer it to an oven and dry it at 60°C for 4 hours to obtain a dense high molecular polymer outer layer. Repeat this step several times to make the outer layer thickness reach the designed thickness of 0.2mm and the porosity of 32%.

[0062] Step 4: washing and drying: the semi-finished vascular graft obtained in step 3 is washed in water for injection for 48 hours, and then transferred to an oven and dried at 60° C. for 4 hours to obtain a vascular graft.

[0063] Example 2: Preparation of artificial blood vessels

[0064] The in vivo experiment was conducted using experimental animals, pigs. The thoracic aorta of the pigs was replaced with the vascular graft prepared in Example 1. After 6 months of normal breeding, the artificial blood vessel was removed by dissection. It was found that a tightly attached inner membrane was formed on the inner surface of the polyester inner layer of the vascular graft, and an elastic outer membrane was formed on the outer surface of the polyurethane outer layer. The outer membrane did not adhere to the polyurethane. Figure 1 and Figure 2 shown.

[0065] Example 3: Related detection of artificial blood vessels

[0066] The mechanical properties of the adventitia of the artificial blood vessel prepared in Example 2 and applied to the aorta were tested. Figure 3 and Figure 4 The specific parameters are as follows.

[0067] Test method: 1. Cut the sample into 3cm×1cm rectangular strips and test the tensile strength, modulus and elongation at break of the sample;

[0068] 2. Equipment name: Computerized tensile testing machine, model: HKE-3511H, manufacturer: Shenzhen Kexing Precision Instrument Co., Ltd.;

[0069] 3. Specific parameters of the test: sample width is 10 mm, test gauge length is 16 mm, and tensile rate is 10 mm / min.

[0070] The results of tensile strength, elongation at break and elastic modulus are shown in Table 1 below. It can be seen that the adventitia grown on the outer surface of the vascular graft exhibits excellent mechanical properties.

[0071] Table 1: Relevant mechanical data of the outer membrane

[0072]

Claims

1. Use of a vascular graft in preparing an artificial blood vessel for repairing and / or replacing a damaged blood vessel, wherein: The vascular graft comprises a polyester inner layer and a polyurethane outer layer, and is implanted in a subject's body at a blood vessel to be repaired and / or replaced for a period of time (e.g., at least 1 month, preferably at least 6 months) to form an artificial blood vessel for repairing and / or replacing a damaged blood vessel.

2. Use of a vascular graft in preparing an artificial blood vessel for bypass transplantation, wherein: The vascular graft comprises a polyester inner layer and a polyurethane outer layer, and is implanted in a subject's body at a site to be bypassed for a period of time (eg, at least 1 month, preferably at least 6 months) to form an artificial blood vessel for bypass transplantation.

3. The use according to claim 1 or 2, wherein The artificial blood vessel comprises a polyester inner layer, a polyurethane outer layer and an outer membrane located on the outer surface of the polyurethane outer layer; preferably, no adhesion occurs between the outer membrane and the polyurethane outer layer.

4. The use according to any one of claims 1 to 3, wherein The polyurethane is polyether polyurethane, polycarbonate polyurethane, polyorganosiloxane-modified polycarbonate polyurethane, or fluoride-modified polycarbonate.

5. The use according to any one of claims 1 to 4, wherein The polyurethane outer layer is a dense structure with a porosity of 5%-50%, preferably 5%-35%, and more preferably less than 10%.

6. The use according to any one of claims 1 to 5, wherein The thickness of the polyurethane outer layer is 0.1 mm to 0.5 mm, preferably 0.2 mm.

7. The use according to any one of claims 1 to 6, wherein The artificial blood vessel further comprises an inner membrane located on the inner surface of the polyester inner layer; preferably, the inner membrane is tightly attached to the polyester inner layer.

8. The use according to any one of claims 1 to 7, wherein The polyester inner layer is a loose porous structure; preferably, the pore size is 0.5 mm to 4 mm, more preferably 1.0 mm to 2.0 mm.

9. The use according to any one of claims 1 to 8, wherein The polyester inner layer is woven from 2-0 to 10-0, preferably 5-0 to 6-0 polyester sutures.

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