DE102024106304A1 - Vascular prosthesis; method for producing a vascular prosthesis - Google Patents

Abstract

Vascular prosthesis (10) with a tubular structure (11) which is substantially impermeable to blood along its wall (12) and has a proximal and distal end (13, 14), wherein the proximal and distal ends (13, 14) are connected to a vessel (100) in use in such a way that blood can flow through the tubular structure (11) in the longitudinal axial direction, and wherein the tubular structure (11) is produced by electrospinning, wherein the tubular structure (11) is at least partially coated with fibrin, wherein the fibrin coating (20) is formed by a fibrin nanostructure made of fibrin threads.

Description

The invention relates to a vascular prosthesis with a tubular structure which is substantially impermeable to blood along its wall and has a proximal and distal end, wherein the proximal and distal ends are connected to a vessel during use in such a way that the tubular structure can be perfused by blood along its longitudinal axis. Such a vascular prosthesis is known, for example, from EP 0 266 035 A1 known.

Vascular prostheses are used to replace natural blood vessels. Vascular prostheses can be used to replace vascular segments that are severely damaged, for example, due to injuries, vascular constrictions, vascular occlusions, aneurysms, or dissections. During implantation, the damaged segment of the vessel is first removed, and then the proximal and distal ends of the vascular prosthesis are connected to the remaining segments of the vessel, thus restoring blood flow. Vascular prostheses can also be used for bypass surgery, where severely damaged segments of the vessel are bridged by the vascular prosthesis.

Known vascular prostheses are often made of synthetic polymers. However, synthetic polymers have properties that negatively influence or prevent the colonization of the vascular prosthesis with the body's own cells, such as endothelial cells. Such vascular prostheses are known, for example, from the aforementioned EP 0 266 035 A1 , the US 4 743 252 A or the US 6 416 537 B1 known. Cell colonization of the vascular prosthesis is important to reduce the risk of thrombus formation.

The invention is therefore based on the object of providing a vascular prosthesis that promotes or at least does not prevent endothelialization and inhibits thrombus formation. Furthermore, the invention is based on the object of providing a method for producing such a vascular prosthesis.

According to the invention, this object is achieved with regard to the vascular prosthesis by the subject matter of claim 1. With regard to the method, this object is achieved by the subject matter of claim 14.

Specifically, the problem is solved by a vascular prosthesis with a tubular structure that is essentially blood-impermeable along its wall and has a proximal and distal end. During use, the proximal and distal ends are connected to a vessel such that the tubular structure is permeable to blood along its longitudinal axis. The tubular structure is manufactured by electrospinning. The tubular structure is at least partially coated with fibrin, the fibrin coating being formed by a fibrin nanostructure composed of fibrin threads.

The invention has several advantages.

The vascular prosthesis according to the invention thus enables the efficient treatment of severely damaged, particularly small-lumen, vascular segments. For this purpose, the tubular, i.e., tube-shaped structure of the vascular prosthesis has a wall that is essentially blood-tight or blood-impermeable. The wall is advantageously designed to be blood-tight over the entire length of the tubular structure, i.e., from one axial end of the tubular structure to the other, so that, when the vascular prosthesis is implanted, blood flow is achieved through the interior or the lumen of the tubular structure. During use, the proximal and distal ends of the tubular structure are connected to the vessel to be treated in such a way that a severely damaged vascular segment is either replaced or bridged by the vascular prosthesis. For example, the proximal and distal ends of the tubular structure are connected to the vessel by a suture (anastomosis).

According to the invention, the tubular structure of the vascular prosthesis is manufactured by electrospinning. The tubular structure can be completely spun by electrospinning. This is to be understood as meaning that the entire vascular prosthesis or tubular structure is manufactured by electrospinning.

The tubular structure can be formed not only partially, but entirely from electrospun fibers. If the tubular structure has multiple layers or plies, all layers of the tubular structure can be produced by electrospinning. This means that the properties of the electrospun material are present throughout the entire tubular structure. Thus, the properties of the vascular prosthesis, such as appropriate blood density, axial stiffness, strength, and/or elongation, can be adjusted by the electrospun material. Alternatively, the tubular structure can be only partially produced by electrospinning.

Furthermore, the tubular structure can be produced by electrospinning from a variety of different polymers. Advantageously, electrospinning has virtually no material-related limitations. This makes it possible to produce the tubular structure from polymers other than PTFE. It is also conceivable It is possible that different layers of the tubular structure are formed from different polymers. In other words, the electrospun fibers of the tubular structure can be formed from or consist of different polymers. Advantageously, electrospinning allows the vascular prosthesis to be manufactured from biodegradable polymers (e.g., polycaprolactone, polylactides, polyglycolides, degradable thermoplastic polyurethanes, or other degradable polymers).

Furthermore, electrospinning makes it possible to produce a vascular prosthesis with a thin and/or adjustable wall thickness. This is advantageous because fine fibers can be produced using electrospinning. For example, the electrospun fibers can have a fiber diameter between 500 nm and 10 µm. The fiber diameter and/or the number of fiber layers can be used to adjust the porosity, pore size, and/or mechanical properties (e.g., elasticity, strength) of the tubular structure or vascular prosthesis in order to achieve the best possible penetration of cells and/or extracellular matrix into the tubular structure or vascular prosthesis, or to achieve the most physiological property profile possible with regard to mechanical properties. Furthermore, the thin wall thickness of the vascular prosthesis makes it particularly suitable for replacing small-lumen vascular segments, for example, those with a maximum diameter of 7 mm.

The vascular prosthesis according to the invention exhibits good hemocompatibility and good healing behavior. For this purpose, the tubular structure of the vascular prosthesis has a coating formed by a fibrin nanostructure made of fibrin threads. Preferably, the tubular structure is completely coated with fibrin. It is conceivable that the tubular structure is only partially coated with fibrin. For example, the inner surface, i.e., the surface of the tubular structure facing the inner lumen of the vascular prosthesis, can be coated with fibrin. The fibrin coating according to the invention promotes the colonization of the vascular prosthesis with endogenous cells until the tubular structure, or the inner surface of the tubular structure, is overgrown with natural endothelium. The fibrin coating supports the adhesion and proliferation of vascular endothelial cells in vitro. The fibrin coating improves cell viability on the tubular structure, resulting in faster and improved endothelialization. This means that, once the vascular prosthesis is implanted, the formation of an endothelial cell layer on the tubular structure is improved and accelerated. In particular, cell colonization of the junctions or seams between the vascular prosthesis and the vessel is promoted, thereby accelerating healing. Colonization of the vascular prosthesis with endothelial cells can reduce the risk of thrombus formation. Furthermore, the penetration of cells (e.g., fibroblasts, smooth muscle cells) through the entire wall thickness of the vascular prosthesis is improved, enabling the fastest possible biological remodeling of the vascular prosthesis. If a degradable polymer is used to manufacture the vascular prosthesis, complete replacement of the polymeric portion of the vascular prosthesis with endogenous (body's own) tissue is advantageous or even necessary. The fibrin coating supports or improves this process.

The electrospun tubular structure is preferably provided with the fibrin coating in such a way that both the initial hemocompatibility, the healing behavior, and the long-term behavior of the electrospun vascular prosthesis are improved. The fibrin coating promotes rapid adhesion and ingrowth of endothelial cells to the electrospun material of the tubular structure. Rapid endothelialization is particularly advantageous when the electrospun tubular structure is made of a degradable polymer.

Another advantage is that the fibrin coating has a stable network structure at the molecular level. This makes the fibrin coating very durable and resistant. The coating can be so durable that the mass of the coating is completely retained for a period of at least four hours, in particular at least 30 days, upon contact with blood or a physiological replacement fluid, e.g., a sodium chloride solution or a Ringer's lactate solution. Such a period of time makes it possible, for example, to coat the vascular prosthesis with an endothelial cell layer, thus naturally preventing thrombus formation. The coating can thus bridge the period from implantation until the vascular prosthesis is naturally covered or encapsulated by an endothelial cell layer.

Regarding the design of the fibrin coating, reference is made to the DE 10 2018 110 591 B4 and the DE 10 2022 134 575 A1 which are attributable to the applicant.

The fibrin coating can have a first layer which forms a matrix, in particular a felt-like or fleece-like matrix, of interlinked fibrin fibres, with some fibrin fibres projecting freely beyond the first layer and a second layer of a, in particular pile-like, individual fibre The first layer, which preferably lies directly on the inner surface of the tubular structure, can have a matrix of cross-linked fibrin fibers. This matrix is particularly dense. Some of the fibrin fibers can protrude beyond the first layer and form a single-fiber structure. The protruding fibrin fibers are preferably uncross-linked in the region of the second layer and rather protrude beyond the first layer as individual fibers. The second layer therefore has a particularly loose fibrin fiber structure. It has been shown that this special structure of the fibrin coating provides an overall increased surface area for the adhesion of endothelial cells. Endothelialization is thereby significantly improved.

Preferred embodiments of the invention are claimed or specified in the subclaims.

The tubular structure can comprise at least one electrospun fiber layer whose fibers have a specific orientation, in particular an orientation of 0° to 90° to a longitudinal axis of the tubular structure. For example, the fibers can have an orientation of approximately 45° and/or approximately 90° to the longitudinal axis of the tubular structure. It is possible to combine different fiber orientations in one fiber layer. This has the advantage that various properties of the tubular structure, such as axial stiffness, strength, and/or elongation, can be adjusted to a desired level. In this case, the properties of the tubular structure are anisotropic, i.e., direction-dependent.

Alternatively, the fibers of the at least one electrospun fiber layer can be randomly aligned. In this case, the properties of the tubular structure are isotropic, i.e., direction-independent. This allows residual elongation to be maintained in the material of the tubular structure, so that the tubular structure exhibits high flexibility and elongation. Furthermore, alignment of the randomly arranged electrospun fibers or those manufactured as a nonwoven can be achieved by post-treatment of the tubular structure. For example, post-drawing or stretching the tubular structure can induce fiber alignment, which allows adjustment of elongation and/or strength.

The tubular structure preferably comprises a plurality of electrospun fiber layers arranged one above the other in the radial direction of the tubular structure and, in particular, made of different materials. The individual fiber layers can be produced one after the other by electrospinning or arranged one above the other. The fibers of the individual fiber layers can have a substantially identical orientation relative to the longitudinal axis of the tubular structure. Alternatively, the fibers of the individual fiber layers can have a different orientation relative to the longitudinal axis of the tubular structure. For example, a fiber layer with a fiber orientation of approximately 45° can be arranged on top of another fiber layer with a fiber orientation of approximately 90°. Furthermore, the wall thickness of the tubular structure is advantageously determined by the number of fiber layers. In other words, the wall thickness of the tubular structure can be adjusted by the number of fiber layers. It is particularly advantageous that the tubular structure, due to its production by electrospinning, has particularly biocompatible properties, particularly compared to conventional vascular prostheses. This allows the vascular prosthesis to be used to replace small-lumen vascular segments. Furthermore, the multiple fiber layers can be made of different materials. This allows different fiber layers to exhibit different properties, such as different axial stiffness, elongation, and/or flexibility, as well as pore size/porosity.

The electrospun fibers of at least a first fiber layer, which is arranged further away from an inner lumen of the vascular prosthesis in the radial direction of the tubular structure than at least a second fiber layer, can have a larger fiber diameter than the electrospun fibers of the second fiber layer. A small fiber diameter in the second fiber layer or the radially inner fiber layer can achieve a high infiltration depth of the cells into the fiber layer. This can improve cell migration and adhesion to the tubular structure. A large fiber diameter in the first fiber layer or the radially outer fiber layer achieves good stability of the tubular structure. The fiber diameter preferably increases from the innermost fiber layer of the tubular structure to the outermost fiber layer of the tubular structure.

The second fiber layer can be designed as a luminal fiber layer. The first fiber layer can be designed as an abluminal fiber layer. The luminal fiber layer is the layer facing the inner lumen of the vascular prosthesis. Accordingly, the abluminal fiber layer faces away from the inner lumen of the vascular prosthesis. However, the first fiber layer or the radially outer fiber layer does not necessarily mean the outermost fiber layer of the tubular structure. Accordingly, the second fiber layer or the radially inner The fiber layer does not necessarily mean the innermost fiber layer of the tubular structure.

The electrospun fibers preferably have a fiber diameter between 0.3 µm and 10 µm, in particular at most 8 µm, in particular at most 6 µm, in particular at most 4 µm, in particular at most 2 µm. It has been shown that cell migration is particularly good with a fiber diameter between 0.3 and 2 µm. Therefore, such a small fiber diameter is preferably provided in the second fiber layer or in fiber layers that are close to the inner lumen of the vascular prosthesis. Furthermore, a fiber diameter between 2 and 10 µm is particularly well suited to achieving appropriate stability of the vascular prosthesis. Therefore, such a large fiber diameter is preferably provided in the first fiber layer or in fiber layers that are distant from the inner lumen of the vascular prosthesis.

The tubular structure can have a porosity between 50% and 95%, in particular at most 90%, in particular at most 80%, in particular at most 70%, in particular at most 60%. This makes it possible to achieve good cell migration on the one hand and sufficient blood density of the tubular structure on the other. If the tubular structure is formed from several fiber layers, the porosity of the individual fiber layers can be different or essentially the same. The pores of the tubular structure and/or the individual fiber layers can have a pore size between 0.5 µm and 20 µm, in particular at most 15 µm, in particular at most 10 µm, in particular at most 5 µm.

The tubular structure can have a wall thickness of 10 µm to 1000 µm, in particular at most 900 µm, in particular at most 700 µm, in particular at most 500 µm, in particular at most 300 µm, in particular at most 100 µm, in particular at most 50 µm. Such a small wall thickness provides the tubular structure with good flexibility, which is particularly suitable for use in vessels with a small diameter.

The tubular structure can have an inner diameter of 0.5 mm to 7 mm, in particular no more than 6 mm, in particular no more than 5 mm, in particular no more than 4 mm, in particular no more than 3 mm, in particular no more than 2 mm, in particular no more than 1 mm. Such a small inner diameter of the tubular structure makes it possible to replace small-lumen vessel sections with a diameter of no more than 7 mm.

The tubular structure is preferably formed from perfluorinated or partially fluorinated polymers (e.g., PTFE), polyurethane (e.g., thermoplastic polyurethane, hydrophilic polyurethane), polyamide (e.g., PA6.6), polyester (e.g., PLA, PLGA, PET), polysulfone (e.g., PSU), polyetheretherketone (PEEK), biological and/or protein-based polymers. Furthermore, the polymers can be optimized by adding specific additives (compounding). Electrospinning can therefore preferably be carried out using different polymers. For the production of the tubular structure, the polymer that exhibits the desired properties for the respective application area can be selected from a wide range of polymers. Furthermore, different fiber layers of the tubular structure can be made from different polymers. For example, one fiber layer can be made from PTFE, while another fiber layer is made from PEEK or PUR (e.g., thermoplastic polyurethane).

The vascular prosthesis can have a tubular lattice structure with lattice elements that delimit lattice openings, wherein the tubular structure at least partially covers the lattice structure or wherein the lattice structure is embedded in the tubular structure. This is preferably to be understood in such a way that the lattice structure can be arranged either on the inner surface or on the outer surface of the electrospun tubular structure. Alternatively, the lattice structure can be integrated into the tubular structure. According to this embodiment of the invention, the vascular prosthesis is produced by electrospinning on the lattice structure. The lattice structure is preferably self-expandable. As a result, the vascular prosthesis has self-expandable properties. Alternatively, the lattice structure can be balloon-expandable. It is therefore possible to introduce the vascular prosthesis into the vessel to be treated during a minimally invasive operation.

The lattice structure can be a mesh of braided wires or a single braided wire. The lattice structure can also be a monolithic lattice structure, for example, a laser-cut lattice structure. The lattice structure can be formed from a shape-memory material, in particular nitinol.

The fibrin coating preferably contains heparin, which is covalently bound to the fibrin threads in such a way that the heparin can be found both on the surface and inside the fibrin coating. The heparin improves the anti-thrombogenicity of the coating. Due to the covalent bond, the heparin is advantageously fixed to the fibrin and thus stably fixed in the fibrin coating. Due to the covalent bond, the atoms of the heparin and the atoms of the fibrin share their valence electrons. Through this electron sharing, the covalent bond is The coating is very stable and robust because the atoms form a noble gas configuration. This prevents or at least slows down the degradation of heparin. The heparin thus remains longer or entirely in the fibrin coating, inhibiting or preventing thrombosis formation in the long term.

If the fibrin coating is multi-layered or bi-layered, the first layer, which is preferably more strongly cross-linked and thus essentially has sponge-like properties, can absorb a greater amount of heparin. This does not preclude the heparin from also binding to the second layer. Rather, the heparin can bond with the fibrin coating across the entire layer thickness.

The fibrin coating can contain a growth factor or a peptide with the functional structure of a growth factor. If the fibrin coating is multilayered, the growth factor or the peptide with the functional structure of a growth factor can be integrated into the multiple layers. If the fibrin coating has two layers, or a first and second layer, the growth factor or the peptide with the functional structure of a growth factor can be integrated into the first layer and/or the second layer. The growth factor or the peptide with the functional structure of a growth factor integrated into the fibrin coating advantageously further improves cell adhesion to the vascular prosthesis and the viability of the adhering cells, which results in better and faster endothelialization.

The growth factor or the peptide with the functional structure of a growth factor is preferably covalently bound to components of the fibrin coating, in particular to fibrin nanofibers. To provide improved endothelialization, it is advantageous if the growth factor or the peptide with the functional structure of a growth factor is covalently bound to components of the fibrin coating. This binding is advantageously achieved via binding to the fibrin nanofibers.

The fibrin coating preferably contains fucoidan, retinoic acid (e.g., all-trans retinoic acid, synthetic retinoid Am80), aptamers (e.g., transcription factor KLF5), and/or heme oxygenase I triggers (e.g., hyperforin, finasteride). For example, fucoidan can further enhance the anticoagulant effect of the fibrin coating.

According to the independent claim 14, the invention relates to a method for producing a vascular prosthesis with a tubular structure. First, a fiber layer of the tubular structure is produced by electrospinning, with the electrospun fibers being deposited on a tubular structure, in particular a mandrel. The mandrel can have a non-stick layer or be provided with a non-stick coating. In the electrospinning process, a polymer solution is finely metered onto an emitter electrode. By applying an electric field, a polymer jet forms, which is accelerated toward a collector. This acceleration directs the polymer jet, and a polymer fiber forms, which becomes thinner with increasing length until it is deposited on the collector electrode (the mandrel). The polymer solution can be formed from one or more polymers. If the tubular structure is to be formed from multiple fiber layers, a further fiber layer can be applied to an already formed fiber layer. This process is repeated until the tubular structure has the desired wall thickness. After electrospinning, the tubular structure can be solidified by post-treatment, particularly by annealing, sintering, and/or chemical treatment. A fibrin coating is then formed on the tubular structure.

If the fibrin coating is to contain heparin, heparin is then covalently bound to this fibrin layer. Specifically, the fibrin coating is functionalized by covalently binding chemically activated heparin to the fibrin threads of a fibrin nanostructure, with the fibrin nanostructure forming the fibrin coating. The covalent binding of the heparin to the fibrin layer continues until the heparin is embedded in the fibrin layer.

• 1a, 1b perspektivische Ansichten erfindungsgemäßer Ausführungsbeispiele einer Gefäßprothese im implantierten Zustand;
• 2 einen Schnitt durch eine Gefäßprothese nach einem erfindungsgemäßen Ausführungsbeispiel mit mehreren Faserlagen;
• 3a-3f mehrere Gefäßprothesen nach erfindungsgemäßen Ausführungsbeispielen mit unterschiedlichen Faserausrichtungen;
• 4 eine mikroskopische Aufnahme einer Faserlage der Gefäßprothese gemäß 1;
• 5 ein Verfahren zur Herstellung eines erfindungsgemäßen Ausführungsbeispiels der Gefäßprothese;
• 6 eine Abbildung zur Darstellung der Bildung der Fibrinbeschichtung auf einer Gefäßprothese nach einem erfindungsgemäßen Ausführungsbeispiel.

The invention will be explained in more detail below using exemplary embodiments with reference to the accompanying drawings.

• 1a , 1b perspective views of embodiments of a vascular prosthesis according to the invention in the implanted state;
• 2 a section through a vascular prosthesis according to an embodiment of the invention with several fiber layers;
• 3a-3f several vascular prostheses according to embodiments of the invention with different fiber orientations;
• 4 a microscopic image of a fiber layer of the vascular prosthesis according to 1 ;
• 5 a method for producing an embodiment of the vascular prosthesis according to the invention;
• 6 an illustration showing the formation of the fibrin coating on a vascular prosthesis according to an embodiment of the invention.

The 1a and 1b show exemplary embodiments of a vascular prosthesis 10 according to the invention. This involves the application of the vascular prosthesis 10 for the treatment of severely damaged or defective vascular segments. The vascular prosthesis 10 is used to treat vascular segments that are damaged, for example, by injuries, vascular constrictions, vascular occlusions, aneurysms, or dissections to such an extent that blood flow through the vascular segments is significantly disrupted or severely restricted.

1b shows that the vascular prosthesis 10 serves to replace a vascular section. The damaged vascular section is removed and replaced with the vascular prosthesis 10, thereby restoring blood flow in the vessel 100.

In 1a It can be seen that the vascular prosthesis 10 serves to bridge a vascular section (bypass). The damaged vascular section remains intact and is bridged or redirected by the vascular prosthesis 10, thereby restoring blood flow in the vessel 100.

The vascular prosthesis 10 has a tubular structure 11. In other words, the vascular prosthesis 10 is tubular or has the shape of a small tube.

The wall 12 of the tubular structure 11 is essentially impermeable to blood. The wall 12 is designed to be blood-tight along the entire length of the tubular structure 11, i.e., from one axial end of the tubular structure 11 to the other, so that, when the vascular prosthesis 10 is implanted, blood flow through the interior of the tubular structure 11 is achieved.

The tubular structure 11 has a proximal and a distal end 13, 14. In the implanted state (cf. 1a , 1b) The proximal and distal ends 13, 14 are each connected to a vessel 100. Both ends 13, 14 of the tubular structure 11 are connected to the vessel 100 by a suture (anastomosis).

1b shows that the vascular prosthesis 10 and the natural vessel 100 are arranged essentially coaxially. The proximal and distal ends 13, 14 of the vascular prosthesis 10 are each fully connected to a circumferential section of the vessel 100. The ends 13, 14 of the vascular prosthesis 10 and the vessel can be arranged slightly overlapping.

In 1a It can be seen that the proximal and distal ends 13, 14 of the tubular structure 11 are each connected to a side or outer wall of the vessel 100, thus achieving a bypass. The natural vessel 100 remains essentially intact.

The tubular structure 11 is produced by electrospinning. In the exemplary embodiment, the tubular structure 11 is 1a and 1b completely spun by electrospinning. This means that the tubular structure 11 is completely produced by electrospinning from the inside out, or from one side to the other. In other words, the tubular structure 11 is completely manufactured by electrospinning and not layer by layer using other methods. The entire wall 12, or wall thickness, of the tubular structure 11 is manufactured by electrospinning or is formed from electrospun fibers 16.

The electrospun tubular structure 11 is coated with fibrin, with the fibrin coating 20 being formed by a fibrin nanostructure of fibrin threads. Due to the fibrin coating 20, the electrospun material of the tubular structure 11 exhibits good hemocompatibility and good healing behavior. The fibrin coating 20 promotes the colonization of the vascular prosthesis 10 with the body's own cells until the electrospun tubular structure 11 is lined with natural endothelium. Cell viability on the electrospun tubular structure 11 is improved by the fibrin coating 20, resulting in faster and improved endothelialization. The colonization of the vascular prosthesis 10 with endothelial cells reduces the risk of thrombus formation. Furthermore, the healing process is accelerated.

The tubular structure 11 comprises at least one electrospun fiber layer 15, the fibers 16 of which have a specific orientation or are arranged randomly. 3a to 3f represent examples of different fiber orientations.

This shows 3a an alignment of the fibers 16 of approximately + 45° to the longitudinal axis L of the tubular structure 11 or the vascular prosthesis 10. An angle of approximately 45° is formed between the fibers 16 and the longitudinal axis L.

3b shows an alignment of the fibers 16 of approximately - 45° to the longitudinal axis L of the tubular structure 11. Similar to 3a , an angle of approximately 45° is formed between the fibers 16 and the longitudinal axis L the tubular structure 11, but in the opposite direction.

Furthermore, in 3c an alignment of the fibers 16 of approximately 90° to the longitudinal axis L of the tubular structure 11 is shown. In other words, the fibers 16 are aligned or oriented essentially orthogonally or perpendicularly to the longitudinal axis L of the tubular structure 11.

In the 3D and 3e It can be seen that different fiber orientations can be combined in one fiber layer 15. 3D the combination of a fiber orientation of + 45°, - 45° and 90° to the longitudinal axis L of the tubular structure 11. 3e shows that the fibers 16 have an orientation of approximately + 45° and approximately - 45° to the longitudinal axis L of the tubular structure 11.

Furthermore, 3f that the fibers 16 of a fiber layer 15 are aligned or arranged arbitrarily or randomly.

At this point, it should be noted that the above-mentioned fiber orientations represent only an average or predominant direction of the fibers 16 relative to the longitudinal axis L of the tubular structure 11. It is possible that individual fibers 16 of a fiber layer 15 deviate from the specified direction.

The tubular structure according to 2 has several, specifically three, electrospun fiber layers 15. The fiber layers 15 are arranged or stacked one above the other in the radial direction of the vascular prosthesis 10 or the tubular structure 11. The wall thickness of the tubular structure 11 is determined by the number of fiber layers 15. The fiber layers 15 are made of a different material in order to optimally adjust the properties of the vascular prosthesis 10. Furthermore, 2 It can be seen that the fiber layers 15 each have a different fiber orientation.

The electrospun fibers 16 of a first fiber layer 17, which is arranged further away from an inner lumen 19 of the vascular prosthesis 10 in the radial direction of the tubular structure 11 than a second fiber layer 18, have a larger fiber diameter than the electrospun fibers 16 of the second fiber layer 18. The fiber diameter increases from the second fiber layer 18 of the tubular structure 11 to the first fiber layer 17. The fibers 16 of the outermost fiber layer have the largest fiber diameter, while the fibers 16 of the innermost fiber layer have the smallest fiber diameter.

4 shows a microscopic image of an electrospun fiber layer 15 of the vascular prosthesis 10. The electrospun fibers 16 have a fiber diameter between 0.3 µm and 10 µm. A fiber diameter between 0.3 and 2 µm is provided in the second fiber layer 17 or in fiber layers that are close to the inner lumen of the vascular prosthesis 10, as this promotes cell migration. Furthermore, a fiber diameter between 2 and 10 µm is provided in the first fiber layer 17 or in fiber layers that are distant from the inner lumen of the vascular prosthesis 10, as this achieves appropriate stability of the vascular prosthesis 10.

The tubular structure 11 has a porosity between 50% and 95%. The porosity of the individual fibers varies. The outermost fiber layer has the lowest porosity, while the innermost fiber layer has the highest porosity. The porosity decreases from the innermost fiber layer to the outermost. This ensures good cell migration and sufficient blood density of the tubular structure 11.

The tubular structure 11 has a wall thickness between 10 µm and 1000 µm. Such a low wall thickness makes the vascular prosthesis 10 suitable for use in vessels 100 with a small diameter (< 7 mm).

The tubular structure 11 has an inner diameter between 0.5 mm and 7 mm. Due to this diameter range of the tubular structure 11, the replacement of small-lumen vessel segments with a maximum diameter of 7 mm is possible.

The tubular structure 11 is formed from perfluorinated or partially fluorinated polymers (e.g., PTFE), polyurethane (e.g., thermoplastic polyurethane, hydrophilic polyurethane), polyamide (e.g., PA6.6), polyester (e.g., PLA, PLGA, PET), polysulfone (e.g., PSU), polyetheretherketone (PEEK), biological and/or protein-based polymers.

In addition to the electrospun tubular structure 11, the vascular prosthesis 10 may comprise a tubular lattice structure with lattice elements that define lattice openings (not shown). The tubular structure 11 may at least partially cover the lattice structure. Alternatively, the lattice structure may be embedded in the tubular structure 11.

The fibrin coating 20 contains heparin, which is covalently bound to the fibrin threads in such a way that the heparin can be found both on the surface and inside the fibrin coating 20. The heparin, which is covalently bound to the fibrin layer 20, is incorporated into the fibrin layer 20 Embedded. The term "embedded" means that the heparin, which is covalently bound to the fibrin coating 20, forms an integral part of the coating 20 and is deeply embedded in the coating 20. The heparin enhances the antithrombogenicity of the fibrin coating 20.

The fibrin coating 20 contains a growth factor or a peptide with the functional structure of a growth factor. This further improves the cell viability of the vascular prosthesis 10, resulting in better and faster endothelialization.

Furthermore, the fibrin coating 20 contains fucoidan, retinoic acid (e.g. all-trans retinoic acid, synthetic retinoid Am80), aptamer (e.g. transcription factor KLF5) and/or heme oxygenase I trigger (e.g. hyperforin, finasteride).

The method for manufacturing the vascular prosthesis 10 is based on the 5 explained in more detail. First, a fiber layer 15 of the tubular structure 11 is produced by electrospinning, with the electrospun fibers 16 being deposited on a mandrel 110. If necessary, further fiber layers 15 are then applied to the first fiber layer 15. The orientation of the fibers 16 can be varied from one fiber layer 15 to the next. Furthermore, different polymers can be used to produce the individual fiber layers 15. The tubular structure 11 is then pulled off the mandrel 110. The vascular prosthesis is then solidified by post-treatment, such as tempering, sintering and/or chemical treatment (not shown). Finally, the fibrin coating 20 is applied to the tubular structure 11.

6 shows the formation of the fibrin coating 20 from fibrinogen on the tubular structure 11. As in 6 As can be seen, fibrinogen can be applied to the tubular structure 11 by adsorption. When the tubular structure 11 is then exposed to a thrombin solution, thrombin can bind to the adsorbed fibrinogen via a biospecific, noncovalent bond. When the surface is subsequently exposed to a fibrinogen solution, the immobilized thrombin converts the fibrinogen derived from the solution into fibrin monomers, which spontaneously join a network of fibrin threads on the tubular structure 11.

List of reference symbols

10

vascular prosthesis

11

tubular structure

12

Wall of the tubular structure

13

proximal end of the tubular structure

14

distal end of the tubular structure

15

electrospun fiber layer

16

electrospun fibers

17

first fiber layer

18

second fiber layer

19

Inner lumen of the vascular prosthesis

20

Fibrin coating

100

vessel

110

tubular structure, mandrel

QUOTES CONTAINED IN THE DESCRIPTION

This list of documents submitted by the applicant was generated automatically and is included solely for the convenience of the reader. This list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• EP 0 266 035 A1 [0001, 0003]
• US 4 743 252 A [0003]
• US 6 416 537 B1 [0003]
• DE 10 2018 110 591 B4 [0016]
• DE 10 2022 134 575 A1 [0016]

Claims (14)

Vascular prosthesis (10) with a tubular structure (11) which is substantially impermeable to blood along its wall (12) and has a proximal and distal end (13, 14), wherein the proximal and distal ends (13, 14) are connected to a vessel (100) in use in such a way that blood can flow through the tubular structure (11) in the longitudinal axial direction and wherein the tubular structure (11) is produced by electrospinning, characterized in that the tubular structure (11) is at least partially coated with fibrin, wherein the fibrin coating (20) is formed by a fibrin nanostructure made of fibrin threads. Vascular prosthesis (10) after Claim 1 , characterized in that the tubular structure (11) comprises at least one electrospun fiber layer (15) whose fibers (16) have a specific orientation, in particular an orientation of 0° to 90° to a longitudinal axis of the tubular structure (11), or are randomly aligned. Vascular prosthesis (10) after Claim 1 or 2 , characterized in that the tubular structure (11) has a plurality of electrospun fiber layers (15) which are arranged one above the other in the radial direction of the tubular structure (11) and are formed in particular from different materials. Vascular prosthesis (10) according to one of the preceding claims, characterized in that the electrospun fibers (16) of at least one first fiber layer (17), which is arranged further away from an inner lumen (19) of the vascular prosthesis (10) in the radial direction of the tubular structure (11) than at least one second fiber layer (18), have a larger fiber diameter than the electrospun fibers (16) of the second fiber layer (18). Vascular prosthesis (10) according to one of the preceding claims, characterized in that the electrospun fibers (16) have a fiber diameter between 0.3 and 10 µm, in particular at most 8 µm, in particular at most 6 µm, in particular at most 4 µm, in particular at most 2 µm. Vascular prosthesis (10) according to one of the preceding claims, characterized in that the tubular structure (11) has a porosity between 50% and 95%, in particular at most 90%, in particular at most 80%, in particular at most 70%, in particular at most 60%. Vascular prosthesis (10) according to one of the preceding claims, characterized in that the tubular structure (11) has a wall thickness of 10 µm to 1000 µm, in particular at most 900 µm, in particular at most 700 µm, in particular at most 500 µm, in particular at most 300 µm, in particular at most 100 µm, in particular at most 50 µm. Vascular prosthesis (10) according to one of the preceding claims, characterized in that the tubular structure (11) has an inner diameter of 0.5 mm to 7 mm, in particular at most 6 mm, in particular at most 5 mm, in particular at most 4 mm, in particular at most 3 mm, in particular at most 2 mm, in particular at most 1 mm. Vascular prosthesis (10) according to one of the preceding claims, characterized in that the tubular structure (11) is formed from perfluorinated or partially fluorinated polymers (e.g. PTFE), polyurethane (e.g. thermoplastic polyurethane, hydrophilic polyurethane), polyamide (e.g. PA6.6), polyester (e.g. PLA, PLGA, PET), polysulfone (e.g. PSU), polyetheretherketone (PEEK), biological and/or protein-based polymer. Vascular prosthesis (10) according to one of the preceding claims, characterized in that the vascular prosthesis (10) has a tubular lattice structure with lattice elements that delimit lattice openings, wherein the tubular structure (11) at least partially covers the lattice structure or wherein the lattice structure is embedded in the tubular structure (11). Vascular prosthesis (10) according to one of the preceding claims, characterized in that the fibrin coating (20) contains heparin which is covalently bound to the fibrin threads in such a way that the heparin can be found both on the surface and in the interior of the fibrin coating (20). Vascular prosthesis (10) according to one of the preceding claims, characterized in that the fibrin coating (20) contains a growth factor or a peptide with the functional structure of a growth factor. Vascular prosthesis (10) according to one of the preceding claims, characterized in that the fibrin coating (20) contains fucoidan, retinoic acid (e.g. all-trans retinoic acid, synthetic retinoid Am80), aptamer (e.g. transcription factor KLF5) and/or heme oxygenase I trigger (e.g. hyperforin, finasteride). A method for producing a vascular prosthesis (10) with a tubular structure (11) according to one of the preceding claims, wherein the method comprises the steps of: a. producing at least one fiber layer (15) of the tubular structure (11) by electrospinning, wherein the electrospun fibers (16) are deposited on a tubular structure (110), in particular a mandrel; b. solidifying the tubular structure (11) by post-treatment, in particular by tempering, sintering and/or chemical treatment; c. forming a fibrin coating (20) on the tubular structure (11).