Vascular repair patch

Abstract

The present invention relates to a patch for repairing damaged vascular systems, particularly for repairing aortic dissection. The vascular repair patch comprises a polymer substrate having first and second major surfaces, and at least first and second polymer fibril layers, wherein the polymer fibrils of the first polymer fibril layer are oriented in parallel and the polymer fibrils of the second polymer fibril layer are randomly oriented. The patch may further comprise a thrombogenic agent and / or an extracellular matrix compound to promote regeneration of vascular tissue at the repair site. The present invention further provides a method for manufacturing the patch.

Description

Field of the Invention

[0001] The present application relates to tissue repair devices that can be used to repair damaged vasculature. More specifically, the present application relates to devices in the form of engineered polymeric patches that are applied to damaged blood vessels to cover and reinforce vascular defects and promote revascularization. The present invention also relates to methods of manufacturing the devices and methods of using the devices to repair damaged vasculature, particularly aortic dissections. Background Art

[0002] The vessel wall can contain up to three different layers, called capsules, with different compositions and functions. The structure of an arterial wall cross section (110) is shown in Figure 1. Figure 1 As shown. The innermost layer (101) of the arterial wall is the "intima", which includes a single layer of endothelial cells called the endothelium (102), supported by a subendothelial layer, which is composed of fragile connective tissue. The intima is supported on an elastic membrane layer called the "internal elastic lamella" (103). The internal elastic lamella separates the intima from the next layer, the "media" (104). The media is a thick middle layer that contains smooth muscle cells (105) embedded in an extracellular matrix (ECM) in the form of collagen and other elastic fibers. The smooth muscle cells are arranged in lamellae and arranged in a circular pattern around the blood vessels. Stimulation of the smooth muscle cells in the media causes the blood vessels to expand and contract. Another elastic membrane layer, called the "external elastic lamella" (106), separates the media from the third and outermost layer of the blood vessel wall, the adventitia (107). The adventitia is mainly composed of collagenous tissue (108) that supports fibroblasts (109) and nerves. In large vessels, the adventitia also contains the vasa vasorum, a network of small blood vessels that can also penetrate into the exterior of the medium and supply oxygen and nutrients to the vessel wall.

[0003] The ECM is a network of molecules that is an active and dynamic structure that serves as a support network for blood vessels. Collagen and elastin are the two main components of the ECM, with the remainder consisting of other smaller but related molecules such as fibronectin, amorphous or soluble proteoglycans, leucine-rich glycoproteins, and microfibrils. Cellular interactions with the ECM regulate key vascular functions such as cell adhesion, migration, proliferation, and tissue architecture. The distribution of proteins in the vessel wall is not linear; some components are secreted and regulated by fibroblasts, smooth muscle cells, and endothelial cells, while others depend on the specific vessel wall layer.

[0004] Collagen is a very strong protein that limits the dilation of blood vessels. Type I and type II collagen are the main collagens in the tunica media and adventitial layers of healthy and damaged arterial walls. Collagen can also interact with vascular cells. In the case of smooth muscle cells, collagen is involved in cell differentiation, adhesion, migration, proliferation, and apoptosis (polymerized collagen increases smooth muscle cell apoptosis by increasing the production of active MMP-1). In the case of endothelial cells, collagen prevents the production and adhesion of this cell type and also affects endothelial cell activity in angiogenesis.

[0005] Elastin is an insoluble and hydrophobic protein. Its deposition is limited to the middle layer, where it forms the main component of the ECM, accounting for 50% of the dry weight of the blood vessel wall. In addition, it is the most important component of elastic fibers (about 90%). In addition to mechanical integrity, elastic sheets also contribute to the elasticity of blood vessels. Arteries in particular are subject to extensive mechanical stress caused by arterial blood pressure, and elastin enables the elastic retraction of arterial walls. In vitro, many cells show migration and proliferation in response to tropoelastin, elastin degradation products, and elastin peptides.

[0006] Fibronectin is a large glycoprotein that is not only a key protein in the extracellular matrix (ECM) but also an abundant component of human plasma and other body fluids. Fibronectin is composed of two nearly identical subunits covalently linked by a pair of disulfide bonds. Each monomer is composed of three types of repeating units: type I, type II, and type III. Fibronectin's structure explains why it mediates a wide variety of cellular interactions. The collection of repeating units forms a binding domain that binds to the cell surface via integrins and also binds to other extracellular matrix molecules such as heparin, collagen / gelatin, and fibrin. Fibronectin is a ligand for dozens of molecules in the integrin receptor family. These are cell-surface heterodimeric receptors that connect fibronectin to the intracellular cytoskeleton, conferring structural functions to cells. Fibronectin's biological activities include mediating cell adhesion, proliferation, and differentiation, as well as embryogenesis and wound healing.

[0007] Laminins are high-molecular-weight proteins that form one of the main components of the vascular basement membrane. They are composed of α, β, and γ chains that intersect to form a cross-shaped structure that can bind to other cell membranes and extracellular matrix molecules. Laminins are believed to be responsible for the biological functions of the basement membrane, such as signal transduction that controls cell migration, survival, proliferation, and differentiation. These biological effects are primarily due to the interaction of the laminin α chain with cell surface receptors.

[0008] Damage to the vessel wall, including its ECM components, compromises vascular integrity, leading to the development of several vascular diseases, such as atherosclerosis, thrombosis, aneurysm, or dissection. Vascular damage can be caused by inflammatory processes, ECM degradation, or external trauma. Therefore, the state of the ECM plays a fundamental role in disease progression.

[0009] Aortic dissection (AD) is the most common and catastrophic manifestation of the so-called acute aortic syndrome. This life-threatening condition is caused by a tear in the aortic intimal layer or bleeding within the aortic wall, leading to the separation (dissection) of the aortic wall layers. Blood flow forces the layers of the aortic wall apart, resulting in the formation of a channel between the layers, called a false lumen. If the blood-filled channel ruptures through the outside of the aortic wall, the condition can be fatal.

[0010] The incidence of aortic dissection is estimated to be approximately 1 in 10,000 people per year, with 67.5% occurring in men. The most common risk factors for developing aortic dissection are age, hypertension (80% of patients), atherosclerosis (30% of patients), previous cardiac surgery (15% of patients), and iatrogenic causes from previous catheter-based procedures (4% of patients). Genetic disorders of connective tissue, such as Marfan and Loeys-Dietz syndromes, are strongly associated with aortic dissection. All aortic dissections demonstrate elastic fiber fragmentation and / or loss of smooth muscle cell nuclei, clearly indicating underlying dysfunction of the vascular intima prior to dissection.

[0011] AD can be triggered by two main events. The most common is the formation of an intimal tear, which allows blood to flow through the arterial wall and forces the layers apart, forming an intimal flap. The second event is the rupture of a nutrient vessel, which also causes intimal bleeding and may ultimately lead to aortic dissection. Both conditions can coexist.

[0012] Treatments to repair AD have not evolved at the same pace as other vascular treatments. Until recently, surgical replacement of the dissected portion (also called open repair) was the only effective treatment. Surgical repair of aortic dissection involves replacing the damaged portion of the aorta with a synthetic, artificial blood vessel and, in the most severe cases, also replacing the valve. The procedure is difficult and invasive, requiring opening the chest, cardiopulmonary bypass, and hypothermia, and is therefore associated with high mortality and morbidity. Approximately 30% of cases require reintervention 5 to 10 years after a successful procedure, and even if patients fully recover from surgery, they will still require lifelong blood pressure medication. Despite its significant invasiveness and side effects, interventional therapy remains the treatment of choice for complex dissections.

[0013] Recently, thoracic endovascular repair for aortic dissection has been developed. Endovascular repair of aortic dissection is a minimally invasive procedure in which a catheter carrying a stent graft is introduced through the femoral artery. The catheter guides the stent, which deploys over the dissected segment, covering the tear and redirecting blood flow. Endovascular repair reduces mortality and hospitalization time compared to open surgery, but it has numerous limitations. Stents originally designed for aortic aneurysms are rarely used off-label for aortic dissection. In many patients, the graft does not conform perfectly to the patient's aorta. If the stent is underexpanded, thrombosis can form and / or the graft can become dislodged over time. If the stent is overexpanded, microlesions along the lumen can occur, further damaging an already compromised vessel. In either case, repeat intervention is inevitable in the long term. Furthermore, the grafts used in open or endovascular repair provide mechanical repair but do not actively promote coagulation and resorption of the false lumen or promote vascular remodeling and regeneration, so the endothelium cannot fully restore its function.

[0014] Therefore, there is a need in the art for devices and methods for treating aortic dissection and other types of vascular injuries that focus on the regeneration of damaged vascular tissue to restore its original form and function. Ideally, such a method would be minimally invasive (i.e., suitable for intravascular deployment), and the device would be able to cover the vascular defect to provide immediate structural repair and, after covering the defect, would promote healing, cell regeneration, and complete vascular restoration. Suitably, the device would be absorbable after complete repair and restoration of vascular function. Cell regeneration of the blood vessels would prevent or minimize any graft-related side effects, thereby reducing reintervention rates.

[0015] According to a first aspect of the present invention, there is provided a vascular repair patch comprising a polymer substrate having first and second major surfaces, wherein the substrate comprises at least:

[0016] (i) a first polymer filament layer adjacent to the first major surface, comprising a plurality of polymer filaments, wherein the polymer filaments are oriented in parallel; and

[0017] (ii) a second polymer filament layer adjacent to the second major surface comprising a plurality of polymer filaments, wherein the polymer filaments are randomly oriented.

[0018] Therefore, the vascular repair patch includes a polymer substrate with two different polymer fibril layers. Due to the different orientations of the polymer fibrils, the first and second polymer fibril layers have very different properties. The first polymer fibril layer includes parallel oriented polymer fibrils, and when the patch is deployed for repairing vascular defects, it is intended to form the cavity side of the patch (i.e., facing away from the vascular wall). The second polymer fibril layer includes randomly oriented polymer fibrils, and when the patch is deployed for repairing vascular defects, it is intended to form the abluminal side of the patch (i.e., close to the vascular wall). Although previous methods of repairing vascular defects involve the use of permanent patches that only cover the defect and redirect blood flow away from the defect, it has been found that the vascular repair patch of the present invention can promote the repair and regeneration of healthy vascular systems.

[0019] In particular, it has been found that, through the orientation of polymer fibrils, the first and second polymer fibril layers can guide the migration and proliferation of endothelial cells and smooth muscle cells, respectively, thereby repairing the structure of healthy blood vessel walls. More specifically, it has been found that the parallel-oriented fibrils of the first polymer fibril layer promote the migration of two-dimensional endothelial cells on the abluminal side of the patch, so that an endothelial cell monolayer is formed on the patch in approximately two to four weeks after the intervention. It has also been found that the randomly oriented fibrils of the second polymer fibril layer promote the migration of three-dimensional smooth muscle cells into the fibril matrix within a period of approximately 12 months after the intervention. Therefore, controlling the fibril orientation of the first and second polymer fibril layers can optimize the performance of the vascular repair patch in vivo.

[0020] It has been found that the patch according to the present invention advantageously has viscoelastic properties similar to those of the aorta. When used in vivo, the patch of the present invention supplements the movement of the aorta so that it does not shift or form a kink or fold that may impair the performance of the patch. In addition, applying the patch of the present invention to the aorta does not result in significant changes in the mechanical properties of the aorta, thereby preventing it from experiencing viscoelastic loss and thus being able to continue to function normally during the repair process. This is in contrast to devices in the art (e.g., stents of transplantation) that do not have viscoelastic properties similar to those of the aorta.

[0021] In a preferred embodiment of the present invention, the polymer substrate has a storage modulus of 1 to 3 MPa, for example, about 2 MPa, as measured by DMA (see Examples for experimental details). This is equivalent to the elasticity of a healthy human aorta, with an elastic range of about 0.75–1.25 MPa. It was found that the modulus of the patch of the present invention is much lower than a contrast patch comprising a monolayer of randomly arranged or oriented fibers. Without wishing to be bound by theory, it is believed that, relative to a monolayer patch (whose mechanical properties are derived from the structure of its own monolayer), the presence of the interface between the two layers in the patch of the present invention provides improved mechanical behavior.

[0022] The vascular repair patch can be conveniently deployed via minimally invasive intravascular methods, such as via a catheter.

[0023] The polymer substrate is preferably a bioabsorbable polymer substrate, wherein the polymer filaments of the first and second polymer filament layers can be formed from one or more bioabsorbable polymers. The bioabsorbable polymer filaments of the first polymer filament layer can comprise the same bioabsorbable polymer as the bioabsorbable polymer filaments of the second polymer filament layer. Alternatively, the bioabsorbable polymer filaments of the first polymer filament layer can comprise a different bioabsorbable polymer than the bioabsorbable polymer filaments of the second polymer filament layer.

[0024] When the polymer substrate comprises more than one bioabsorbable polymer, the first and second polymer filament layers may comprise the same combination of bioabsorbable polymers in different weight ratios or in the same weight ratio. Preferably, the filaments of the first and second polymer filament layers have the same polymer composition with respect to the type of bioabsorbable polymers used and their weight ratios (if applicable).

[0025] In the context of the present invention, the term "bioabsorbable" refers to polymeric materials that are capable of being safely absorbed by the body over a period of time. Suitable bioresorbable polymers include bioresorbable polyesters, such as one or more selected from polylactic acid (PLA), poly-L-lactide (PLLA), poly-D-lactide (PDLA), poly-DL-lactide (PDLLA), polyglycolic acid (PGA), polyglycolide (PG), poly(lactic acid-co-glycolic acid) (PLGA), poly(glycolide-co-caprolactone) (PGCL), poly(glycolide-co-trimethylene carbonate (PGA-co-TMC), polycaprolactone (PCL), poly(L-lactide-co-caprolactone) (PLLA-co-CL), poly(D-lactide-co-caprolactone) (PDLA-co-CL), poly-(DL-lactide-co-caprolactone) (PDLLA-co-CL). Copolymers as defined herein include random copolymers, block copolymers, and alternating copolymers.

[0026] When the polymer filaments comprise more than one type of bioabsorbable polymer, the polymer filaments preferably each comprise a blend of bioabsorbable polymers. However, it is not excluded that the polymer filaments within a layer may comprise a plurality of filaments comprising a first bioabsorbable polymer or polymer blend, and another plurality of filaments comprising a second bioabsorbable polymer or polymer blend.

[0027] Preferred bioresorbable polymers include PCL and PGLA, wherein the PGLA comprises a lactide:glycolide ratio of 80:20 to 20:80, preferably about 50:50. In preferred substrates, the polymer filaments of at least one of the first and second polymer filament layers comprise or consist of PCL or PGLA. More preferably, the bioresorbable substrate is a substrate wherein the polymer filaments of both the first and second polymer filament layers comprise or consist of PCL or PGLA. Still more preferably, the polymer filaments of both the first and second polymer filament layers comprise or consist of PCL; or the polymer filaments of both the first and second polymer filament layers comprise or consist of PGLA.

[0028] In one embodiment, the polymer filaments of at least one of the first and second polymer filament layers comprise at least 50 wt% PCL, more preferably at least 60 wt% PCL, more preferably at least 70 wt% PCL, and more preferably at least 80 wt% PCL. For example, the polymer filaments of at least one of the first and second polymer filament layers may comprise at least 90 wt% PCL, at least 95 wt% PCL, at least 98 wt% PCL, at least 99 wt% PCL, or 100 wt% PCL.

[0029] Optionally, the polymer filaments of at least one of the first and second polymer filament layers comprise at least 50 wt% PCL and up to 50 wt% PLA, PLLA, PDLA, PDLLA, PGA, PG, PLGA, PGCL, PLLA-co-CL, PDLA-co-CL, or PDLLA-co-CL. It has been found that including a small amount of one or more of PLA, PLLA, PDLA, PDLLA, PGA, PG, PLGA, PGCL, PLLA-co-CL, PDLA-co-CL, or PDLLA-co-CL in the polymer filaments along with PCL reduces the bioabsorption time of the bioabsorbable polymer compared to PCL alone.

[0030] More preferably, the polymer filaments of at least one of the first and second polymer filament layers comprise at least 50 wt% PCL and up to 50 wt% PLGA, more preferably at least 60 wt% PCL and up to 40 wt% PLGA, more preferably at least 70 wt% PCL and up to 30 wt% PLGA, and even more preferably at least 80 wt% PCL and up to 20 wt% PLGA. As described above, the inclusion of PLGA provides a preferred means of reducing the bioabsorption time of the bioresorbable polymer compared to PCL alone. The ratio of lactide to glycolide monomers in the PLGA is preferably between 80:20 and 20:80, more preferably about 50:50, although other ratios may be selected depending on the desired bioabsorption properties.

[0031] Optionally, the polymer filaments of at least one of the first and second polymer filament layers comprise a blend of at least 50 wt% PCL or PGLA, more preferably at least 60 wt% PCL or PGLA, more preferably at least 70 wt% PCL or PGLA, more preferably about 80 wt% PCL or PGLA, and at least one of gelatin, squalene and triethyl citrate.

[0032] For example, the polymer filaments of at least one of the first and second polymer filament layers may comprise a blend of at least 70 wt% PCL or PGLA and up to 30 wt% gelatin, more preferably at least 80 wt% PCL or PGLA and up to 20 wt% gelatin. For example, the polymer filaments of at least one of the first and second polymer filament layers may comprise 80 wt% PCL or PGLA and 20 wt% gelatin.

[0033] Alternatively, the polymer filaments of at least one of the first and second layers of polymer filaments comprise a blend of at least 80 wt% PCL or PGLA and up to 20 wt% squalene, more preferably at least 85 wt% PCL or PGLA and up to 15 wt% squalene. For example, the polymer filaments of at least one of the first and second layers of polymer filaments may comprise 85 wt% PCL or PGLA and 15 wt% squalene. It has been found that including squalene in the polymer filaments reduces stiffness and improves viscoelastic properties compared to PCL or PGLA alone.

[0034] Alternatively, the polymer filaments of at least one of the first and second polymer filament layers comprise a blend of at least 80 wt% PCL or PGLA and up to 20 wt% triethyl citrate, more preferably at least 85 wt% PCL or PGLA and up to 15 wt% triethyl citrate. For example, the polymer filaments of at least one of the first and second polymer filament layers may comprise 85 wt% PCL or PGLA and 15 wt% triethyl citrate. It has also been found that including triethyl citrate in the polymer filaments reduces stiffness and further improves viscoelastic properties compared to PCL or PGLA alone.

[0035] The bioabsorbable polymer is appropriately selected so that bioabsorption occurs slowly over a period of one to two years following surgery. This timescale has been found to allow sufficient repair of the vascular defect to eliminate the need for additional mechanical support from the patch to cover the defect and reinforce the regenerating vessel wall.

[0036] The average filament diameter of the polymer filaments of the first and second polymer filament layers is suitably 1 to 20 μm, more preferably 1 to 15 μm, more preferably 2 to 10 μm, more preferably 3 to 8 μm, more preferably about 5 μm. As used herein, the average filament diameter refers to the average of the diameters of at least 25 filaments, wherein the filament diameter is determined by measuring perpendicular to the long axis of the filament in a scanning electron microscope (SEM) image (see Examples for experimental details).

[0037] The fibril diameters of the first and second polymer fibril layers can optionally form a bimodal distribution, with one peak in the range of 0.2 to 2 μm and a second peak in the range of 2.5 to 10 μm. It has been found that the inclusion of smaller diameter fibrils provides an improved matrix for the initial colonization of smooth muscle cells. Once the extracellular matrix is ​​repaired, these smaller diameter fibrils are bioabsorbed.

[0038] The filaments preferably have a consistent diameter along their length and the diameter does not vary by more than 20% of the maximum diameter, preferably by more than 10% of the maximum diameter.

[0039] The polymer filaments are preferably electrospun filaments. Electrospinning is a method for manufacturing polymer filaments in which electric power is used to direct charged fibers of a polymer solution from a spiral tip to a grounded collector. The grounded current collector comprises a conductive material that is grounded to generate a potential difference with the spiral tip and to draw the polymer solution from the spiral tip. The collector can have a variety of configurations, such as a flat plate (producing a randomly oriented net of electrospun filaments) or a rotating drum (producing an aligned net of electrospun filaments, the degree of alignment of which depends on the rotation speed of the drum). The use of electrospun filaments provides a simple means of obtaining the desired parallel orientation and random orientation layers of a vascular repair patch. In addition, it has been found that electrospun polymer filaments reduce the stiffness of the patch, thereby providing a patch with mechanical properties similar to those of a healthy blood vessel.

[0040] In preferred embodiments, the polymer substrate has a Young's modulus of 0.5 to 3.0 MPa. In comparison, the human aorta ranges from about 0.3 to 10 MPa (a value of 0.3 MPa represents a healthy, young aorta; a value of 10 MPa represents an aged and unhealthy aorta).

[0041] The SEM images of parallel oriented PCL fibers are shown in Figure 2. Figure 2 As shown in Figure 2, the SEM images of randomly oriented PCL fibrils are shown in Figure 2. Figure 3 shown.

[0042] As used herein, the terms "parallel oriented" and "parallel orientation" mean that the filaments of the first polymer filament layer are oriented with a standard deviation of no more than 36° (i.e., 20% of 180°), and most preferably no more than 18° (i.e., 10% of 180°).

[0043] As used herein, the terms "randomly oriented" and "randomly oriented" mean that the filaments of the second polymer filament layer are oriented with a standard deviation of at least 45° (i.e., 25% of 180°) and more preferably at least 54° (i.e., 30% of 180°), more preferably at least 63° (i.e., 35% of 180°), more preferably at least 72° (i.e., 40% of 180°), more preferably at least 81° (i.e., 45% of 180°), and more preferably at least 90° (i.e., 50% of 180°).

[0044] Preferably, the filaments of the first polymeric filament layer are oriented with a standard deviation of no more than 36° and the filaments of the second polymeric filament layer are oriented with a standard deviation of at least 45°, more preferably at least 54°, more preferably at least 63°, more preferably at least 72°.

[0045] Even more preferably, the filaments of the first polymeric filament layer are oriented with a standard deviation of no more than 18° and the filaments of the second polymeric filament layer are oriented with a standard deviation of at least 63°, more preferably at least 72°, more preferably at least 81°, more preferably at least 90°.

[0046] As described herein, the orientation of the fibrils in each layer refers to measurements determined using the standard open source ImageJ plugin OrientationJ, which creates an orientation distribution output. For example, the measurements can be determined using ImageJ (v1.52i).

[0047] The average porosity of the second polymer filament layer is suitably from 30 to 70%, preferably from 40 to 60%, more preferably about 50%.

[0048] The average pore size of the second polymer fibril layer is suitably 50 to 300 μm, more preferably 100 to 250 μm, and even more preferably 150 to 200 μm. The pore structure formed by the randomly oriented polymer fibrils of the second polymer fibril layer provides multiple channels or pathways for the migration and growth of smooth muscle cells. The lateral diameter of smooth muscle cells ranges from 5 to 100 μm. Therefore, at the preferred pore sizes listed above, each pore in the randomly oriented fibril network of the second polymer fibril layer can typically accommodate a network of 2 to 5 interconnected cells.

[0049] The porosity and pore size described herein refer to measurements determined using the standard open source ImageJ plugin DiameterJ, which creates a pore size distribution output. The term "porosity" as defined herein is calculated based on area (pore area / total area). For example, measurements can be determined using ImageJ (v1.52i).

[0050] Each of the first and second polymer filament layers preferably has a thickness independently of 10 μm to 200 μm, more preferably 20 μm to 100 μm, more preferably 30 μm to 70 μm, for example 50 μm.

[0051] The vascular repair patch of the present invention is substantially two-dimensional / planar in form, with the length and width of the first and second major surfaces being substantially greater than the thickness of the patch.

[0052] The total thickness of the vascular repair patch of the present invention is preferably 20 μm to 500 μm, more preferably 50 μm to 200 μm, more preferably 50 μm to 150 μm, for example, about 100 μm.

[0053] The length and width of the vascular repair patch of the present invention are preferably each independently in the range of 10 to 50 mm, more preferably in the range of 20 to 40 mm. For example, the patch may have a length of 25 to 35 mm and a width of 15 to 25 mm, and particularly preferred sizes for patches used for aortic repair include a length of 30 mm and a width of 20 mm.

[0054] The vascular repair patch of the present invention can have any shape suitable for deployment on a vascular defect. For example, the patch can be square, rectangular, circular or oval.

[0055] In a preferred embodiment, the filaments of the first polymer fibril layer are substantially parallel to the length of the vascular repair patch, and the length of the patch is greater than the width, for example, at least 20% or at least 50% greater than the width. In this configuration, the luminal surface of the patch includes fibrils that can be oriented parallel to blood flow through the damaged blood vessel after the patch is deployed. In this configuration, the parallel orientation of the fibrils provides minimal resistance to blood flow on the surface of the vascular repair patch, which reduces the possibility of the patch shifting or detaching.

[0056] The first polymer fibril layer of vascular repair patch preferably includes one or more extracellular matrix compounds. As mentioned above, extracellular matrix is ​​the molecular network found in vascular wall, and it has been found that providing extracellular matrix compounds on the luminal surface of vascular repair patch can promote endothelial cells to migrate on the near-luminal side of patch, so that endothelial cell monolayer is formed on patch. Extracellular matrix compounds suitably include one or more collagens (particularly type I and II collagen), elastin, fibronectin, laminin, VE-cadherin, vitronectin, integrin, heparan sulfate, chondroitin sulfate, ketaran sulfate (ketaran sulfate), hyaluronic acid and the most relevant peptide sequence with cell adhesion and migration, such as Arg-Gly.-Asp (RGD), Arg-Glu-Asp-Val (REDV), Tyr-Ile-Gly-Ser-Arg (YIGSR) etc. Extracellular matrix compounds can be hydrogen bonded or covalently bonded to the polymer fibrils of the first polymer fibril layer, to prevent washing away due to vascular flow.

[0057] Preferably, the extracellular matrix compound is selected from fibronectin, laminin (particularly laminin-511) and VE-cadherin. A particularly preferred extracellular matrix compound is fibronectin.

[0058] The first polymer filament layer of the vascular repair patch preferably comprises one or more extracellular matrix compounds, wherein the area amount of the extracellular matrix compound is 0.5 μg / cm based on the surface area of ​​the first surface of the patch. 2 Up to 100 μg / cm 2 More preferably, the first polymer filament layer of the vascular repair patch comprises one or more extracellular matrix compounds, and the area amount of the extracellular matrix compound is 1 μg / cm based on the surface area of ​​the first surface of the patch. 2 Up to 50 μg / cm 2 , more preferably 1.5 μg / cm 2 Up to 20 μg / cm 2 , more preferably 2 μg / cm 2 Up to 15 μg / cm 2 , more preferably 2.5 μg / cm 2 Up to 10 μg / cm 2 , more preferably 3 μg / cm 2 Up to 7 μg / cm 2 .

[0059] The second surface of the vascular repair patch can be provided with a coating of a suitable biocompatible adhesive to help the patch be firmly adhered to the vessel wall and withstand vascular flow. Suitable biocompatible adhesives are well known in the art and include synthetic adhesives (such as acrylates, cyanoacrylates and polyurethanes) and natural polymers (such as hyaluronic acid, cellulose and alginate). The mechanism of adhesion can be included in the formation of covalent bonds and / or hydrogen bonds between the adhesive and the vascular tissue. In some embodiments of the present invention, the biocompatible adhesive is ethyl cyanoacrylate, a mixture of ethyl cyanoacrylate and silica particles or butyl cyanoacrylate.

[0060] Alternatively or additionally, the second surface of the vascular repair patch can be provided with a physical fixing device, such as a plurality of microneedles, to help the patch adhere firmly to the vessel wall and withstand vascular flow. The microneedles are suitably formed of a bioabsorbable material, such as one or more of the above-mentioned bioabsorbable polymer materials.

[0061] The second polymer fibril layer may optionally contain one or more thrombotic agents, particularly one or more components of the coagulation cascade, such as tissue factor (TF, or factor III), factor VII, factor X, and fibrin. A preferred thrombotic agent is TF. It has been found that incorporating a thrombotic agent such as TF into the second polymer fibril layer of the vascular repair patch promotes the migration of smooth muscle cells into the randomly oriented fibril matrix.

[0062] Based on the surface area of ​​the second surface of the patch, the second polymer filament layer of the vascular repair patch preferably comprises one or more polymers in an area amount of 0.5 μg / cm 2 Up to 100 μg / cm 2 More preferably, the first polymer filament layer of the vascular repair patch comprises one or more thrombotic agents, and the area amount of the thrombotic agent is 1 μg / cm based on the surface area of ​​the first surface of the patch. 2 Up to 50 μg / cm 2 , more preferably 1.5 μg / cm 2 Up to 20 μg / cm 2 , more preferably 2 μg / cm 2 Up to 15 μg / cm 2 , more preferably 2.5 μg / cm 2 Up to 10 μg / cm 2 , more preferably 3 μg / cm 2 Up to 7 μg / cm 2 .

[0063] refer to Figure 4 The vascular repair patch according to the first aspect of the present invention is schematically described. Figure 4A patch is shown having a length (401), a width (402), and a thickness (403), wherein the length and the thickness are each substantially greater than the thickness, such that the patch is substantially two-dimensional / planar in shape. The patch has a first polymer filament layer (404) adjacent to a first major surface (405) and a second polymer filament layer (406) adjacent to a second major surface (407). The first polymer filament layer includes a plurality of parallel-oriented filaments, and the second polymer filament layer includes a plurality of randomly oriented filaments. Figure 5 A variation of the patch is shown in which the second major surface is provided with a plurality of microneedles (501).

[0064] According to a second aspect of the present invention, a vascular repair patch is provided, which includes a polymer substrate having a first and a second major surface, wherein the polymer substrate includes at least one polymer filament layer adjacent to the first major surface; and wherein one or more extracellular matrix compounds are disposed on the first major surface of the polymer substrate.

[0065] According to a second aspect of the present invention, extracellular matrix compound is suitably selected from one or more of the following: collagen (particularly type I and II collagen), elastin, fibronectin, laminin, VE-cadherin, vitronectin, integrin, heparan sulfate, chondroitin sulfate, ketaran sulfate (ketaran sulfate), hyaluronic acid and the peptide sequence most relevant to cell adhesion and migration, such as Arg-Gly.-Asp (RGD), Arg-Glu-Asp-Val (REDV), Tyr-Ile-Gly-Ser-Arg (YIGSR) etc. Extracellular matrix compound can be covalently bonded on the polymer fibrils of the first polymer fibril layer to prevent being washed away due to vascular flow. Preferably, extracellular matrix compound is selected from fibronectin, laminin (particularly laminin-511) and VE-cadherin. Particularly preferred extracellular matrix compound is fibronectin.

[0066] The at least one polymer filament layer preferably comprises one or more polymers in an area amount of 0.5 μg / cm based on the surface area of ​​the first surface of the patch. 2 Up to 100 μg / cm 2 More preferably, the first polymer filament layer of the vascular repair patch comprises one or more extracellular matrix compounds, and the area amount of the extracellular matrix compound is 1 μg / cm based on the surface area of ​​the first surface of the patch. 2 Up to 50 μg / cm 2 , more preferably 1.5 μg / cm 2 Up to 20 μg / cm 2 , more preferably 2 μg / cm 2 Up to 15 μg / cm2 , more preferably 2.5 μg / cm 2 Up to 10 μg / cm 2 , more preferably 3 μg / cm 2 Up to 7 μg / cm 2 .

[0067] At least one polymer fibril layer preferably includes a plurality of polymer fibrils, wherein the polymer fibrils are oriented in parallel. Optionally, the length of the patch is greater than the width, for example, at least 20% or at least 50% greater than the width, and the fibrils of the first polymer fibril layer are substantially parallel to the length direction of the vascular repair patch. In this configuration, the luminal surface of the patch includes fibrils that can be oriented parallel to the blood flow through the damaged blood vessel after the patch is deployed. In this configuration, the parallel-oriented fibrils provide minimal resistance to blood flow on the surface of the vascular repair patch, and this reduces the possibility of the patch shifting or detaching.

[0068] The polymer substrate is preferably a bioabsorbable polymer substrate, wherein the polymer filaments of at least one polymer filament layer may be formed from one or more bioabsorbable polymers. According to the second aspect of the present invention, the polymer filaments may have any of the features described with respect to the first aspect of the present invention. Any feature of the polymer filament identified as "preferred" in the context of the first aspect of the present invention is also preferred in the context of the second aspect of the present invention.

[0069] The thickness of the at least one layer of polymer filaments is preferably in the range of 10 μm to 200 μm, more preferably 20 μm to 100 μm, more preferably 30 μm to 70 μm, for example about 50 μm.

[0070] The second surface of the vascular repair patch can be provided with a coating of a suitable biocompatible adhesive to help the patch adhere firmly to the vessel wall and withstand vascular flow. Suitable biocompatible adhesives are as described above. Alternatively or in addition, the second surface of the vascular repair patch can be provided with a physical fixing device as described above.

[0071] According to the first and second aspects of the present invention, the vascular repair patch may be provided with markings to indicate the orientation of the parallel-oriented fibrils. These markings may be in the form of printed markings or embossed / indented patterns on the patch surface. Alternatively, the vascular repair patch may be provided in packaging that includes markings to indicate the orientation of the parallel-oriented fibrils.

[0072] According to a third aspect of the present invention, a vascular repair patch is provided, which includes a polymer substrate having a first and a second major surface, wherein the polymer substrate includes at least one polymer filament layer adjacent to the second major surface; and wherein one or more thrombogenic agents are arranged on the second major surface of the polymer substrate.

[0073] The one or more thrombotic agents may be selected from one or more components of the coagulation cascade, such as tissue factor (TF or Factor III), Factor VII, Factor X and fibrin. A preferred thrombotic agent is TF.

[0074] At least one polymer filament layer preferably comprises one or more polymers in an area amount of 0.5 μg / cm based on the surface area of ​​the second surface of the patch. 2 Up to 100 μg / cm 2 More preferably, the first polymer filament layer of the vascular repair patch comprises one or more thrombotic agents, and the area amount of the thrombotic agent is 1 μg / cm based on the surface area of ​​the first surface of the patch. 2 Up to 50 μg / cm 2 , more preferably 1.5 μg / cm 2 Up to 20 μg / cm 2 , more preferably 2 μg / cm 2 Up to 15 μg / cm 2 , more preferably 2.5 μg / cm 2 Up to 10 μg / cm 2 , more preferably 3 μg / cm 2 Up to 7 μg / cm 2 .

[0075] The at least one polymer filament layer preferably comprises a plurality of polymer filaments, wherein the polymer filaments are randomly oriented.

[0076] The polymer substrate is preferably a bioabsorbable polymer substrate, wherein the polymer filaments of at least one polymer filament layer may be formed from one or more bioabsorbable polymers. According to the third aspect of the present invention, the polymer filaments may have any of the features described with respect to the first aspect of the present invention. Any feature of the polymer filament identified as "preferred" in the context of the first aspect of the present invention is also preferred in the context of the third aspect of the present invention.

[0077] The thickness of the at least one layer of polymer filaments is preferably in the range of 10 μm to 200 μm, more preferably 20 μm to 100 μm, more preferably 30 μm to 70 μm, for example about 50 μm.

[0078] The second surface of the vascular repair patch can be provided with a coating of a suitable biocompatible adhesive to help the patch adhere firmly to the vessel wall and withstand vascular flow. Suitable biocompatible adhesives are as described above. Alternatively or in addition, the second surface of the vascular repair patch can be provided with a physical fixing device as described above.

[0079] According to the first, second, and third aspects of the present invention, the vascular repair patch can be provided with markings to indicate its first and second surfaces. As described above, the patch of the present invention is preferably unfolded so that the first surface forms the luminal side of the patch and the second surface forms the abluminal side of the patch. Alternatively, the vascular repair patch can be provided in packaging, wherein the packaging is provided with markings to indicate the orientation direction of the parallel-oriented filaments.

[0080] Where the patch comprises parallel-oriented filaments, these markings on the patch or its packaging can both indicate the orientation direction of the parallel-oriented filaments and distinguish between the first and second surfaces of the patch.

[0081] Optionally, the vascular repair patch according to the first, second or third aspect of the present invention may be coated with one or more antibiotics to reduce the risk of infection after implantation.

[0082] According to a fourth aspect of the present invention, a method for treating a vascular defect is provided, comprising placing a vascular repair patch according to any one of the first, second and third aspects of the present invention across the vascular defect such that the vascular repair patch conforms to the interior of the vascular wall.

[0083] "Spanning" a vascular defect generally means that the vascular repair patch will extend in two dimensions to completely cover the vascular defect and substantially prevent blood from flowing into the vascular defect. Where the vascular repair patch comprises parallel-oriented filaments, it is preferred that the patch be deployed such that the parallel-oriented filaments adjacent to the luminal surface of the patch are oriented parallel to blood flow through the damaged vessel after the patch is deployed. This reduces resistance to blood flow over the surface of the vascular repair patch and reduces the likelihood of the patch becoming dislodged or becoming detached.

[0084] The vascular defect may be a tear in a blood vessel wall, such as an arterial or venous wall. More preferably, the vascular defect is an aortic dissection.

[0085] According to a fourth aspect of the present invention, the vascular repair patch is preferably deployed via an intravascular delivery system, such as using a catheter or guidewire to deploy the vascular repair patch. The delivery system should be able to apply sufficient force to the patch to facilitate fixation of the patch to the vessel wall across the vascular defect and subsequent release of the patch.

[0086] The vascular repair patch is preferably unfolded so that the first surface forms the luminal side of the patch and the second surface forms the abluminal side of the patch. Typically, the vascular repair patch is fixed in place by a bioadhesive on the second surface and / or by a physical fixture, such as a plurality of microneedles, formed on the second surface of the vascular repair patch. However, it is not excluded that the patch can be fixed in place by an external fixture, such as a stent.

[0087] refer to Figures 6A to 6D The method of the present invention is schematically described. Figure 6A A complete artery (601) is shown, with the direction of blood flow indicated by arrows (602). Figure 6B The formation of a vascular defect (603) and the formation of a false lumen (604) are shown. Figure 6C The present invention shows a catheter (605) for carrying a vascular repair patch (606) to a vascular defect site, and Figure 6D Deployment of the patch over a vascular defect is shown.

[0088] refer to Figure 7 A to 7F schematically describe the operation of the vascular repair patch of the present invention. Figure 7 A shows a healthy blood vessel (701), including the endothelium (702) of the intima and smooth muscle cells (703) of the media (the adventitia is not shown). The direction of blood flow is indicated by arrows (704). Figure 7 B shows the formation of a vascular defect (705) and the ingress of arterial blood (706), creating a false lumen (707) between the layers of the vessel wall. Figure 7 C shows a vascular repair patch (708) according to the present invention deployed on a vascular defect (705), wherein the patch includes a first polymer filament layer (709) and a second polymer filament layer (710), wherein the first polymer filament layer (709) includes a plurality of parallel polymer filaments; and the second polymer filament layer (710) includes a plurality of randomly oriented polymer filaments.

[0089] The patch is deployed with the first major (luminal) surface of the first substrate layer (709) facing the inner lumen of the blood vessel and the second major (abluminal) surface of the second substrate layer comprising randomly oriented filaments arranged against the vessel wall. Figure 7 D depicts the vascular repair patch of the present invention approximately 2-4 weeks after surgical intervention, at which time a monolayer of epithelial cells (711) has formed on the luminal surface. Figure 7 E depicts the vascular repair patch of the present invention approximately one to twelve months after surgical intervention, at which time smooth muscle cells (712) have migrated into the second polymer filament layer of the device. Finally, Figure 7F depicts the formation of healthy regenerated blood vessels following complete recellularization of the vessel wall and bioabsorption of the vascular repair patch.

[0090] According to a fifth aspect of the present invention, there is provided an extracellular matrix compound for use in a method for treating a vascular defect, wherein the extracellular matrix compound is in the form of a vascular repair patch according to the first or second aspect of the present invention, wherein the method comprises placing the vascular repair patch across the vascular defect such that the vascular repair patch conforms to the interior of the vascular wall.

[0091] The extracellular matrix compound may be selected from one or more of the following: collagen (particularly type I and II collagen), elastin, fibronectin, laminin, VE-cadherin, vitronectin, integrins, heparan sulfate, chondroitin sulfate, catalan sulfate, hyaluronic acid, and a peptide sequence selected from the examples Arg-Gly.-Asp (RGD), Arg-Glu-Asp-Val (REDV), Tyr-Ile-Gly-Ser-Arg (YIGSR).

[0092] Preferably, the extracellular matrix compound is selected from fibronectin, laminin (particularly laminin-511) and VE-cadherin. More preferably, the extracellular matrix compound is fibronectin.

[0093] According to a sixth aspect of the present invention, there is provided a thrombogenic agent for use in a method for treating a vascular defect, wherein the thrombogenic agent is in the form of a vascular repair patch according to the first or third aspect of the present invention, wherein the method comprises placing the vascular repair patch across the vascular defect such that the vascular repair patch conforms to the interior of the vascular wall.

[0094] The thrombotic agent may be selected from one or more components of the coagulation cascade, such as tissue factor (TF or Factor III), Factor VII, Factor X and fibrin. Preferably, the thrombotic agent is TF.

[0095] According to a seventh aspect of the present invention, there is provided a method for manufacturing the vascular repair patch according to the first aspect of the present invention, the method comprising:

[0096] (a) providing a polymeric substrate having first and second major surfaces by forming at least one of (i) and (ii): wherein (i) is a first polymer filament layer comprising a plurality of polymer filaments, wherein the polymer filaments are oriented in parallel; and (ii) is a second polymer filament layer comprising a plurality of polymer filaments, wherein the polymer filaments are randomly oriented.

[0097] The method may optionally further comprise the steps of:

[0098] (b) applying one or more extracellular matrix compounds to the first major surface of the polymeric substrate; and / or

[0099] (c) applying one or more thrombogenic agents to the second major surface of the polymeric substrate.

[0100] The method of the seventh aspect of the present invention may have any of the preferred / optional features already described with respect to the first aspect of the present invention. In particular, the type and size of the polymer filaments, and the type and amount of the extracellular matrix compound and / or thrombogenic agent may be as described with reference to the first aspect of the present invention. Similarly, the polymer substrate may have any size, shape or physical properties described with reference to the first aspect of the present invention.

[0101] Step (a) may include forming the first layer of polymer filaments and / or the second layer of polymer filaments by electrospinning. The collector may have a variety of configurations, such as a flat plate (producing a randomly oriented web of electrospun filaments) or a rotating drum (producing an aligned web of electrospun filaments, the degree of alignment of which depends on the rotational speed of the drum). For example, a polymer (e.g., a bioabsorbable polymer as described above) may be dissolved in a solvent at a concentration of 5% to 15% w / v.

[0102] Suitable solvents include chloroform, a mixture of chloroform and dimethylformamide (e.g. 90% by volume chloroform and 10% by volume dimethylformamide), or a mixture of chloroform and dimethylsulfoxide (e.g. 90% by volume chloroform and 10% by volume dimethylsulfoxide).

[0103] The polymer solution is then placed in a syringe pump and propelled toward a collector at a volume flow rate of 500 to 5,000 μL / h. The syringe pump is typically placed 15 to 30 cm from the collector, and a potential between 20 and 30 kV is applied between the syringe and the collector. The resulting electrospun filament web is then dried before being removed from the collector.

[0104] The first and second polymer filament layers may optionally be formed separately and subsequently bonded together. Alternatively, the first and second polymer filament layers may be formed by electrospinning the layers sequentially.

[0105] Prior to step (b) and / or (c), the polymer substrate may be plasma treated to increase the adhesion of the extracellular matrix compound and / or thrombogenic agent to the patch and to prevent these components from being washed out of the patch by blood flow. The plasma treatment may be performed using atmospheric pressure corona discharge or under vacuum using a gas that may include air, oxygen, nitrogen, argon, and combinations thereof. Preferably, the plasma treatment uses oxygen or a mixture of oxygen and argon at a pressure of about 0.15 mbar.

[0106] The extracellular matrix compound and / or thrombogenic agent can be applied to the polymeric substrate by any suitable method, for example, using a spray applicator, a roller applicator, or by applying an aqueous solution of the extracellular matrix compound and / or thrombogenic agent by immersing the substrate surface in an aqueous solution.

[0107] In a preferred method, the first surface of the polymeric substrate is immersed in an aqueous solution containing about 100 μg / mL of one or more extracellular matrix compounds to impregnate the first substrate layer with the solution of the one or more extracellular matrix compounds. The impregnated substrate is then dried to provide a dispersion of the one or more extracellular matrix compounds in the first substrate layer.

[0108] In another preferred method, the second surface of the polymeric substrate is immersed in an aqueous solution containing about 100 μg / mL of one or more thrombotic agents to impregnate the second substrate layer with the solution of the one or more thrombotic agents. The impregnated substrate is then dried to provide a dispersion of the one or more thrombotic agents in the second substrate layer.

[0109] The method may further comprise providing a coating of a biocompatible adhesive on the second surface of the polymeric substrate. Suitable biocompatible adhesives are as described in relation to the first aspect of the invention.

[0110] The method may further include providing a physical fixation device, such as a plurality of microneedles, on the second surface of the polymeric substrate.

[0111] According to an eighth aspect of the present invention, there is provided a method for manufacturing the vascular repair patch according to the second aspect of the present invention, the method comprising:

[0112] (a) providing a polymeric substrate having first and second major surfaces by forming at least one polymeric filament layer comprising a plurality of polymeric filaments, wherein the polymeric filaments are oriented in parallel; and

[0113] (b) applying one or more extracellular matrix compounds to the first major surface of the polymeric substrate.

[0114] The method of the eighth aspect of the present invention can have any preferred / optional features that have been set forth with respect to the first aspect of the present invention. In particular, the type and size of the polymer filaments, and the type and amount of the extracellular matrix compound can be as described with reference to the first aspect of the present invention. Similarly, the polymer substrate and at least one polymer filament layer can have any size, shape or physical properties described with reference to the polymer substrate and the first polymer filament layer described with respect to the first aspect of the present invention.

[0115] Step (a) may comprise forming at least one layer of polymer filaments by electrospinning as described above in relation to the seventh aspect of the invention.

[0116] As described above in relation to the seventh aspect of the present invention, the polymer substrate may be plasma treated prior to step (b).

[0117] The extracellular matrix compound can be applied to the polymeric substrate by any suitable method, for example, an aqueous solution of the extracellular matrix compound can be applied using a spray applicator, a roller applicator, or by immersing the substrate surface in the aqueous solution.

[0118] In a preferred method, the first surface of the polymeric substrate is immersed in an aqueous solution containing about 100 μg / mL of one or more extracellular matrix compounds to impregnate the first substrate layer with the solution of the one or more extracellular matrix compounds. The impregnated substrate is then dried to provide a dispersion of the one or more extracellular matrix compounds in the first substrate layer.

[0119] The method may further comprise providing a coating of a biocompatible adhesive on the second surface of the polymeric substrate. Suitable biocompatible adhesives are as described in relation to the first aspect of the invention.

[0120] The method may further include providing a physical fixation device, such as a plurality of microneedles, on the second surface of the polymeric substrate.

[0121] According to a ninth aspect of the present invention, there is provided a method for manufacturing the vascular repair patch according to the third aspect of the present invention, the method comprising:

[0122] (a) providing a polymeric substrate having first and second major surfaces by forming at least one polymeric filament layer comprising a plurality of polymeric filaments, wherein the polymeric filaments are randomly oriented; and

[0123] (b) applying one or more thrombogenic agents to the second major surface of the polymeric substrate.

[0124] The method of the ninth aspect of the present invention may have any of the preferred / optional features already described with respect to the first aspect of the present invention. In particular, the type and size of the polymer filaments, and the type and amount of the thrombogenic agent may be as described with reference to the first aspect of the present invention. Similarly, the polymer substrate and at least one polymer filament layer may have any of the sizes, shapes, or physical properties described with reference to the polymer substrate and second polymer filament layer described with respect to the first aspect of the present invention.

[0125] Step (a) may comprise forming at least one layer of polymer filaments by electrospinning as described above in relation to the seventh aspect of the invention.

[0126] As described above in relation to the seventh aspect of the present invention, the polymer substrate may be plasma treated prior to step (b).

[0127] The thrombogenic agent may be applied to the polymeric substrate by any suitable method, for example, an aqueous solution of the thrombogenic agent may be applied using a spray applicator, a roller applicator, or by dipping the substrate surface into the aqueous solution.

[0128] In a preferred method, the second surface of the polymeric substrate is immersed in an aqueous solution containing about 100 μg / mL of one or more thrombotic agents to impregnate the second substrate layer with the solution of the one or more thrombotic agents. The impregnated substrate is then dried to provide a dispersion of the one or more thrombotic agents in the second substrate layer.

[0129] The method may further comprise providing a coating of a biocompatible adhesive on the second surface of the polymeric substrate. Suitable biocompatible adhesives are as described in relation to the first aspect of the invention.

[0130] The method may further include providing a physical fixation device, such as a plurality of microneedles, on the second surface of the polymeric substrate. BRIEF DESCRIPTION OF THE DRAWINGS

[0132] Figure 1 is a representation of the structure of a cross section (110) of an arterial wall.

[0133] Figure 2 is a SEM image of parallel-oriented PCL fibers.

[0134] Figure 3 is a SEM image of randomly oriented PCL fibers.

[0135] Figure 4 The vascular repair patch of the first aspect of the present invention is schematically depicted.

[0136] Figure 5 A variation of the patch is shown in which the second major surface is provided with a plurality of microneedles (501).

[0137] 6A to 6D The method of the present invention is schematically depicted.

[0138] The Figure 7 A to 7F describe the operation of the vascular repair patch of the present invention.

[0139] Figure 8 is a graph showing the cell density of human aortic endothelial cells / human smooth muscle cells in the fiber layer used in the patch of the present invention. The data are provided in Table 2.

[0140] Figure 9 Graph showing the cell velocity of human aortic endothelial cells / human smooth muscle cells in the fiber layer used in the patch of the present invention. The data are provided in Table 2.

[0141] Figure 10 is a graph showing the cell density of human aortic endothelial cells / human smooth muscle cells used in a control experiment. The data are provided in Table 2.

[0142] Figure 11 is an epifluorescence microscope image of a patch tested using human aortic endothelial cells according to the method of Example 2. This patch is a 1-layer patch, wherein the layers have randomly oriented fibers.

[0143] Figure 12 is an epifluorescence microscopy image of a patch tested using human aortic endothelial cells according to the method of Example 2. The patch is a 2-layer patch, wherein both layers have parallel-oriented fibers.

[0144] Figure 13 is an epifluorescence microscopy image of a patch tested using human aortic endothelial cells according to the method of Example 2. The patch is a 2-layer patch, wherein both layers have randomly oriented fibers.

[0145] Figure 14 is an epifluorescence microscopy image of a patch tested using human smooth muscle cells according to the method of Example 2. This patch is a 1-layer patch, wherein the layers have randomly oriented fibers.

[0146] Figure 15 is an epifluorescence microscopy image of a patch tested using human smooth muscle cells according to the method of Example 2. The patch is a 2-layer patch, wherein both layers have parallel-oriented fibers.

[0147] Figure 16 is an epifluorescence microscopy image of a patch tested using human smooth muscle cells according to the method of Example 2. The patch is a 2-layer patch, wherein both layers have randomly oriented fibers.

[0148] Figure 17 is an epifluorescence microscopy image of a patch tested according to the method of Example 2, depicting an example area used to calculate cell density.

[0149] Figure 18 is an epifluorescence microscopy image of a patch tested according to the method of Example 2, depicting example lengths used to calculate cell velocity.

[0150] Figure 19 This is an epifluorescence microscopy image of a patch tested according to the “control experiment” method.

[0151] Figure 20 is a graph showing dynamic modulus analysis (DMA) data for a one-ply patch with parallel fiber orientation.

[0152] Figure 21 is a graph showing DMA data for a one-layer patch with random fiber orientation.

[0153] Figure 22 is a graph showing DMA data for a patch of the present invention comprising one layer with parallel fiber orientation and one layer with random fiber orientation. Example

[0154] The SEM images of the patch of the present invention were obtained using the following method. Sample preparation: Take a sample of the patch of the present invention and place it in a sample holder and bond the sample to the holder using carbon tape. The sample is then placed in a gold sputtering system, the pressure is reduced to 0.05mPa, and the sample is sputtered with gold for 20 seconds. The chamber is then filled to ambient pressure and the sample is removed. Capture the SEM image: The SEM chamber is vented to reach ambient pressure. The sample is introduced into the sample stage and the sample chamber is closed and evacuated. An electric current (up to 25μA) is applied through a tungsten filament in the SEM device to heat it. SEM images are then taken for all samples using the same conditions: spot size = 50%, voltage = 10kV, distance = 10mm, magnification = 2000x.

[0155] The viscoelastic properties of the patch of the present invention were measured using a DMATA instrument, DMAQ-800. The sample (patch) was fixed between fixtures and a sinusoidal stress was applied to the sample. All experiments were performed at a frequency of 1 Hz, a preload of 0.03 N, and an amplitude of 1.25x the preload. Elastic modulus and loss modulus were extracted by measuring strain / stress at each time point.

[0156] The Young's modulus of the patches of the present invention was measured using a TA Instruments DMAQ-800. Tensile tests were performed in which the sample (patch) was stretched until deformation occurred. The instrument measures the stress experienced by each patch at a specific strain. All experiments were performed with a preload of 0.0010 N, an initial strain of 0.9%, an initial displacement of 10.0 m, and a time delay of 5.0% min. -1 to 30%min -1 The Young's modulus of the patch of the present invention is provided below.

[0157]

[0158] Table 1: Young's modulus of the patch of the present invention.

[0159] Example 1

[0160] Dissolve 1.20 g of polycaprolactone (PCL) in 10 mL of chloroform to a concentration of 12% w / v. Add PCL particles to the solvent in small portions under steady but not vigorous stirring. Once all particles have dissolved, the mixture is ready for use.

[0161] The PCL mixture was drawn through a syringe with a narrow tip to prevent bubble formation. The syringe was placed in a fume hood with the tip pointing upwards to remove any bubbles that were present and to prevent evaporation of the solvent.

[0162] The syringe was placed on a syringe pump system and the mixture was advanced at a volumetric flow rate of 2000 μL / h. The syringe pump was positioned horizontally, 24.5 cm from the collector. A 25 kV potential was applied between the syringe pump and the collector. The mixture was allowed to deposit on the collector for approximately 1 hour. The patch was then air-dried for approximately 1 hour.

[0163] Circular patches with a diameter of 15.6 mm were cut from the entire electrospun surface.

[0164] The surface of the patch was then exposed to a plasma treatment to increase the hydrophilicity of the nanofibers. A low-temperature plasma generator was used. Pure oxygen gas was ignited at a pressure of 150 Pa and a glow discharge was ignited for 3 minutes. This process was performed using an open duty cycle and 70 W of power.

[0165] Immediately after treatment, the patch was placed on a 24-well plate containing 100 μL of bioadhesive. In parallel, 200 μL of fibronectin dissolved in phosphate-buffered saline (PBS) at a concentration of 100 μg / mL was placed on the top surface of the patch. After 5 minutes, the patch was removed from the 24-well plate.

[0166] 1 million cells / cm 2 A culture of human aortic endothelial cells seeded on a 6-well plate was injured at the center using a plastic cell scraper. The patch was placed at the site of injury and pressed against the plate surface.

[0167] The cells were incubated in culture medium for 48 hours. Afterwards, the cells were fixed with 4% paraformaldehyde for 20 minutes at room temperature. After two consecutive 10-minute washes with PBS, the cells were permeabilized with 0.2% Triton (in PBS) for 10 minutes. The cells were then washed twice with PBS for ten minutes each and blotted with 5% goat serum in PBS-BSA (PBS, 1% bovine serum albumin) for 1 hour. The cells were labeled with phalloidin and DAPI for 1 hour. Two additional 10-minute washes were performed with PBS to remove all unbound reagents.

[0168] Cell migration was examined by visualizing cells along the plate and patch using a fluorescence microscope. The cell density of cells migrating toward the top of the patch was quantified using the image analysis software Fiji.

[0169] Example 2

[0170] The following experiments demonstrate the effect of fiber orientation and / or number of layers on cell migration within the patch of the present invention.

[0171] First, one or two layers of PCL sheets were electrospun using the same procedure as in Example 1, except that the following conditions were used: voltage = 18.6 kV, distance from the current collector = 18 cm, flow rate = 2000 μL / h, volume = 2 mL. The first layer was produced using a collector with a rotation speed of 0 rpm. This layer had a random orientation of the fibers. The second layer was produced using a collector with a rotation speed of 1000 rpm. This layer had an aligned orientation of the fibers.

[0172] Patches measuring 2 cm x 1 cm were cut using surgical blades. A poly(butyl acrylate: acrylic acid)-based glue (100 μL) was sprayed onto each patch from a distance of 15 cm, and each patch was then placed on a 6-well tissue culture plate. The wells were washed three times for 5 minutes using 2 mL of cell culture medium. The cell culture medium used was the same as that used for the experiment, including Endothelial Growth Medium-2 Complete (Promocell), containing 5% fetal bovine serum and 1% penicillin / streptomycin.

[0173] Each patch was treated with plasma corona for 1 minute, and then 50 μL of 100 μg / mL bovine plasma fibronectin was deposited onto each patch. The patches were then placed at 37°C for 2 hours.

[0174] The fibronectin was then gently removed and each patch was covered with a 2 cm x 1 cm x 1 cm silicone cover. Human aortic endothelial cells or human aortic smooth muscle cells (300,000 cells) suspended in 2.5 mL of culture medium were then seeded onto the plates and placed in a 37°C incubator with 5% CO2.

[0175] After 12 hours, the silicone cover was removed from each patch and the culture medium was replaced with 2.5 mL of fresh cell culture medium. The patches were returned to the incubator and the cell culture medium was changed every 24 hours. The experiment was terminated 72 hours after the silicone cover was removed.

[0176] The tissue culture plates were rinsed with PBS and fixed with 4% paraformaldehyde for 30 minutes at room temperature. Afterwards, the cells were washed twice with PBS for 5 minutes. Any excess aldehyde was quenched with glycine (0.2 mol / L) in PBS for 10 minutes, followed by two 5-minute washes with PBS and permeabilization with Triton X-100 (0.2%) in PBS.

[0177] After washing with PBS twice for 10 minutes, the cells were labeled with phalloidin-rhodamine 1:100 and DAPI 1:1000 for 1 hour to stain actin and nuclei.

[0178] After two consecutive 5-min PBS washes, the samples were detached from the 6-well plates, placed in a face-down orientation between two microscope slides, and imaged using a Nikon epifluorescence microscope.

[0179] Images were taken at 4x and 10x to quantify cell colonization of each patch, observing both the distance traveled by cells and cell density, such as the number of cells per unit area. Figure 11-18 is an epifluorescence image of the patch of the present invention.

[0180] The pixel-to-distance ratio was calculated using the microscope scale embedded in the microscope software. The number of cells was quantified using the software "FIJI". The cell invasion area density was calculated by counting the number of cells in the invasion area and dividing by the size of the area (e.g., see Figure 17 ). Cell velocity was calculated as the distance traveled by the cell (e.g., see Figure 18 ) divided by the experimental time.

[0181] Control experiment

[0182] A control experiment was performed following the same procedure as described in Example 2, except that each patch was not covered with a silicone cap, thereby allowing the patch to be completely covered with human endothelial cells / smooth muscle cells, which could adhere to each patch just like the 6-well tissue culture plate upon which they were added.

[0183] Therefore, the data obtained from these experiments are controls for 72-hour "total" patch colonization. Figure 10 Data obtained from control experiments with human endothelial cells and smooth muscle cells are shown (see "ADH" entry in Table 2).

[0184] A control for colonization rate was not measured because the patches were “colonized” from the start of the experiment.

[0185] The results confirmed that when the fibers in the luminal layer were aligned, endothelial cells exhibited a higher cell density than when the fibers were randomly oriented. In addition, endothelial cells migrated faster when the fibers in the layer were aligned than when the fibers in the layer were randomly oriented.

[0186] When the patch had two layers, smooth muscle cells exhibited a lower cell density than when it had only one layer. Furthermore, when the fibers in the layers were aligned, smooth muscle cells had a lower cell density than when the fibers in the layers were randomly oriented. Finally, when the fibers in the layers were randomly oriented, smooth muscle cells migrated faster than when the fibers in the layers were aligned. The aligned fibers appear to hinder the smooth muscle cells' progress through the patch.

[0187] patch cell <![CDATA[Density (cells / mm 2 )]]> Speed ​​(μm / h) 1L-R EC 909±167 2.4±0.89 2L-R EC 509±121 3.2±0.74 2L-A EC 984±327 6.0±1.66 1L-R SMC 1234±110 5.6±0.70 2L-R SMC 631±335 6.6±1.37 2L-A SMC 562±173 2.6±0.80 2L-AADH EC 2620±687 2L-AADH SMC 876±155

[0188] Table 2: Average cell density and velocity of human endothelial cells (EC) and smooth muscle cells (SMC) on the luminal surface of the patch calculated by epifluorescence microscopy. Values ​​are the means of at least 7 independent samples and are shown as mean ± standard error.

[0189] 1L-R = one layer patch with random fiber orientation.

[0190] 1L-A = One layer patch with parallel (aligned) fiber orientation.

[0191] 2L-R = Two-layer patch: the abluminal surface has parallel fiber orientation, and the luminal surface has random fiber orientation.

[0192] 2L-A = two-layer patch: the abluminal surface has random fiber orientation, and the luminal surface has parallel fiber orientation.

[0193] ADH = Adhesion - Positive Control

[0194] Figure 8 and 9 The non-control data shown in Table 2 are illustrated.

[0195] The results demonstrate how the specific structural features of the patch of the present invention provide an improved patch with optimized in vivo performance. Thus, the device of the present invention comprises two layers; a first layer and a second layer, wherein the first layer comprises parallel oriented polymer filaments and the second layer comprises randomly oriented polymer filaments. When in use, i.e. in vivo, the second layer is the abluminal layer (i.e. the layer in contact with smooth muscle cells), while the first layer is the luminal layer (i.e. the layer in contact with the blood flow). The alignment of the fibers allows endothelial cells to quickly flow through and colonize in the first (luminal) layer, thereby promoting faster re-endothelialization of the layer in contact with the blood flow. In addition, the random orientation of the fibers in the second layer (abluminal layer) allows smooth muscle cells to quickly flow through and colonize in the second layer.

[0196] However, smooth muscle cells cannot move rapidly through the aligned first (luminal) layer (cf. Figure 9 ), thus the first layer of the patch of the present invention effectively provides a barrier to smooth muscle cells, causing them to reside primarily in the second (abluminal) layer.

[0197] Example 3

[0198] The inventors developed an ex vivo test that evaluates the patch's resistance to flow to the aorta. The test utilizes a porcine descending aorta (1.5 cm diameter), a diaphragm pump actuated with compressed air, PVC tubing, the adhesive patch of the invention, and water (at room temperature).

[0199] First, a 2-4 mm tear is created in the aorta using a surgical punch. A cable tie is then used to connect the aorta to a PVC tube. The PVC tube is then connected to a diaphragm pump.

[0200] The compressed air of the diaphragm pump is stable at 2 bar g At this pressure, the pump delivered a pulsatile water flow at 6 L / min and 1 Hz, simulating the physiological blood flow to which the aorta is exposed.

[0201] Inspect the tear to ensure that water jets are observed from the tear once the pump is activated. If no water jets are observed, stop the pump and inspect the tear to ensure that it is sufficiently extended through the aorta. If necessary, increase the tear and repeat the inspection until water jets are observed from the tear.

[0202] Once the inspection is complete, the diaphragm pump is stopped and an adhesive patch according to the claim is manually introduced to cover the tear from the inside of the aorta. The size of the patch is 2 cm × 1 cm (as in Example 2). The adhesive includes ethyl cyanoacrylate (50 μL), a mixture of ethyl cyanoacrylate (100 μL) and silica particles (4%) and butyl cyanoacrylate (20 μL). Pressure is applied to the patch for 5 seconds to ensure that the patch adheres to the aorta. After the patch is adhered, the diaphragm pump is turned on again and water flows through the aorta.

[0203] With the pump running, the patch performance was visually assessed. If the patch detached from the aorta, it would be ejected from the system and leakage from the tear would be observed. If the adhesive maintained the patch adhered to the aorta, no leakage would be observed. The patch tested as described above was found to remain adhered to the aorta throughout the experiment, and no leakage was observed.

[0204] The above is a detailed description of the present invention to assist those skilled in the art in implementing the invention defined in the claims. Various modifications and variations may be made to the specific embodiments of the invention described herein without departing from the spirit and scope of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the invention belongs. All publications, patent applications, patents, and other references identified herein are incorporated herein by reference in their entirety.

[0205] statement

[0206] The present invention is further described with reference to the following numbered statements.

[0207] 1. A vascular repair patch comprising a polymer substrate having first and second major surfaces, wherein the substrate comprises at least:

[0208] (i) a first polymer filament layer adjacent to the first major surface, comprising a plurality of polymer filaments, wherein the polymer filaments are oriented in parallel; and

[0209] (ii) a second polymer filament layer adjacent to the second major surface comprising a plurality of polymer filaments, wherein the polymer filaments are randomly oriented.

[0210] 2. The vascular repair patch according to statement 1, wherein the first polymer filament layer of the vascular repair patch comprises one or more extracellular matrix compounds, optionally wherein:

[0211] (a) the one or more extracellular matrix compounds are selected from collagen (particularly type I and II collagen), elastin, fibronectin, laminin, VE-cadherin, vitronectin, integrins, heparan sulfate, chondroitin sulfate, catalan sulfate, hyaluronic acid, and peptide sequences selected from the group consisting of Arg-Gly.-Asp (RGD), Arg-Glu-Asp-Val (REDV), Tyr-Ile-Gly-Ser-Arg (YIGSR); and / or

[0212] (b) the first polymer filament layer comprises one or more extracellular matrix compounds, wherein the amount of the extracellular matrix compound is 0.5 μg / cm based on the surface area of ​​the first major surface of the patch. 2 Up to 100 μg / cm 2 , preferably 1 μg / cm 2 Up to 50 μg / cm 2 , more preferably 1.5 μg / cm 2 Up to 20 μg / cm 2 , more preferably 2 μg / cm 2 Up to 15 μg / cm 2 , more preferably 2.5 μg / cm 2 Up to 10 μg / cm 2 , more preferably 3 μg / cm 2 Up to 7 μg / cm 2 .

[0213] 3. The vascular repair patch according to statement 1 or statement 2, wherein the second polymer filament layer of the polymer substrate comprises one or more thrombogenic agents, optionally wherein:

[0214] (a) the one or more thrombotic agents are selected from tissue factor (TF or Factor III), Factor VII, Factor X and fibrin; and / or

[0215] (b) the second polymer filament layer comprises one or more thrombogenic agents in an area amount of 0.5 μg / cm based on the surface area of ​​the second major surface of the patch; 2 Up to 100 μg / cm 2 , preferably 1 μg / cm 2 Up to 50 μg / cm2 , more preferably 1.5 μg / cm 2 Up to 20 μg / cm 2 , more preferably 2 μg / cm 2 to 15 μg / cm2, more preferably 2.5 μg / cm 2 Up to 10 μg / cm 2 , more preferably 3 μg / cm 2 Up to 7 μg / cm 2 .

[0216] 4. A vascular repair patch according to any of the preceding statements, wherein the polymer substrate is bioabsorbable, optionally wherein the polymer filaments of the first and second polymer filament layers comprise one or more bioabsorbable polymers, optionally wherein the one or more bioabsorbable polymers are selected from polylactic acid (PLA), poly-L-lactide (PLLA), poly-D-lactide (PDLA), poly-DL-lactide (PDLLA), polyglycolic acid (PGA), polyglycolide (PG), poly(lactic-co-glycolic acid) (PLGA), poly(glycolide-co-caprolactone) (PGCL), poly(glycolide-co-trimethylene carbonate (PGA-co-TMC), polycaprolactone (PCL), poly(L-lactide-co-caprolactone) (PLLA-co-CL), poly(D-lactide-co-caprolactone) (PDLA-co-CL), poly-(DL-lactide-co-caprolactone) (PDLLA-co-CL).

[0217] 5. The vascular repair patch of claim 4, wherein the polymer filaments of one or both of the first and second polymer filament layers comprise or consist of PCL or PGLA, wherein the PGLA has a lactide:glycolide ratio of 80:20 to 20:80, optionally wherein the polymer filaments of at least one of the first and second polymer filament layers comprise at least 50 wt% PCL, preferably at least 60 wt% PCL, more preferably at least 70 wt% PCL, more preferably at least 80 wt% PCL.

[0218] 6. The vascular repair patch of claim 5, wherein the polymer filaments of at least one of the first and second polymer filament layers comprise at least 50 wt% PCL and up to 50 wt% PLA, PLLA, PDLA, PDLLA, PGA, PG, PLGA, PGCL, PLLA-co-CL, PDLA-co-CL or PDLLA-co-CL, optionally, wherein the polymer filaments of at least one of the first and second polymer filament layers comprise at least 50 wt% PCL and up to 50 wt% PLGA, preferably at least 60 wt% PCL and up to 40 wt% PLGA, more preferably at least 70 wt% PCL and up to 30 wt% PLGA, more preferably at least 80 wt% PCL and up to 20 wt% PLGA.

[0219] 7. The vascular repair patch according to any of the preceding statements, wherein:

[0220] (a) the polymer filaments of the first and second polymer filament layers have an average filament diameter of 1 to 20 μm, more preferably 1 to 15 μm, more preferably 2 to 10 μm, more preferably 3 to 8 μm, more preferably about 5 μm; and / or

[0221] (b) the filament diameters of at least one of the first and second polymer filament layers form a bimodal distribution with one peak in the range of 0.2 to 2 μm and a second peak in the range of 2.5 to 10 μm; and / or

[0222] (c) the polymer filaments of the first and second polymer filament layers are electrospun filaments; and / or

[0223] (d) the filaments of the first layer of polymeric filaments are oriented with a standard deviation of no more than 36°, preferably no more than 18°; and / or

[0224] (e) The filaments of the second polymer filament layer are oriented with a standard deviation of at least 45°, preferably at least 54°, more preferably at least 63°, more preferably at least 72°, more preferably at least 81°, more preferably at least 90°.

[0225] 8. The vascular repair patch according to any of the preceding statements, wherein the polymer substrate has a Young's modulus of 0.5 to 3.0 MPa.

[0226] 9. A vascular repair patch according to any of the preceding statements, wherein the second polymer filament layer has an average porosity of 30 to 70%, preferably 40 to 60%, more preferably about 50%, and / or an average pore size of 50 to 300 μm, more preferably 100 to 250 μm, more preferably 150 to 200 μm.

[0227] 10. A vascular repair patch according to any preceding statement, wherein each of the first and second polymer filament layers independently has a thickness of 10 to 200 μm, more preferably 20 to 100 μm, more preferably 30 to 70 μm, for example about 50 μm.

[0228] 11. The vascular repair patch according to any one of the preceding statements, comprising:

[0229] (a) a total thickness of 20 μm to 500 μm, more preferably 50 μm to 200 μm, more preferably 50 μm to 150 μm, for example about 100 μm; and / or

[0230] (b) The length and width are independently 10 to 50 mm, more preferably 20 to 40 mm.

[0231] 12. A vascular repair patch according to any of the preceding statements, wherein the filaments of the first polymer filament layer are substantially parallel to the length direction of the vascular repair patch and the length of the patch is greater than the width, preferably wherein the length of the patch is at least 20% or at least 50% greater than the width.

[0232] 13. A vascular repair patch according to any of the preceding statements, wherein a coating of a biocompatible adhesive is provided on the second major surface of the polymer substrate, optionally wherein the biocompatible adhesive is selected from synthetic adhesives (e.g., acrylates, cyanoacrylates, and polyurethanes) and natural polymers (e.g., hyaluronic acid, cellulose, and alginates).

[0233] 14. A vascular repair patch according to any of the preceding statements, wherein the second surface of the polymer substrate comprises a physical fixing device suitable for fixing the vascular repair patch to the blood vessel wall, optionally wherein the physical fixing device comprises a plurality of microneedles, optionally wherein the plurality of microneedles are formed of a bioresorbable material.

[0234] 15. A method of manufacturing a vascular repair patch as defined in any one of claims 1 to 14, the method comprising:

[0235] (a) providing a polymeric substrate having first and second major surfaces by forming at least one of (i) and (ii): wherein (i) is a first polymeric filament layer comprising a plurality of polymeric filaments, wherein the polymeric filaments are oriented in parallel; and (ii) is a second polymeric filament layer comprising a plurality of polymeric filaments, wherein the polymeric filaments are randomly oriented; and optionally, further comprising the steps of:

[0236] (b) applying one or more extracellular matrix compounds to the first major surface of the polymeric substrate; and / or

[0237] (c) applying one or more thrombogenic agents to the second major surface of the polymeric substrate.

Claims

1. A vascular repair patch comprising a polymer substrate having first and second major surfaces, wherein the substrate comprises at least: (i) a first polymer filament layer adjacent to the first major surface, comprising a plurality of polymer filaments, wherein the polymer filaments are oriented in parallel; and (ii) a second polymer filament layer adjacent to the second major surface, comprising a plurality of polymer filaments, wherein the polymer filaments are randomly oriented; wherein the polymer filaments of the first and second layers of polymer filaments comprise at least 50 wt% polycaprolactone (PCL) and up to 50 wt% poly(lactic-co-glycolic acid) (PLGA), wherein the PLGA has a lactide:glycolide ratio of 80:20 to 20:80; wherein the average filament diameter of the polymer filaments of the first and second polymer filament layers is 1 to 20 μm, and wherein the filament diameter of at least one of the first and second polymer filament layers forms a bimodal distribution with one peak in the range of 0.2 to 2 μm and a second peak in the range of 2.5 to 10 μm; wherein the polymer filaments of the first layer of polymer filaments are oriented with a standard deviation of no more than 18°, and the polymer filaments of the second layer of polymer filaments are oriented with a standard deviation of at least 63°; wherein the average porosity of the second polymer filament layer is 40% to 60%; wherein the vascular repair patch has a total thickness of 50 μm to 500 μm, and wherein the second polymer filament layer independently has a thickness of 20 μm to 200 μm; wherein the vascular repair patch is configured such that, in use, the polymer filaments in the first polymer filament layer are oriented parallel to blood flow through the blood vessel, wherein the polymer substrate has a Young's modulus of 0.5 to 3.0 MPa; and wherein the vascular repair patch is configured such that, in use, the vascular repair patch conforms to the interior of a blood vessel wall; wherein the patch is configured such that, in use, the first polymer filament layer is adjacent to the blood stream; and wherein the patch further comprises an interface between the first layer of polymer filaments and the second layer of polymer filaments, and wherein: a) the second major surface of the polymer substrate comprises physical fixing means suitable for fixing the vascular repair patch to the vessel wall, and / or b) A coating of a biocompatible adhesive is disposed on the second major surface of the polymeric substrate.

2. The vascular repair patch according to claim 1, wherein the polymer substrate is bioabsorbable. 3 . The vascular repair patch according to claim 1 , wherein the polymer filaments of at least one of the first and second polymer filament layers comprise at least 60 wt % PCL. 4 . The vascular repair patch according to claim 1 , wherein the polymer filaments of at least one of the first and second polymer filament layers comprise at least 70 wt % PCL. 5 . The vascular repair patch according to claim 1 , wherein the polymer filaments of at least one of the first and second polymer filament layers comprise at least 80 wt % PCL.

6. The vascular repair patch according to claim 1 or 2, wherein the polymer filaments of at least one of the first and second polymer filament layers comprise at least 90 wt% PCL.

7. The vascular repair patch according to claim 1 or 2, wherein the polymer filaments of at least one of the first and second polymer filament layers contain 95 wt% PCL.

8. The vascular repair patch according to claim 1 or 2, wherein the polymer filaments of at least one of the first and second polymer filament layers comprise at least 98 wt% PCL.

9. The vascular repair patch according to claim 1 or 2, wherein the polymer filaments of at least one of the first and second polymer filament layers comprise at least 99 wt% PCL.

10. The vascular repair patch according to claim 1 or 2, wherein the polymer filaments of at least one of the first and second polymer filament layers contain 100 wt% PCL.

11. The vascular repair patch of claim 1 or 2, wherein the polymer filaments of at least one of the first and second polymer filament layers comprise at least 60 wt% PCL and up to 40 wt% PLGA.

12. The vascular repair patch of claim 1 or 2, wherein the polymer filaments of at least one of the first and second polymer filament layers comprise at least 70 wt% PCL and up to 30 wt% PLGA.

13. The vascular repair patch of claim 1 or 2, wherein the polymer filaments of at least one of the first and second polymer filament layers comprise at least 80 wt% PCL and up to 20 wt% PLGA. 14 . The vascular repair patch according to claim 1 , wherein the average filament diameter of the polymer filaments of the first and second polymer filament layers is 1 to 15 μm. 15 . The blood vessel repair patch according to claim 1 , wherein the average filament diameter of the polymer filaments of the first and second polymer filament layers is 2 to 10 μm. 16 . The blood vessel repair patch according to claim 1 , wherein the average filament diameter of the polymer filaments of the first and second polymer filament layers is 3 to 8 μm. 17 . The vascular repair patch according to claim 1 , wherein the average filament diameter of the polymer filaments of the first and second polymer filament layers is 5 μm.

18. The vascular repair patch according to claim 1 or 2, wherein the polymer filaments of the first and second polymer filament layers are electrospun filaments. The vascular repair patch according to claim 1 or 2 , wherein the polymer substrate has a storage modulus of 1 to 3 MPa.

20. The vascular repair patch of claim 1 or 2, wherein the filaments of the second polymer filament layer are oriented with a standard deviation of at least 72°.

21. The vascular repair patch of claim 1 or 2, wherein the filaments of the second polymer filament layer are oriented with a standard deviation of at least 81°.

22. The vascular repair patch of claim 1 or 2, wherein the filaments of the second polymer filament layer are oriented with a standard deviation of at least 90°.

23. The vascular repair patch according to claim 1 or 2, wherein: The filaments of the first layer of polymeric filaments are oriented with a standard deviation of no more than 18°, and the filaments of the second layer of polymeric filaments are oriented with a standard deviation of at least 72°.

24. The vascular repair patch according to claim 1 or 2, wherein: The filaments of the first layer of polymeric filaments are oriented with a standard deviation of no more than 18°, and the filaments of the second layer of polymeric filaments are oriented with a standard deviation of at least 81°.

25. The vascular repair patch according to claim 1 or 2, wherein: The filaments of the first layer of polymeric filaments are oriented with a standard deviation of no more than 18°, and the filaments of the second layer of polymeric filaments are oriented with a standard deviation of at least 90°.

26. The vascular repair patch according to claim 1 or 2, wherein the average porosity of the second polymer filament layer is 50%.

27. A vascular repair patch according to claim 1 or 2, wherein the second polymer filament layer suitably has an average pore size of 50 to 300 μm.

28. A vascular repair patch according to claim 1 or 2, wherein the second polymer filament layer suitably has an average pore size of 100 to 250 μm.

29. A vascular repair patch according to claim 1 or 2, wherein the second polymer filament layer suitably has an average pore size of 150 to 200 μm.

30. The vascular repair patch of claim 1 or 2, wherein each of the first and second polymer filament layers independently has a thickness of 20 μm to 100 μm.

31. The vascular repair patch of claim 1 or 2, wherein each of the first and second polymer filament layers independently has a thickness of 30 μm to 70 μm.

32. The vascular repair patch of claim 1 or 2, wherein each of the first and second polymer filament layers independently has a thickness of 50 μm.

33. The vascular repair patch according to claim 1 or 2, which has a total thickness of 50 μm to 200 μm.

34. The vascular repair patch according to claim 1 or 2, which has a total thickness of 50 μm to 150 μm.

35. The vascular repair patch according to claim 1 or 2, which has a total thickness of 100 μm.

36. The vascular repair patch according to claim 1 or 2, wherein the length and width thereof are independently 10 to 50 mm.

37. The vascular repair patch according to claim 1 or 2, wherein the length and width thereof are independently 20 to 40 mm.

38. The vascular repair patch according to claim 36, having a length of 25 to 35 mm and a width of 15 to 25 mm.

39. The vascular repair patch according to claim 36, having a length of 30 mm and a width of 20 mm.

40. The vascular repair patch according to claim 1 or 2, wherein the filaments of the first polymer filament layer are substantially parallel to the length direction of the vascular repair patch and the length of the vascular repair patch is greater than the width of the vascular repair patch.

41. The vascular repair patch of claim 40, wherein the length of the patch is at least 20% greater than its width.

42. The vascular repair patch of claim 40, wherein the length of the patch is at least 50% greater than its width.

43. The vascular repair patch according to claim 1 or 2, wherein the first polymer filament layer of the vascular repair patch comprises one or more extracellular matrix compounds.

44. The vascular repair patch of claim 43, wherein the one or more extracellular matrix compounds are selected from collagen, elastin, fibronectin, laminin, VE-cadherin, vitronectin, integrin, heparan sulfate, chondroitin sulfate, catalan sulfate, hyaluronic acid, and peptide sequences selected from examples Arg-Gly.-Asp (RGD), Arg-Glu-Asp-Val (REDV), Tyr-Ile-Gly-Ser-Arg (YIGSR).

45. The vascular repair patch of claim 44, wherein the collagen is type I and II collagen.

46. ​​The vascular repair patch according to claim 43, wherein: The first polymer filament layer comprises one or more extracellular matrix compounds in an area amount of 0.5 μg / cm based on the surface area of ​​the first major surface of the patch. 2 Up to 100 µg / cm 2 .

47. The vascular repair patch according to claim 43, wherein: The first polymer filament layer comprises one or more extracellular matrix compounds in an area amount of 1 μg / cm based on the surface area of ​​the first major surface of the patch. 2 Up to 50 µg / cm 2 .

48. The vascular repair patch according to claim 43, wherein: The first polymer fibril layer comprises one or more extracellular matrix compounds in an area amount of 1.5 μg / cm based on the surface area of ​​the first major surface of the patch. 2 Up to 20 µg / cm 2 .

49. The vascular repair patch according to claim 43, wherein: The first polymer filament layer comprises one or more extracellular matrix compounds in an area amount of 2 μg / cm based on the surface area of ​​the first major surface of the patch. 2 Up to 15 µg / cm 2 .

50. The vascular repair patch according to claim 43, wherein: The first polymer filament layer comprises one or more extracellular matrix compounds in an area amount of 2.5 μg / cm based on the surface area of ​​the first major surface of the patch. 2 Up to 10 µg / cm 2 .

51. The vascular repair patch according to claim 43, wherein: The first polymer filament layer comprises one or more extracellular matrix compounds, wherein the amount of the extracellular matrix compound is 3 μg / cm based on the surface area of ​​the first major surface of the patch. 2 Up to 7µg / cm 2 .

52. The vascular repair patch according to claim 1 or 2, wherein the biocompatible adhesive is selected from the group consisting of synthetic adhesives and natural polymers.

53. The vascular repair patch of claim 52, wherein the synthetic adhesive is selected from the group consisting of acrylates, cyanoacrylates, and polyurethanes.

54. The vascular repair patch of claim 52, wherein the natural polymer is selected from the group consisting of hyaluronic acid, cellulose and alginate.

55. The vascular repair patch of claim 1 or 2, wherein the physical fixation device comprises a plurality of microneedles.

56. The vascular repair patch of claim 55, wherein the plurality of microneedles are formed of a bioabsorbable material.

57. The vascular repair patch of claim 1 or 2, wherein the second polymer filament layer of the polymer substrate comprises one or more thrombogenic agents.

58. The vascular repair patch of claim 57, wherein the one or more thrombogenic agents are selected from tissue factor, factor VII, factor X, and fibrin.

59. The vascular repair patch according to claim 57, wherein: The second polymer filament layer comprises one or more thrombogenic agents in an area amount of 0.5 μg / cm based on the surface area of ​​the second major surface of the patch. 2 Up to 100 µg / cm 2 .

60. The vascular repair patch according to claim 57, wherein: The second polymer filament layer comprises one or more thrombogenic agents in an area amount of 1 μg / cm based on the surface area of ​​the second major surface of the patch. 2 Up to 50 µg / cm 2 .

61. The vascular repair patch according to claim 57, wherein: The second polymer filament layer comprises one or more thrombogenic agents in an area amount of 1.5 μg / cm based on the surface area of ​​the second major surface of the patch. 2 Up to 20 µg / cm 2 .

62. The vascular repair patch according to claim 57, wherein: The second polymer filament layer comprises one or more thrombogenic agents in an area amount of 2 μg / cm based on the surface area of ​​the second major surface of the patch. 2 Up to 15 µg / cm 2 .

63. The vascular repair patch according to claim 57, wherein: The second polymer filament layer comprises one or more thrombogenic agents in an area amount of 2.5 μg / cm based on the surface area of ​​the second major surface of the patch. 2 Up to 10 µg / cm 2 .

64. The vascular repair patch according to claim 57, wherein: The second polymer filament layer comprises one or more thrombogenic agents in an area amount of 3 μg / cm based on the surface area of ​​the second major surface of the patch. 2 Up to 7µg / cm 2 .

65. The vascular repair patch according to claim 1 or 2, which is used to repair damage in a blood vessel wall.

66. The vascular repair patch of claim 1 or 2, wherein the vascular repair patch is configured such that, in use, the second polymer filament layer is disposed adjacent to the vessel wall.

67. The vascular repair patch of claim 1 or 2, wherein the vascular repair patch is substantially two-dimensional / planar in form, with the length and width of the first and second major surfaces being substantially greater than the thickness of the patch.

68. The vascular repair patch according to claim 1 or 2, which is provided with markings to indicate the orientation direction of the parallel-oriented filaments.

69. The vascular repair patch of claim 1 or 2, provided in a package, wherein the package is provided with markings to indicate the orientation direction of the parallel-oriented filaments.

70. Use of a vascular repair patch in preparing a device for use in a method for treating vascular defects, wherein the vascular repair patch comprises a polymer substrate having a first major surface and a second major surface, wherein the substrate comprises at least: (i) a first polymer filament layer adjacent to the first major surface, comprising a plurality of polymer filaments, wherein the polymer filaments are oriented in parallel; and (ii) a second polymer filament layer adjacent to the second major surface, comprising a plurality of polymer filaments, wherein the polymer filaments are randomly oriented; wherein the polymer filaments of the first and second layers of polymer filaments comprise at least 50 wt% polycaprolactone (PCL) and up to 50 wt% poly(lactic-co-glycolic acid) (PLGA), wherein the PLGA has a lactide:glycolide ratio of 80:20 to 20:80; wherein the average filament diameter of the polymer filaments of the first and second polymer filament layers is 1 to 20 μm, and wherein the filament diameter of at least one of the first and second polymer filament layers forms a bimodal distribution with one peak in the range of 0.2 to 2 μm and a second peak in the range of 2.5 to 10 μm; wherein the polymer filaments of the first layer of polymer filaments are oriented with a standard deviation of no more than 18°, and the polymer filaments of the second layer of polymer filaments are oriented with a standard deviation of at least 63°; wherein the average porosity of the second polymer filament layer is 40% to 60%; wherein the vascular repair patch has a total thickness of 50 μm to 500 μm, and wherein the second polymer filament layer independently has a thickness of 20 μm to 200 μm; wherein the vascular repair patch is configured such that, in use, the polymer filaments in the first polymer filament layer are oriented parallel to blood flow through the blood vessel, wherein the polymer substrate has a Young's modulus of 0.5 to 3.0 MPa; and wherein the vascular repair patch is configured such that, in use, the vascular repair patch conforms to the interior of a blood vessel wall; wherein the patch is configured such that, in use, the first polymer filament layer is adjacent to the blood stream; and wherein the patch further comprises an interface between the first layer of polymer filaments and the second layer of polymer filaments, The method comprises placing the vascular repair patch as defined in any one of claims 1 to 69 across a vascular defect such that the vascular repair patch conforms to the interior of the vascular wall; and wherein the vascular repair patch is unfolded such that the first major surface forms the luminal side of the patch and the second major surface forms the distal luminal side of the patch.

71. The use according to claim 70, wherein the vascular repair patch is as defined in any one of claims 1 to 69.

72. Use according to claim 70 or 71, wherein the vascular defect is a tear in the vascular wall.

73. The use according to claim 70 or 71, wherein the vascular defect is aortic dissection.

74. The use according to claim 70 or 71, wherein The vascular repair patch is deployed via an intravascular delivery system.

75. The use according to claim 70 or 71, wherein The vascular repair patch is deployed through an intravascular delivery system, and a catheter or a guide wire is used to deploy the vascular repair patch.

76. A method of manufacturing a vascular repair patch as defined in any one of claims 1 to 69, the method comprising: (a) providing a polymeric substrate having first and second major surfaces by forming at least one of (i) and (ii): wherein (i) is a first polymer filament layer comprising a plurality of polymer filaments, wherein the polymer filaments are oriented in parallel; and (ii) is a second polymer filament layer comprising a plurality of polymer filaments, wherein the polymer filaments are randomly oriented.

77. The method of claim 76, further comprising the steps of: (b) applying one or more extracellular matrix compounds to the first major surface of the polymeric substrate; and / or (c) applying one or more thrombogenic agents to the second major surface of the polymeric substrate.

78. Use of a thrombogenic agent in the form of a vascular repair patch as defined in any one of claims 1 to 69 in the preparation of a drug, wherein the drug is used in a method for treating vascular defects, the method comprising placing the thrombogenic agent in the form of a vascular repair patch as defined in any one of claims 1 to 69 across the vascular defect so that the vascular repair patch conforms to the interior of the vascular wall; wherein the vascular repair patch is unfolded so that the first major surface forms the luminal side of the patch, and the second major surface forms the distal luminal side of the patch.

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