Vascular repair patch

Abstract

The present invention relates to a patch for repairing damaged vasculature, in particular for repairing aortic dissection. A vascular repair patch includes a polymeric substrate having first and second major surfaces, and at least first and second layers of polymeric filaments wherein the polymeric filaments of the first layer of polymeric filaments are oriented in parallel and the polymeric filaments of the second layer of polymeric filaments are oriented randomly. The patch may further include a thrombogenic agent and / or an extracellular matrix compound to promote vascular tissue regeneration at the repair site. The invention further provides a method of manufacturing the patch.

Description

[0001] This application is a divisional application of the application with the filing date of 13 March 2019, the title of “Vascular repair patch”, the international application number of PCT / EP2019 / 056358 and the Chinese national application number of 201980029801.1. TECHNICAL FIELD

[0002] The present application relates to a tissue repair device which can be used to repair damaged vasculature. More particularly, the present application relates to a device in the form of an engineered polymeric patch which is applied to a damaged blood vessel to cover and reinforce the blood vessel defect and to promote blood vessel regeneration. The present application also relates to a method of manufacturing the device, and to a method of using the device to repair damaged vasculature, in particular to repair aortic dissection. BACKGROUND

[0003] A blood vessel wall can comprise up to three distinct layers, known as tunics, with different composition and function. The structure of an arterial wall cross-section (110) is shown in Figure 1 The innermost layer of the arterial wall (101) is the “tunica intima”, which comprises a single layer of endothelial cells (102) known as the endothelium, supported by an underlying layer of delicate connective tissue. The tunica intima is supported on an elastic membrane layer known as the “internal elastic lamina” (103). The internal elastic lamina separates the tunica intima from the next layer, the “tunica media” (104). The tunica media is a thick middle layer which contains smooth muscle cells (105) embedded in the extracellular matrix (ECM) in the form of collagen and other elastic fibres. The smooth muscle cells are arranged in sheets and circularly around the vessel. Stimulation of the smooth muscle cells of the tunica media causes the vessel to dilate and constrict. Another elastic membrane layer, known as the “external elastic lamina” (106), separates the tunica media from the third, outermost layer of the blood vessel wall, the tunica adventitia (107). The tunica adventitia is mainly composed of collagenous tissue (108) supporting fibroblasts (109) and nerves. In large vessels, the adventitia also contains vasa vasorum, small networks of blood vessels which can also penetrate into the exterior of the medium and provide oxygen and nutrients to the vessel wall.

[0004] The ECM is a network of molecules which is an active and dynamic structure that acts as a support network for the blood vessel. Collagen and elastin are the two main components of the ECM, the rest being made up 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 blood vessel functions such as cell adhesion, migration, proliferation and tissue architecture. The distribution of proteins in all walls is not linear; some components are secreted and regulated by fibroblasts, smooth muscle cells and endothelial cells, while others depend on the layer of the specific blood vessel wall.

[0005] Collagen is a very tough protein that restricts vessel dilation. Collagen types I and II are the main collagens in the tunica media and adventitia 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 (aggregated 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 collagen also affects endothelial cell activity in angiogenesis.

[0006] Elastin is an insoluble and hydrophobic protein. Its deposition is limited to the media layer, where it forms the main component of the ECM, accounting for 50% of the dry weight of the vessel wall. Furthermore, it is the main component of elastic fibers (about 90%). In addition to mechanical integrity, the elastic lamellae also contribute to the elasticity of the vessel. In particular, arteries are subjected to extensive mechanical stress caused by arterial blood pressure, and elastin is able to elastically recoil the arterial wall. In vitro, many cells exhibit migration and proliferation in response to tropoelastin, elastin degradation products and elastin peptides.

[0007] Fibronectin is a large glycoprotein that is not only an important protein of the ECM, but also a rich component of human plasma and other body fluids. Fibronectin consists 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. The structure of fibronectin explains why this protein mediates a wide variety of cell interactions. The collection of repeating units makes up binding domains that bind to the cell surface through integrins and also bind 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 heterodimer receptors that link fibronectin to the intracellular cytoskeleton, thereby conferring structural functions to the cell. The biological activities of fibronectin include mediating cell adhesion, proliferation and differentiation, as well as embryogenesis and wound healing.

[0008] Laminins are high molecular weight proteins that are one of the main components of the basement membrane of blood vessels. They are composed of α, β and γ chains that cross to form a cruciform structure that can bind to other cell membranes and extracellular matrix molecules. Laminins are thought 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 mainly due to the interaction of the laminin α chain with cell surface receptors.

[0009] Damage to the vessel wall, including ECM components, compromises the integrity of the vessel, triggering the development of several vascular diseases, such as atherosclerosis, thrombosis, aneurysm or dissection. Vessel damage can be caused by inflammatory processes, ECM degradation processes or external trauma. Thus, the ECM status plays a fundamental role in disease progression.

[0010] Aortic dissection (AD) is the most common and catastrophic manifestation of the so-called acute aortic syndrome. It is a life-threatening condition resulting from a tear in the intimal layer of the aorta or internal bleeding in the aortic wall leading to separation (dissection) of the aortic wall layers. Blood flow forces the aortic wall layers apart, resulting in the formation of a channel between the layers, called a false lumen. The condition can be fatal if the blood-filled channel ruptures through the outside of the aortic wall.

[0011] The incidence of aortic dissection is estimated at about 1 per 10,000 people per year, with 67.5% of males. 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). Connective tissue genetic disorders such as Marfan and Loeys-Dietz syndromes are strongly associated with aortic dissection. All aortic dissections show fragmentation of elastic fibers and / or loss of smooth muscle cell nuclei, clearly indicating a pre-dissection dysfunction of the vessel intima.

[0012] AD can be triggered by two main events. Most commonly, the formation of an intimal tear, which allows blood flow through the arterial wall and forces the layers apart, forming an intimal flap. The second event is the rupture of a nutrient blood vessel, which also causes intimal bleeding and can eventually form an aortic dissection. Both situations can coexist.

[0013] Therapy to repair AD has not developed at the same pace as other vascular therapies. Until recently, surgical replacement of the dissected portion, also known as 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, replacing the valve as well. The surgery is very difficult and invasive, requiring the opening of the chest, cardiopulmonary bypass and lowering of body temperature, and therefore has a high mortality and morbidity. About 30% of cases require re-intervention 5 to 10 years after a successful surgery, and even if the patient recovers completely from the surgery, they still need to take blood pressure medication for the rest of their life. Despite the obvious invasiveness and side effects of the intervention, it is still the treatment of choice for complex dissections.

[0014] Recently, endovascular repair of thoracic aortic dissection has been developed. Endovascular repair of aortic dissection is a minimally invasive intervention in which a catheter with a graft stent is introduced through the femoral artery. The catheter guides the stent to be deployed over the dissected segment, covering the tear and redirecting blood flow. Compared to open surgery, endovascular repair can reduce mortality and hospital stay, but has many limitations. The stents, originally designed for the treatment of aortic aneurysms, are used almost off-label for aortic dissection. In many patients, the graft does not perfectly fit the patient's aorta. If the stent is not expanded enough, thrombosis and / or graft migration over time can occur. If the stent is over-expanded, micro-injuries along the lumen can occur, which further compromise the already dangerous blood vessel. In either case, re-intervention is inevitable in the long term. Moreover, the grafts used in open or endovascular repair provide a mechanical repair, but do not actively promote coagulation and absorption of the false lumen, nor do they promote reconstitution and regeneration of the blood vessel, so that the endothelium cannot fully recover its function.

[0015] Therefore, there is a need in the art for devices and methods for treating aortic dissection and other types of blood vessel injury that focus on the regeneration of the damaged blood vessel tissue to restore its original form and function. Ideally, such a method would be minimally invasive (i.e. suitable for endovascular deployment), and the device would be able to cover the blood vessel defect to provide immediate structural repair, and would promote healing, cell regeneration and complete blood vessel restoration after covering the defect. Suitably, the device would be resorbable after complete repair and restoration of blood vessel function. Cell regeneration of the blood vessel would prevent or minimize any side effects related to the graft, thereby reducing the rate of re-intervention. SUMMARY

[0016] According to a first aspect of the present application, there is provided a vascular repair patch comprising a polymeric substrate having first and second major surfaces, wherein the substrate comprises at least:

[0017] (i) a first layer of polymeric filaments adjacent to the first major surface, comprising a plurality of polymeric filaments, wherein the polymeric filaments are oriented in parallel; and

[0018] (ii) a second layer of polymeric filaments adjacent to the second major surface, comprising a plurality of polymeric filaments, wherein the polymeric filaments are oriented randomly.

[0019] Accordingly, the vascular repair patch comprises a polymer substrate having two distinct layers of polymer filaments. Due to the different orientation of the polymer filaments, the first and second layers of polymer filaments have very different properties. The first layer of polymer filaments comprises parallel oriented polymer filaments and is intended to form the luminal side of the patch (i.e. facing away from the vessel wall) when the patch is deployed for repairing a vascular defect. The second layer of polymer filaments comprises randomly oriented polymer filaments and is intended to form the abluminal side of the patch (i.e. arranged against the vessel wall) when the patch is deployed for repairing a vascular defect. 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 a healthy vasculature.

[0020] In particular, it has been found that, by the orientation of the polymer filaments, the first and second layers of polymer filaments are able to direct the migration and proliferation of endothelial cells and smooth muscle cells, respectively, to repair the structure of a healthy vessel wall. More specifically, it has been found that the parallel oriented filaments of the first layer of polymer filaments promote the migration of two-dimensional endothelial cells on the abluminal side of the patch, such that an endothelial cell monolayer is formed on the patch about two to four weeks after the intervention. It has also been found that the randomly oriented filaments of the second layer of polymer filaments promote the migration of three-dimensional smooth muscle cells into the filament matrix over a period of about 12 months after the intervention. Thus, controlling the filament orientation of the first and second layers of polymer filaments can optimize the performance of the vascular repair patch in vivo.

[0021] It has been found that the patch according to the present invention advantageously has viscoelastic properties similar to the aorta. When used in vivo, the patch of the present invention complements the movement of the aorta such that it does not displace or form kinks or folds that can impair the performance of the patch. Furthermore, the application of the patch of the present invention to the aorta does not result in a significant change in the mechanical properties of the aorta, such that it does not experience a loss of viscoelasticity and is thus able to continue to function normally during the repair process. This is in contrast to devices of the art (e.g. grafted stents) that do not have viscoelastic properties similar to the aorta.

[0022] 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 experimental details in the examples). This corresponds to the elasticity of a healthy human aorta, which has an elasticity range of about 0.75 - 1.25 MPa. It has been found that the modulus of the patch of the present invention is much lower than comparative patches comprising a single layer of randomly arranged or oriented fibres. Without wishing to be bound by theory, it is believed that the presence of the interface between the two layers in the patch of the present invention provides an improved mechanical behaviour relative to a single layer patch, whose mechanical properties stem from the structure of its own single layer.

[0023] The vascular repair patch can be conveniently deployed by minimally invasive endovascular methods, for example by catheter.

[0024] The polymeric substrate is preferably a bioabsorbable polymeric substrate, wherein the polymeric filaments of the first and second polymeric filament layers can be formed from one or more bioabsorbable polymers. The bioabsorbable polymeric filaments of the first polymeric filament layer can comprise the same bioabsorbable polymer as the bioabsorbable polymeric filaments of the second polymeric filament layer. Alternatively, the bioabsorbable polymeric filaments of the first polymeric filament layer can comprise a different bioabsorbable polymer to the bioabsorbable polymeric filaments of the second polymeric filament layer.

[0025] When the polymeric substrate comprises more than one bioabsorbable polymer, the first and second polymeric filament layers can comprise the same combination of bioabsorbable polymers in different weight ratios or the same weight ratios. Preferably, the filaments of the first and second polymeric filament layers have the same polymeric composition in terms of the type of bioabsorbable polymer used and its weight ratio, as applicable.

[0026] In the context of the present application, the term "bioabsorbable" refers to a polymeric material that is capable of being safely absorbed by the body over a period of time. Suitable bioabsorbable polymers include bioabsorbable polyesters, for example one or more of bioabsorbable polyesters selected from poly-lactic acid (PLA), poly-L-lactide (PLLA), poly-D-lactide (PDLA), poly-DL-lactide (PDLLA), poly-glycolic acid (PGA), poly-glycolide (PG), poly(lactic-co-glycolic acid) (PLGA), poly(glycolide-co-caprolactone) (PGCL), poly(glycolide-co-trimethylene carbonate (PGA-co-TMC), poly-caprolactone (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.

[0027] When the polymeric filaments comprise more than one type of bioabsorbable polymer, the polymeric filaments preferably each comprise a blend of bioabsorbable polymers. However, it is not excluded that the polymeric filaments within a layer can 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.

[0028] Preferred bioabsorbable polymers include PCL and PGLA, where PGLA includes a ratio of lactide:glycolide 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 bioabsorbable substrate is one in which 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.

[0029] 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, more preferably at least 80 wt% PCL. For example, the polymer filaments of at least one of the first and second polymer filament layers can 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.

[0030] 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% of PLA, PLLA, PDLA, PDLLA, PGA, PG, PLGA, PGCL, PLLA-co-CL, PDLA-co-CL or PDLLA-co-CL. It has been found that the inclusion of 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 with PCL reduces the bioabsorption time of the bioabsorbable polymer compared to PCL alone.

[0031] 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, more preferably at least 80 wt% PCL and up to 20 wt% PLGA. As noted above, the inclusion of PLGA provides a preferred way of reducing the bioabsorption time of the bioabsorbable polymer compared to PCL alone. The ratio of lactide to glycolide monomers in the PLGA is preferably 80:20 to 20:80, more preferably about 50:50, although other ratios can be selected depending on the desired bioabsorption properties.

[0032] Optionally, the polymer filaments of at least one of the first and second polymer filament layers comprise at least 50 wt% of a blend of PCL or PGLA, more preferably at least 60 wt% of a blend of PCL or PGLA, more preferably at least 70 wt% of a blend of PCL or PGLA, more preferably about 80 wt% of a blend of PCL or PGLA, and at least one of gelatin, squalene, and triethyl citrate.

[0033] For example, the polymer filaments of at least one of the first and second polymer filament layers can comprise a blend of at least 70 wt% of PCL or PGLA and up to 30 wt% of gelatin, more preferably at least 80 wt% of PCL or PGLA and up to 20 wt% of gelatin. For example, the polymer filaments of at least one of the first and second polymer filament layers can comprise 80 wt% of PCL or PGLA and 20 wt% of gelatin.

[0034] Alternatively, the polymer filaments of at least one of the first and second polymer filament layers comprise at least 80 wt% of a blend of PCL or PGLA and up to 20 wt% of squalene, more preferably at least 85 wt% of a blend of PCL or PGLA and up to 15 wt% of squalene. For example, the polymer filaments of at least one of the first and second polymer filament layers can comprise 85 wt% of PCL or PGLA and 15 wt% of squalene. It has been found that the inclusion of squalene in the polymer filaments reduces stiffness and improves viscoelasticity compared to PCL or PGLA alone.

[0035] Alternatively, the polymer filaments of at least one of the first and second polymer filament layers comprise at least 80 wt% of a blend of PCL or PGLA and up to 20 wt% of triethyl citrate, more preferably at least 85 wt% of a blend of PCL or PGLA and up to 15 wt% of triethyl citrate. For example, the polymer filaments of at least one of the first and second polymer filament layers can comprise 85 wt% of PCL or PGLA and 15 wt% of triethyl citrate. It has also been found that the inclusion of triethyl citrate in the polymer filaments reduces stiffness and further improves viscoelasticity compared to PCL or PGLA alone.

[0036] The bioabsorbable polymer is suitably chosen so that bioabsorption occurs slowly over a period of one to two years after the surgical procedure. It has been found that this timescale allows sufficient repair of the vascular defect so that additional mechanical support from the patch is no longer needed in order to cover the defect and to strengthen the newly regenerated vessel wall.

[0037] The average filament diameter of the polymer filaments of the first and second polymer filament layers is suitably from 1 to 20 μιη, more preferably from 1 to 15 μιη, more preferably from 2 to 10 μιη, more preferably from 3 to 8 μιη, more preferably about 5 μιη. As used herein, 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 experimental details in the Examples).

[0038] The filament diameters of the first and second polymer filament layers can optionally form a bimodal distribution, with one peak in the range of 0.2 to 2 μιη and a second peak in the range of 2.5 to 10 μιη. It has been found that the inclusion of smaller diameter filaments provides an improved substrate for initial colonization by smooth muscle cells. Once the extracellular matrix is repaired, these smaller diameter filaments are bioabsorbed.

[0039] The filaments preferably have a uniform diameter along their length, and the diameter varies by no more than 20% of the maximum diameter, preferably no more than 10% of the maximum diameter.

[0040] The polymer filaments are preferably electrospun filaments. Electrospinning is a method of manufacturing polymer filaments in which an electric charge is used to draw a charged fiber of a polymer solution from a spiral tip towards a grounded collector. The grounded collector comprises an electrically conductive material that is grounded to create a potential difference with the spiral tip and draw the polymer solution from the spiral tip. The collector can have a variety of configurations, such as a flat plate (producing a random oriented web of electrospun filaments) or a rotating drum (producing an aligned web of electrospun filaments, the degree of alignment depending on the speed of rotation of the drum). The use of electrospun filaments provides a simple means of obtaining the required parallel oriented and randomly oriented layers of the vascular repair patch. In addition, it has been found that electrospun polymer filaments reduce the stiffness of the patch, thereby providing a patch with similar mechanical properties to a healthy blood vessel.

[0041] In preferred embodiments, the Young's modulus of the polymer substrate is from 0.5 to 3.0 MPa. In comparison, the range for a human aorta is about 0.3 to 10 MPa (the value of 0.3 MPa represents a healthy, young aorta; the value of 10 MPa represents an aged and unhealthy aorta).

[0042] SEM images of the parallel oriented PCL fibers are shown in Figure 1 1, while SEM images of the randomly oriented PCL filaments are shown in Figure 12. Figure 2 Figure 3 SEM images of the parallel oriented PCL fibers are shown in Figure 1 1, while SEM images of the randomly oriented PCL filaments are shown in Figure 12.

[0043] As used herein, the terms "parallelly 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°). ​

[0044] As used herein, the terms "randomly oriented" and "random orientation" mean that the filaments of the second polymeric 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°), more preferably at least 90° (i.e. 50% of 180°).

[0045] 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°.

[0046] More preferably still, 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°.

[0047] As described herein, the filament orientation in each layer refers to a measurement determined using the standard open source ImageJ plugin OrientationJ which creates an orientation distribution output. For example, the measurement can be determined using ImageJ (v1.52i).

[0048] The average porosity of the second polymeric filament layer is suitably from 30 to 70%, preferably from 40 to 60%, more preferably about 50%.

[0049] The average pore size of the second polymeric filament layer is suitably from 50 to 300 pm, more preferably from 100 to 250 pm, more preferably from 150 to 200 pm. The pore structure formed by the randomly oriented polymeric filaments of the second polymeric filament layer provides multiple channels or pathways for the migration and growth of smooth muscle cells. The lateral diameter of smooth muscle cells is in the range of 5 to 100 pm, and thus, at the preferred pore sizes listed above, each pore in the randomly oriented filament network of the second polymeric filament layer can typically accommodate a network of 2 to 5 interconnected cells.

[0050] 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 on an area basis (pore area / total area). For example, the measurement can be determined using ImageJ (v1.52i).

[0051] Each of the first and second polymer filament layers preferably has a thickness independently of 10 μιη to 200 μιη, more preferably 20 μιη to 100 μιη, more preferably 30 μιη to 70 μιη, for example 50 μιη.

[0052] The vascular repair patch of the present application is essentially 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.

[0053] The total thickness of the vascular repair patch of the present application is preferably 20 μιη to 500 μιη, more preferably 50 μιη to 200 μιη, more preferably 50 μιη to 150 μιη, for example about 100 μιη.

[0054] The length and width of the vascular repair patch of the present application 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 can have a length of 25 to 35 mm and a width of 15 to 25 mm, and particularly preferred dimensions for a patch for aortic repair include a length of 30 mm and a width of 20 mm.

[0055] The vascular repair patch of the present application can have any shape suitable for deployment over a vascular defect. For example, the patch can be square, rectangular, circular or oval.

[0056] In preferred embodiments, the filaments of the first polymer filament 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 comprises filaments which, upon deployment of the patch, can be oriented parallel to the blood flow through the damaged blood vessel. In this configuration, the parallel oriented filaments provide minimal resistance to blood flow over the surface of the vascular repair patch, and this reduces the likelihood of patch migration or dislodgement.

[0057] The first polymer filament layer of the vascular repair patch preferably comprises one or more extracellular matrix compounds. As mentioned above, the extracellular matrix is a network of molecules found in the blood vessel wall and it has been found that providing extracellular matrix compounds on the luminal surface of the vascular repair patch can promote endothelial cell migration on the luminal side of the patch, such that an endothelial cell monolayer is formed on the patch. The extracellular matrix compounds suitably comprise one or more of collagen (in particular collagen types I and II), elastin, fibronectin, laminin, VE-cadherin, vitronectin, integrins, heparan sulfate, chondroitin sulfate, ketaran sulfate, hyaluronic acid and peptide sequences most relevant to cell adhesion and migration, such as Arg-Gly-Asp (RGD), Arg-Glu-Asp-Val (REDV), Tyr-Ile-Gly-Ser-Arg (YIGSR) and the like. The extracellular matrix compounds can be hydrogen or covalently bonded to the polymer filaments of the first polymer filament layer to prevent washout due to blood flow.

[0058] Preferably, the extracellular matrix compound is selected from fibronectin, laminin (in particular laminin-511) and VE-cadherin. A particularly preferred extracellular matrix compound is fibronectin.

[0059] The first polymer filament layer of the vascular repair patch preferably comprises one or more extracellular matrix compounds in an area amount of 0.5 pg / cm 2 to 100 pg / cm 2 of the first surface of the patch. More preferably, the first polymer filament layer of the vascular repair patch comprises one or more extracellular matrix compounds in an area amount of 1 pg / cm 2 to 50 pg / cm 2 of the first surface of the patch, more preferably 1.5 pg / cm 2 to 20 pg / cm 2 of the first surface of the patch, more preferably 2 pg / cm 2 to 15 pg / cm 2 of the first surface of the patch, more preferably 2.5 pg / cm 2 to 10 pg / cm 2 of the first surface of the patch, more preferably 3 pg / cm 2 to 7 pg / cm 2 of the first surface of the patch.

[0060] 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 vessel flow. Suitable biocompatible adhesives are well known in the art and include synthetic adhesives (e.g. acrylates, cyanoacrylates and polyurethanes) and natural polymers (e.g. hyaluronic acid, cellulose and alginate). The mechanism of adhesion can include the formation of covalent and / or hydrogen bonds between the adhesive and the vessel tissue. In some embodiments of the application, the biocompatible adhesive is ethyl cyanoacrylate, a mixture of ethyl cyanoacrylate and silica particles or butyl cyanoacrylate.

[0061] Alternatively or additionally, the second surface of the vascular repair patch can be provided with a physical fixation means, such as a plurality of microneedles, to help the patch adhere firmly to the vessel wall and withstand vessel flow. The microneedles are suitably formed from a bioabsorbable material, such as one or more of the bioabsorbable polymeric materials described above.

[0062] The second polymeric filament layer can optionally comprise one or more thrombogenic agents, in particular one or more components of the coagulation cascade, such as tissue factor (TF, or Factor III), Factor VII, Factor X and fibrin. The preferred thrombogenic agent is TF. It has been found that the incorporation of a thrombogenic agent such as TF into the second polymeric filament layer of the vascular repair patch promotes the migration of smooth muscle cells into the randomly oriented filament matrix.

[0063] The second polymeric filament layer of the vascular repair patch preferably comprises one or more thrombogenic agents in an area amount of 0.5 pg / cm 2 to 100 pg / cm 2 of the first surface of the patch. More preferably, the first polymeric filament layer of the vascular repair patch comprises one or more thrombogenic agents in an area amount of 1 pg / cm 2 to 50 pg / cm 2 , more preferably 1.5 pg / cm 2 to 20 pg / cm 2 , more preferably 2 pg / cm 2 to 15 pg / cm 2 , more preferably 2.5 pg / cm 2 to 10 pg / cm 2 , more preferably 3 pg / cm 2 to 7 pg / cm 2 .

[0064] Reference is made to Figure 4 the vascular repair patch of the first aspect of the application is described schematically. Figure 4A patch having a length (401), a width (402) and a thickness (403) is shown, wherein the length and the thickness are each substantially greater than the thickness, such that the patch is substantially a two-dimensional / planar shape. The patch has a first layer of polymer filaments (404) adjacent to a first major surface (405) and a second layer of polymer filaments (406) adjacent to a second major surface (407). The first layer of polymer filaments comprises a plurality of filaments oriented in parallel, and the second layer of polymer filaments comprises a plurality of filaments oriented randomly. Figure 5 A variant of the patch is shown, wherein the second major surface is provided with a plurality of microneedles (501).

[0065] According to a second aspect of the present application, there is provided a vascular repair patch comprising a polymer substrate having first and second major surfaces, wherein the polymer substrate comprises at least one layer of polymer filaments 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.

[0066] According to the second aspect of the present application, the extracellular matrix compound is suitably selected from one or more of the following: collagen (in particular collagen types I and II), elastin, fibronectin, laminin, VE-cadherin, vitronectin, integrins, heparan sulfate, chondroitin sulfate, ketaran sulfate, hyaluronic acid and peptide sequences most relevant to cell adhesion and migration, such as Arg-Gly-Asp (RGD), Arg-Glu-Asp-Val (REDV), Tyr-Ile-Gly-Ser-Arg (YIGSR) and the like. The extracellular matrix compound can be covalently bonded to the polymer filaments of the first layer of polymer filaments to prevent being washed away due to blood flow. Preferably, the extracellular matrix compound is selected from fibronectin, laminin (in particular laminin-511) and VE-cadherin. A particularly preferred extracellular matrix compound is fibronectin.

[0067] The at least one layer of polymer filaments preferably comprises one or more extracellular matrix compounds in an area amount of 0.5 pg / cm 2 to 100 pg / cm 2 of the first surface of the patch. More preferably, the first layer of polymer filaments of the vascular repair patch comprises one or more extracellular matrix compounds in an area amount of 1 pg / cm 2 to 50 pg / cm 2 , more preferably 1.5 pg / cm 2 to 20 pg / cm 2 , more preferably 2 pg / cm 2 to 15 pg / cm2 more preferably 2.5 pg / cm 2 to 10 pg / cm 2 more preferably 3 pg / cm 2 to 7 pg / cm 2 .

[0068] The at least one layer of polymer filaments preferably comprises a plurality of polymer filaments, wherein the polymer filaments 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 filaments of the first layer of polymer filaments are substantially parallel to the length direction of the vascular repair patch. In this configuration, the luminal surface of the patch comprises filaments which, upon deployment of the patch, can be oriented parallel to the blood flow through the damaged blood vessel. In this configuration, the parallel oriented filaments provide minimal resistance to blood flow across the surface of the vascular repair patch, and this reduces the likelihood of patch migration or dislodgement.

[0069] The polymer substrate is preferably a bioabsorbable polymer substrate, wherein the polymer filaments of the at least one layer of polymer filaments can be formed from one or more bioabsorbable polymers. The polymer filaments can have any of the features described in relation to the first aspect of the application. Any feature of the polymer filaments identified as “preferred” in the context of the first aspect of the application is also preferred in the context of the second aspect of the application.

[0070] The thickness of the at least one layer of polymer filaments is preferably in the range 10 pm to 200 pm, more preferably 20 pm to 100 pm, more preferably 30 pm to 70 pm, for example about 50 pm.

[0071] The second surface of the vascular repair patch can be provided with a coating of a suitable biocompatible adhesive to assist in securely adhering the patch to the blood vessel wall and to withstand blood 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 fixation means as described above.

[0072] According to the first and second aspects of the application, the vascular repair patch can be provided with indicia to indicate the orientation direction of the parallel oriented filaments. These indicia can take the form of printed indicia or can take the form of embossing / indentations in the surface of the patch. Alternatively, the vascular repair patch can be provided in packaging, wherein the packaging is provided with indicia to indicate the orientation direction of the parallel oriented filaments.

[0073] According to a third aspect of the application, there is provided a vascular repair patch comprising a polymeric substrate having first and second major surfaces, wherein the polymeric substrate comprises at least one layer of polymeric filaments adjacent to the second major surface; and wherein one or more thrombogenic agents are disposed on the second major surface of the polymeric substrate.

[0074] The one or more thrombogenic agents can 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 thrombogenic agent is TF.

[0075] The at least one layer of polymeric filaments preferably comprises one or more thrombogenic agents in an area amount of 0.5 pg / cm 2 to 100 pg / cm 2 of the second surface of the patch. More preferably, the first layer of polymeric filaments of the vascular repair patch comprises one or more thrombogenic agents in an area amount of 1 pg / cm 2 to 50 pg / cm 2 , more preferably 1.5 pg / cm 2 to 20 pg / cm 2 , more preferably 2 pg / cm 2 to 15 pg / cm 2 , more preferably 2.5 pg / cm 2 to 10 pg / cm 2 , more preferably 3 pg / cm 2 to 7 pg / cm 2 of the first surface of the patch.

[0076] The at least one layer of polymeric filaments preferably comprises a plurality of polymeric filaments, wherein the polymeric filaments are randomly oriented.

[0077] The polymeric substrate is preferably a bioabsorbable polymeric substrate, wherein the polymeric filaments of the at least one layer of polymeric filaments can be formed from one or more bioabsorbable polymers. The polymeric filaments according to the third aspect of the application can have any of the features described in relation to the first aspect of the application. Any feature of the polymeric filaments identified as "preferred" in the context of the first aspect of the application is also preferred in the context of the third aspect of the application.

[0078] The thickness of the at least one layer of polymeric filaments is preferably in the range of 10 pm to 200 pm, more preferably 20 pm to 100 pm, more preferably 30 pm to 70 pm, for example about 50 pm.

[0079] The second surface of the vascular repair patch can be provided with a coating of a suitable biocompatible adhesive to assist in securely adhering the patch to the vessel wall and to withstand vessel flow. Suitable biocompatible adhesives are as described above. Alternatively or additionally, the second surface of the vascular repair patch can be provided with a physical fixation means as described above.

[0080] According to the first, second and third aspects of the application, the vascular repair patch can be provided with indicia to indicate its first and second surfaces. As described above, the patch of the application is preferably deployed such that the first surface forms the lumen 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 indicia to indicate the orientation direction of the parallel oriented filaments.

[0081] In the case where the patch comprises parallel oriented filaments, these indicia on the patch or packaging of the patch can simultaneously indicate the orientation direction of the parallel oriented filaments and distinguish the first and second surfaces of the patch.

[0082] Optionally, the vascular repair patch according to the first, second or third aspects of the application can be coated with one or more antibiotics to reduce the risk of infection following implantation.

[0083] According to the fourth aspect of the application, there is provided a method of treating a vascular defect, the method comprising placing a vascular repair patch according to any of the first, second and third aspects of the application across the vascular defect such that the vascular repair patch conforms to the interior of the vessel wall.

[0084] By "across" the vascular defect it is generally meant that the vascular repair patch will extend in two dimensions to completely cover the vascular defect and substantially prevent blood flow into the vascular defect. In the case where the vascular repair patch comprises parallel oriented filaments, it is preferred that the patch is deployed such that the orientation of the parallel oriented filaments adjacent to the lumen surface of the patch is parallel to the blood flow through the damaged vessel following deployment of the patch. This reduces the resistance to blood flow over the surface of the vascular repair patch and this reduces the likelihood of the patch migrating or falling off.

[0085] The vascular defect can be a tear in the vessel wall, for example an arterial or venous wall. More preferably, the vascular defect is a aortic dissection.

[0086] According to the fourth aspect of the application, the vascular repair patch is preferably deployed by an endovascular delivery system, for example using a catheter or guide wire to deploy the vascular repair patch. The delivery system should be able to exert sufficient force on the patch to facilitate securing the patch to the vessel wall across the vascular defect and subsequently releasing the patch.

[0087] The vascular repair patch is preferably deployed such that the first surface forms the lumen 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 biological adhesive on the second surface and / or by physical fixation means formed on the second surface of the vascular repair patch, such as a plurality of microneedles. However, it is not excluded that the patch can be fixed in place by external fixation means such as a stent.

[0088] Reference is made to Figures 6A to 6D The method of the present application is schematically described. Figure 6A A complete artery (601) is shown, the direction of blood flow being indicated by the arrow (602). Figure 6B The formation of a vascular defect (603) and the formation of a false lumen (604) are shown. Figure 6C A catheter (605) carrying a vascular repair patch (606) according to the present application to the site of the vascular defect is shown, and Figure 6D The deployment of the patch over the vascular defect is shown.

[0089] Reference is made to Figure 7 A to F schematically describe the operation of the vascular repair patch of the present application. Figure 7 A shows a healthy blood vessel (701), including the endothelium (702) of the intima and the smooth muscle cells (703) of the media (blood vessel adventitia not shown). The direction of blood flow is indicated by the arrow (704). Figure 7 B shows the formation of a vascular defect (705) and the entry of arterial blood (706), thereby forming a false lumen (707) between the layers of the blood vessel wall. Figure 7 C shows a vascular repair patch (708) according to the present application deployed over the vascular defect (705), said patch comprising a first layer of polymer filaments (709) comprising a plurality of parallel polymer filaments; and a second layer of polymer filaments (710) comprising a plurality of randomly oriented polymer filaments.

[0090] The patch is deployed with the first major (luminal) surface of the first base layer (709) facing the inner lumen of the blood vessel, and the second major (abluminal) surface of the second base layer comprising randomly oriented filaments arranged against the blood vessel wall. Figure 7 D depicts the vascular repair patch of the present application about 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 application about one to twelve months after surgical intervention, at which time smooth muscle cells (712) have migrated into the second layer of polymer filaments of the device. Finally, Figure 7F depicts a healthy regenerated blood vessel formed after complete cellular regeneration of the blood vessel wall and bioresorption of the vascular repair patch.

[0091] According to a fifth aspect of the application, there is provided an extracellular matrix compound for use in a method of treating a blood vessel defect, wherein the extracellular matrix compound is in the form of a vascular repair patch according to the first or second aspect of the application, wherein the method comprises placing the vascular repair patch across the blood vessel defect such that the vascular repair patch conforms to the interior of the blood vessel wall.

[0092] The extracellular matrix compound can be selected from one or more of the following: collagen (in particular types I and II collagen), elastin, fibronectin, laminin, VE-cadherin, vitronectin, integrin, heparan sulfate, chondroitin sulfate, catharanthine sulfate, hyaluronic acid, and a peptide sequence selected from the group consisting of Arg-Gly-Asp (RGD), Arg-Glu-Asp-Val (REDV), Tyr-Ile-Gly-Ser-Arg (YIGSR).

[0093] Preferably, the extracellular matrix compound is selected from fibronectin, laminin (in particular laminin-511) and VE-cadherin. More preferably, the extracellular matrix compound is fibronectin.

[0094] According to a sixth aspect of the application, there is provided a thrombogenic agent for use in a method of treating a blood vessel defect, wherein the thrombogenic agent is in the form of a vascular repair patch according to the first or third aspect of the application, wherein the method comprises placing the vascular repair patch across the blood vessel defect such that the vascular repair patch conforms to the interior of the blood vessel wall.

[0095] The thrombogenic agent can 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 thrombogenic agent is TF.

[0096] According to a seventh aspect of the application, there is provided a method for manufacturing a vascular repair patch according to the first aspect of the application, the method comprising:

[0097] (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; (ii) is a second polymeric filament layer comprising a plurality of polymeric filaments, wherein the polymeric filaments are oriented randomly.

[0098] The method can optionally further comprise the step of:

[0099] (b) applying one or more extracellular matrix compounds to the first major surface of the polymeric substrate; and / or

[0100] (c) applying one or more thrombogenic agents to the second major surface of the polymeric substrate.

[0101] The method of the seventh aspect of the application can have any of the preferred / optional features set out in relation to the first aspect of the application. In particular, the type and size of the polymeric filaments, and the type and amount of extracellular matrix compounds and / or thrombogenic agents can be as described with reference to the first aspect of the application. Similarly, the polymeric substrate can have any of the dimensions, shapes or physical properties described with reference to the first aspect of the application.

[0102] Step (a) can comprise forming the first and / or second layers of polymeric filaments by electrospinning. The collector can have a variety of configurations, such as a flat plate (producing a random- oriented web of electrospun filaments) or a rotating drum (producing an aligned web of electrospun filaments, the degree of alignment depending on the speed of rotation of the drum). For example, the polymer (e.g. a bioabsorbable polymer as described above) can be dissolved in a solvent at a concentration of 5% to 15% w / v.

[0103] 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).

[0104] The polymer solution is then placed in a syringe pump and advanced towards the collector at a volumetric flow rate of 500 to 5,000 μί / ίη. The syringe pump is typically placed at a distance of 15 to 30 cm from the collector, and an electric potential of between 20 to 30 kV is applied between the syringe and the collector. The electrospun filament web thus formed is dried before being removed from the collector.

[0105] The first and second layers of polymeric filaments can optionally be formed separately and subsequently joined together. Alternatively, the first and second layers of polymeric filaments can be formed by electrospinning the layers sequentially.

[0106] Prior to steps (b) and / or (c), the polymeric substrate can be subjected to a plasma treatment to increase the adhesion of the extracellular matrix compounds and / or thrombogenic agents to the patch, and to prevent these components from being washed out of the patch by the flow of blood. The plasma treatment can be carried out using atmospheric pressure corona discharge or under vacuum, using a gas which can include air, oxygen, nitrogen, argon and combinations thereof. A preferred plasma treatment uses oxygen or a mixture of oxygen and argon at a pressure of about 0.15 mbar.

[0107] 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 immersing the surface of the substrate in an aqueous solution of the extracellular matrix compound and / or thrombogenic agent.

[0108] In one preferred method, the first surface of the polymeric substrate is immersed in an aqueous solution comprising about 100 pg / mL of one or more extracellular matrix compounds, so as to impregnate the first substrate layer with a 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.

[0109] In another preferred method, the second surface of the polymeric substrate is immersed in an aqueous solution comprising about 100 pg / mL of one or more thrombogenic agents, so as to impregnate the second substrate layer with a solution of the one or more thrombogenic agents. The impregnated substrate is then dried to provide a dispersion of the one or more thrombogenic agents in the second substrate layer.

[0110] The method can further comprise providing a coating of biocompatible adhesive on the second surface of the polymeric substrate. Suitable biocompatible adhesives are as described in relation to the first aspect of the application.

[0111] The method can further comprise providing a physical fixation device, for example a plurality of microneedles, on the second surface of the polymeric substrate.

[0112] According to an eighth aspect of the application, there is provided a method for manufacturing a vascular repair patch according to the second aspect of the application, the method comprising:

[0113] (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

[0114] (b) applying one or more extracellular matrix compounds to the first major surface of the polymeric substrate.

[0115] The method of the eighth aspect of the application can have any of the preferred / optional features set out in relation to the first aspect of the application. In particular, the type and size of the polymeric filaments, and the type and amount of the extracellular matrix compounds, can be as described with reference to the first aspect of the application. Similarly, the polymeric substrate and at least one polymeric filament layer can have any of the dimensions, shapes or physical properties described with reference to the polymeric substrate and first polymeric filament layer described in relation to the first aspect of the application.

[0116] Step (a) can comprise forming the at least one polymeric filament layer by electrospinning as described above in relation to the seventh aspect of the application.

[0117] The polymer substrate can be plasma treated prior to step (b), as described above in relation to the seventh aspect of the application.

[0118] The extracellular matrix compound can be applied to the polymer 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.

[0119] In a preferred method, the first surface of the polymer substrate is immersed in an aqueous solution comprising about 100 pg / mL of one or more extracellular matrix compounds, so as to impregnate the first substrate layer with a 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.

[0120] The method can further comprise providing a coating of biocompatible adhesive on the second surface of the polymer substrate. Suitable biocompatible adhesives are as described in relation to the first aspect of the application.

[0121] The method can further comprise providing a physical fixation device on the second surface of the polymer substrate, for example a plurality of microneedles.

[0122] According to a ninth aspect of the application, there is provided a method for manufacturing a vascular repair patch according to the third aspect of the application, the method comprising:

[0123] (a) providing a polymer substrate having first and second major surfaces by forming at least one polymer filament layer comprising a plurality of polymer filaments, wherein the polymer filaments are randomly oriented; and

[0124] (b) applying one or more thrombogenic agents to the second major surface of the polymer substrate.

[0125] The method of the ninth aspect of the application can have any of the preferred / optional features set out in relation to the first aspect of the application. In particular, the type and size of the polymer filaments, and the type and amount of the thrombogenic agent can be as described with reference to the first aspect of the application. Similarly, the polymer substrate and at least one polymer filament layer can have any of the dimensions, shapes or physical properties described with reference to the polymer substrate and second polymer filament layer described in relation to the first aspect of the application.

[0126] Step (a) can comprise forming the at least one polymer filament layer by electrospinning, as described above in relation to the seventh aspect of the application.

[0127] The polymer substrate can be plasma treated prior to step (b), as described above in relation to the seventh aspect of the application.

[0128] The thrombogenic agent can be applied to the polymeric substrate by any suitable method, for example, an aqueous solution of the thrombogenic agent can be applied using a spray applicator, a roller applicator or by immersing the surface of the substrate in the aqueous solution.

[0129] In a preferred method, the second surface of the polymeric substrate is immersed in an aqueous solution comprising about 100 pg / mL of one or more thrombogenic agents, so as to impregnate the second substrate layer with a solution of the one or more thrombogenic agents. The impregnated substrate is then dried to provide a dispersion of the one or more thrombogenic agents in the second substrate layer.

[0130] The method can 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 application.

[0131] The method can further comprise providing a physical fixation means on the second surface of the polymeric substrate, for example a plurality of microneedles. BRIEF DESCRIPTION OF DRAWINGS

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

[0133] Figure 2 is an SEM image of PCL fibres in parallel orientation.

[0134] Figure 3 is an SEM image of PCL fibres in random orientation.

[0135] Figure 4 A vascular repair patch of the first aspect of the application is schematically depicted.

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

[0137] Figures 6A to 6D A method of the application is schematically depicted.

[0138] The method described Figure 7 A to 7F describe the operation of a vascular repair patch of the application.

[0139] Figure 8 is a graph showing the cell density of human aortic endothelial cells / human smooth muscle cells in a fibrous layer used in a patch of the application. Data is provided in Table 2.

[0140] Figure 9 is a graph showing the cell velocity of human aortic endothelial cells / human smooth muscle cells in a fibrous layer used in a patch of the application. Data is provided in Table 2.

[0141] Figure 10 is a graph showing cell density of human aortic endothelial cells / human smooth muscle cells for a control experiment. Data is provided in Table 2.

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

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

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

[0145] Figure 14 is an epifluorescence microscope image of a patch tested according to the method of Example 2 using human smooth muscle cells. The patch is a 1 -layer patch, where the layer has randomly oriented fibers.

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

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

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

[0150] Figure 19 is an epifluorescence microscope image of a patch tested according to the method of “Control Experiment”.

[0151] Figure 20 is a graph showing dynamic modulus analysis (DMA) data for a 1 -layer 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 invention comprising one layer with parallel fiber orientation and one layer with random fiber orientation. DETAILED DESCRIPTION

[0154] Example

[0155] SEM images of the patches of the invention were obtained using the following method. Sample Preparation: Take a sample of the patch of the invention and place it in a sample holder, using carbon tape to adhere the sample to the holder. Then place the sample in a gold sputter system, reduce the pressure to 0.05 mPa, and sputter the sample with gold for 20 seconds. Then fill the chamber to ambient pressure and remove the sample. Capture SEM image: Evacuate the SEM chamber to reach ambient pressure. Introduce the sample into the sample stage, and close and evacuate the sample chamber. Apply a current through a tungsten filament in the SEM device (up to 25 μΑ) to heat it. Then take SEM images of all samples using the same conditions: Spot size = 50%, Voltage = 10 kV, Distance = 10 mm, Magnification = 2000x.

[0156] The viscoelasticity of the patches of the invention was measured using a TA Instruments DMA Q-800. The sample (patch) was fixed between clamps and a sinusoidal stress was applied to the sample. All experiments were performed at a frequency of 1 Hz, a pre-tension of 0.03 N and an amplitude of 1.25x pre-tension. The elastic modulus and loss modulus were extracted by measuring the strain / stress at each time point.

[0157] The Young’s modulus of the patches of the invention was measured using a TA Instruments DMA Q-800. Tensile testing was performed in which the sample (patch) was stretched until deformation occurred. The instrument measured the stress experienced by each patch at a particular strain. All experiments were performed at a pre-tension of 0.0010 N, an initial strain of 0.9%, an initial displacement of 10.0 mm and a strain ramp of 5.0% min -1 to 30% min -1 The Young’s modulus of the patches of the invention is provided below.

[0158]

[0159] Table 1: Young’s modulus of the patches of the invention.

[0160] Example 1

[0161] Dissolve 1.20 g of polycaprolactone (PCL) in 10 mL of chloroform to yield a concentration of 12% w / v. Add the PCL granules to the solvent in small portions under stable but not vigorous stirring. Once all the granules are dissolved, the mixture can be used.

[0162] Aspirate the PCL mixture through a syringe with a narrow tip to prevent bubble formation. Place the tip of the syringe upwards inside a fume hood to remove any bubbles present and not to evaporate the solvent.

[0163] Place the syringe on a syringe pump system and advance the mixture at a volumetric flow rate of 2000 μL / h. Place the syringe pump horizontally at a distance of 24.5 centimeters from the collector. Apply a potential of 25 kV between the syringe pump and the collector. Deposit the mixture on the collector for about 1 hour. Then let the patch air dry for about 1 hour.

[0164] Cut out a circular patch of 15.6 mm in diameter from the entire electrospun surface.

[0165] Then expose the surface of the patch to a plasma treatment to increase the hydrophilicity of the nanofibers. Use a low-temperature plasma generator. Ignite pure oxygen at a pressure of 150 Pa and ignite the glow discharge for 3 minutes. The procedure is performed using an open duty cycle and a power of 70 W.

[0166] Immediately after the treatment, place the patch on a 24-well plate containing 100 μL of bioadhesive. In parallel, place 200 μL of fibronectin dissolved in phosphate saline buffer (PBS) at a concentration of 100 μg / mL on the upper surface of the patch. After 5 minutes, remove the patch from the 24-well plate.

[0167] Seed 1 million cells / cm 2 The culture of human aortic endothelial cells seeded on a 6-well plate was injured in its center by a plastic cell scraper. Place the patch on the injured site and press on the surface of the plate.

[0168] Incubate the cells in culture medium for 48 hours. After that, fix the cells using 4% paraformaldehyde for 20 minutes at room temperature. After two consecutive washes with PBS for 10 minutes, permeabilize the cells with 0.2% Triton in PBS for 10 minutes. Then wash the cells twice with PBS for ten minutes each and blot with 5% goat serum in PBS-BSA (PBS, 1% bovine serum albumin) for 1 hour. Label the cells with phalloidin and DAPI for 1 hour. Wash with PBS for two additional 10 minutes to remove all unbound reagents.

[0169] Cells were visualized along the plates and patches using a fluorescent microscope to check for migration. Image analysis software Fiji was used to quantify the cell density of cells that migrated towards the top of the patch.

[0170] Example 2

[0171] The following experiments demonstrate the effect of fiber orientation and / or number of layers on cell migration within the patches of the present invention.

[0172] First, one or two layers of PCL thin sheets were electrospun using the same procedure as Example 1, with the exception of the following conditions: voltage = 18.6 kV, distance from the collector = 18 cm, flow rate = 2000 pL / h, volume = 2 mL. The first layer was made using a collector with a rotation speed of 0 rpm. This layer had a random orientation of fibers. The second layer was made using a collector with a rotation speed of 1000 rpm. This layer had an aligned orientation of fibers.

[0173] The patches were cut to a size of 2 cm x 1 cm using a surgical scalpel blade. Poly(butyl acrylate:acrylic acid)-based glue (100 pL) was sprayed onto each patch from a distance of 15 cm, and then each patch was placed on a 6-well tissue culture plate. The wells were washed 3 times with 2 mL of cell culture medium for 5 minutes. The cell culture medium used was the same as the cell culture medium used for the experiment, including Endothelial Growth Medium-2 Complete (Promocell) with 5% fetal bovine serum and 1% penicillin / streptomycin.

[0174] Each patch was treated with plasma corona for 1 minute, and then 50 pL of 100 pg / mL bovine plasma fibronectin was deposited onto each patch. The patches were then left to sit at 37 °C for 2 hours.

[0175] 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 medium were then seeded onto the plates, and the plates were placed in a 37 °C incubator with 5% CO2.

[0176] After 12 h, the silicone cover was removed from each patch, and the 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 h. The experiment ended after the silicone cover was removed 72 h.

[0177] The tissue culture plates were rinsed with PBS and fixed with 4% paraformaldehyde for 30 minutes at room temperature. After this, the cells were washed twice with PBS for 5 minutes. Any excess aldehyde was quenched with a solution of glycine (0.2 mol / L) in PBS for 10 minutes, then washed twice with PBS for 5 minutes before permeabilising the cells with a solution of X-100 Triton (0.2%) in PBS.

[0178] After two 10 minute washes with PBS, the cells were labelled with phalloidin-rhodamine 1 : 100 and DAPI 1 : 1000 for 1 hour to stain the actin and nuclei of the cells.

[0179] After two 5 minute washes with PBS, the samples were detached from the 6-well plates, placed between two microscope slides in a downwards orientation and then imaged using a Nikon epifluorescence microscope.

[0180] Images were taken at 4x and 10x to quantify the cell colonisation of each patch, as well as to observe the distance travelled by the cells and the cell density, e.g. the number of cells per unit area. Figures 11-18 is an epifluorescence image of a patch of the application.

[0181] The scale of the pixels to distance 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 invaded area and dividing by the size of the area (see, for example, Figure 17 ). The cell velocity was calculated as the distance travelled by the cells (see, for example, Figure 18 ) divided by the experimental time.

[0182] Control experiment

[0183] The control experiment was performed according to the same procedure as described in Example 2, but where each patch was not covered with a silicone cap, such that the patch was fully colonised by human endothelial / smooth muscle cells which could adhere to each patch as in the 6-well tissue culture plate when they were added.

[0184] Thus, the data obtained from these experiments is a control for the “total” patch colonisation over 72 hours. Figure 10 The data obtained from the control experiment with human endothelial and smooth muscle cells is shown (see the “ADH” entry in Table 2).

[0185] The control for the colonisation velocity was not measured, as the patches were “colonised” from the start of the experiment.

[0186] The results demonstrate that when the fibers in the luminal layer are aligned, the endothelial cells exhibit a higher cell density than when the fibers are randomly oriented. Furthermore, when the fibers in the layer are aligned, the migration of the endothelial cells is faster than when the fibers in the layer are randomly oriented.

[0187] When the patch has two layers, the smooth muscle cells exhibit a lower cell density than when it has one layer. Furthermore, when the fibers in the layer are aligned, the smooth muscle cells have a lower cell density than when the fibers in the layer are randomly oriented. Finally, when the fibers in the layer are randomly oriented, the migration of the smooth muscle cells is faster than when the fibers in the layer are aligned. Aligned fibers appear to hinder the progress of the smooth muscle cells through the patch.

[0188] Patch Cells Density (cells / mm2) 2 )]> Speed (pm / 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-A ADH EC 2620±687 2L-A ADH SMC 876±155

[0189] 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 using epifluorescence microscopy. Values are the mean of at least 7 independent samples, shown as the mean ± standard error.

[0190] 1L-R = One layer patch with random fiber orientation.

[0191] 1L-A = One layer patch with parallel (aligned) fiber orientation.

[0192] 2L-R = Two layer patch: near-luminal face has parallel fiber orientation, luminal face has random fiber orientation.

[0193] 2L-A = Two layer patch: near-luminal face has random fiber orientation, luminal face has parallel fiber orientation.

[0194] ADH = Adhesion-positive control

[0195] Figure 8 and 9 Figures illustrating the non-control data shown in Table 2.

[0196] The results demonstrate how the specific structural features of the patch of the present application provide an improved patch with optimized in vivo performance. Thus, the device of the present application 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. In use, i.e. in vivo, the second layer is the near-luminal layer (i.e. the layer in contact with the smooth muscle cells) and the first layer is the luminal layer (i.e. the layer in contact with the blood flow). The alignment of the fibers allows the endothelial cells to flow rapidly through and colonize in the first (luminal) layer, thereby facilitating a faster re-endothelization of the layer in contact with the blood flow. Furthermore, the random orientation of the fibers in the second (near-luminal) layer allows the smooth muscle cells to flow rapidly through and colonize in the second layer.

[0197] However, smooth muscle cells cannot move quickly through the aligned first (luminal) layer (see Figure 9 ), thus the first layer of the present patch effectively provides a barrier to smooth muscle cells, such that they are predominantly present in the second (abluminal) layer.

[0198] Example 3

[0199] The inventors developed an ex vivo test that assesses the resistance of a patch to flow into the aorta. The test utilises a pig descending aorta (1.5 cm in diameter), a compressed air actuated diaphragm pump, PVC tubing, an adherent patch of the invention and water (at room temperature).

[0200] Firstly, a 2-4 mm tear is generated on the aorta using a surgical punch. The aorta is then connected to the PVC tubing using a cable tie. The PVC tubing is connected to the diaphragm pump.

[0201] The compressed air to the diaphragm pump is stabilised at 2 bar g At this pressure, the pump delivers a pulsatile water flow at 6 L / min and 1 Hz, simulating the physiological blood flow to which the aorta is exposed.

[0202] The tear is inspected to ensure that, once the pump is running, a water jet is observed to emanate from the tear. If a water jet is not observed, the pump is stopped and the tear is inspected to ensure that it is sufficiently extended through the aorta. If necessary, the tear is increased and the inspection is repeated until a water jet is observed to emanate from the tear.

[0203] Once the inspection is complete, the diaphragm pump is stopped and an adherent patch according to the claims is manually introduced to cover the tear from the inside of the aorta. The patch is 2 cm x 1 cm in size (as in Example 2). The adhesive comprises a mixture of cyanoacrylate (50 μί), cyanoacrylate (100 μί) and silica particles (4%) and butyl cyanoacrylate (20 μί). Pressure is applied to the patch for 5 seconds to ensure that the patch adheres to the aorta. Once the patch is adhered, the diaphragm pump is turned on again and water flows through the aorta.

[0204] The performance of the patch is assessed visually with the pump running. If the patch detaches from the aorta, the patch will pop out of the system and water will be observed to leak from the tear. If the adhesive keeps the patch adhered to the aorta, no water leakage will be observed. It was found that the patch tested as described above remained adhered to the aorta throughout the experiment and no water leakage was observed.

[0205] The foregoing is a detailed description of the invention to assist those skilled in the art in implementing the invention as 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 stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All publications, patent applications, patents, and other references identified herein are incorporated herein by reference in their entirety.

[0206] Statement

[0207] The invention is further described with reference to the following numbered statements.

[0208] 1. A vascular repair patch comprising a polymer substrate having first and second main surfaces, wherein the substrate comprises at least:

[0209] (i) a first polymer filament layer adjacent to the first main surface, comprising a plurality of polymer filaments wherein the polymer filaments are oriented in parallel; and

[0210] (ii) A second polymer filament layer adjacent to the second main surface, comprising a plurality of polymer filaments, wherein the polymer filaments are randomly oriented.

[0211] 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:

[0212] (a) The one or more extracellular matrix compounds are selected from collagen (especially type I and II collagen), elastin, fibronectin, laminin, VE-cadherin, hyaluronic acid, heparan sulfate, chondroitin sulfate, catarrhalan sulfate, hyaluronic acid, and peptide sequences selected from examples Arg-Gly.-Asp(RGD), Arg-Glu-Asp-Val(REDV), Tyr-Ile-Gly-Ser-Arg(YIGSR); and / or

[0213] (b) The first polymer filament layer comprises one or more extracellular matrix compounds, and the area amount of the extracellular matrix compound is 0.5 μg / cm² based on the surface area of ​​the first master surface of the patch. 2 Up to 100 μg / cm 2 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 2to 20 pg / cm2 2 , more preferably 2 pg / cm2 2 to 10 pg / cm2 2 , more preferably 3 pg / cm2 2 to 7 pg / cm2 2 .

[0214] 3. The vascular repair patch of either of statements 1 or 2, wherein the second polymer filament layer of the polymer base comprises one or more thrombogenic agents, optionally wherein:

[0215] (a) the one or more thrombogenic agents are selected from the group consisting of tissue factor (TF or Factor III), Factor VII, Factor X, and fibrin; and / or

[0216] (b) the second polymer filament layer comprises one or more thrombogenic agents in an area amount of 0.5 pg / cm2 2 to 100 pg / cm2 2 , preferably 1 pg / cm2 2 to 50 pg / cm2 2 , more preferably 1.5 pg / cm2 2 to 20 pg / cm2 2 , more preferably 2 pg / cm2 2 to 15 pg / cm2, more preferably 2.5 pg / cm2 2 to 10 pg / cm2 2 , more preferably 3 pg / cm2 2 to 7 pg / cm2 2 .

[0217] 4. The vascular repair patch of any of the preceding statements, wherein the polymer base 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 the group consisting of 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).

[0218] 5. The vascular repair patch according to statement 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 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.

[0219] 6. The vascular repair patch according to statement 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.

[0220] 7. The vascular repair patch according to any one of the preceding statements, wherein:

[0221] (a) the average filament diameter of the polymer filaments of the first and second polymer filament layers is 1 to 20 pm, more preferably 1 to 15 pm, more preferably 2 to 10 pm, more preferably 3 to 8 pm, more preferably about 5 pm; and / or

[0222] (b) the filament diameter of at least one of the first and second polymer filament layers forms a bimodal distribution, wherein one peak is in the range of 0.2 to 2 pm and the second peak is in the range of 2.5 to 10 pm; and / or

[0223] (c) the polymer filaments of the first and second polymer filament layers are electrospun filaments; and / or

[0224] (d) the filaments of the first polymer filament layer are oriented with a standard deviation of no more than 36°, preferably no more than 18°; and / or

[0225] (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°.

[0226] 8. The vascular repair patch according to any of the preceding statements, wherein the Young’s modulus of the polymeric substrate is 0.5 to 3.0 MPa.

[0227] 9. The vascular repair patch according to any of the preceding statements, wherein the second polymeric 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 pm, more preferably 100 to 250 pm, more preferably 150 to 200 pm.

[0228] 10. The vascular repair patch according to any of the preceding statements, wherein each of the first and second polymeric filament layers independently has a thickness of 10 pm to 200 pm, more preferably 20 pm to 100 pm, more preferably 30 pm to 70 pm, for example about 50 pm.

[0229] 11. The vascular repair patch according to any of the preceding statements, having:

[0230] (a) a total thickness of 20 pm to 500 pm, more preferably 50 pm to 200 pm, more preferably 50 pm to 150 pm, for example about 100 pm; and / or

[0231] (b) a length and width independently of 10 to 50 mm, more preferably 20 to 40 mm.

[0232] 12. The vascular repair patch according to any of the preceding statements, wherein the filaments of the first polymeric filament layer are substantially parallel to the length 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.

[0233] 13. The vascular repair patch according to any of the preceding statements, wherein a coating of a biocompatible adhesive is disposed on the second major surface of the polymeric substrate, optionally wherein the biocompatible adhesive is selected from synthetic adhesives (such as acrylates, cyanoacrylates and polyurethanes) and natural polymers (such as hyaluronic acid, cellulose and alginate).

[0234] 14. The vascular repair patch according to any of the preceding statements, wherein the second surface of the polymeric substrate comprises a physical fixation means adapted to secure the vascular repair patch to a blood vessel wall, optionally wherein the physical fixation means comprises a plurality of microneedles, optionally wherein the plurality of microneedles are formed from a bioabsorbable material.

[0235] 15. A method of manufacturing a vascular repair patch as defined in any of statements 1 to 14, the method comprising:

[0236] (a) providing a polymer 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; (ii) is a second polymer filament layer comprising a plurality of polymer filaments, wherein the polymer filaments are oriented randomly; and optionally, further comprising the steps of:

[0237] (b) applying one or more extracellular matrix compounds to the first major surface of the polymer substrate; and / or

[0238] (c) applying one or more thrombogenic agents to the second major surface of the polymer substrate.

Claims

1. A vascular repair patch comprising a polymeric substrate having first and second major surfaces, wherein the substrate comprises at least: (i) a first layer of polymeric filaments adjacent to the first major surface, comprising a plurality of polymeric filaments, wherein the polymeric filaments are oriented in parallel; and (ii) a second layer of polymeric filaments adjacent to the second major surface, comprising a plurality of polymeric filaments, wherein the polymeric filaments are oriented randomly; wherein the polymeric filaments of the first and second layers of polymeric 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 polymeric filaments of the first and second layers of polymeric filaments is 1 to 20 pm, and wherein the filament diameter of at least one of the first and second layers of polymeric filaments forms a bimodal distribution, with one peak in the range of 0.2 to 2 pm and a second peak in the range of 2.5 to 10 pm; wherein the polymeric filaments of the first layer of polymeric filaments are oriented with a standard deviation of no greater than 18°, and the polymeric filaments of the second layer of polymeric filaments are oriented with a standard deviation of at least 63°; wherein the average porosity of the second layer of polymeric filaments is 40% to 60%; wherein the vascular repair patch has a total thickness of 50 pm to 500 pm, and wherein the second layer of polymeric filaments independently has a thickness of 20 pm to 200 pm; and wherein the polymeric substrate has a Young's modulus of 0.5 to 3.0 MPa, wherein the vascular repair patch is configured such that, in use, the vascular repair patch conforms to the interior of a blood vessel wall.

2. The vascular repair patch of claim 1, wherein the polymeric substrate is bioabsorbable.

3. The vascular repair patch of claim 1 or 2, wherein the polymeric filaments of at least one of the first and second layers of polymeric filaments comprise at least 60 wt% PCL.

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

5. The vascular repair patch of claim 1 or 2, wherein the average filament diameter of the polymeric filaments of the first and second layers of polymeric filaments is 1 to 15 pm.

6. The vascular repair patch of claim 1 or 2, wherein the polymeric filaments of the first and second layers of polymeric filaments are electrospun filaments.

7. The vascular repair patch of claim 1 or 2, wherein the polymeric substrate has a storage modulus of 1.0 to 3.0 MPa.

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

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

10. The vascular repair patch of claim 1 or 2, wherein the second polymer filament layer has an average porosity of 50%.

11. The vascular repair patch of claim 1 or 2, wherein the second polymer filament layer suitably has an average pore size of 50 to 300 pm.

12. 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 pm to 100 pm.

13. The vascular repair patch of claim 1 or 2, having a total thickness of 50 pm to 200 pm.

14. The vascular repair patch of claim 1 or 2, having a length and width independently of 10 to 50 mm.

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

16. The vascular repair patch of claim 15, wherein the length of the patch is at least 20% greater than the width.

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

18. The vascular repair patch of claim 17, wherein the one or more extracellular matrix compounds are selected from the group consisting of collagen, elastin, fibronectin, laminin, VE-cadherin, vitronectin, integrin, heparan sulfate, chondroitin sulfate, catharanthine sulfate, hyaluronic acid, and a peptide sequence selected from the group consisting of Arg-Gly-Asp (RGD), Arg-Glu-Asp-Val (REDV), Tyr-Ile-Gly-Ser-Arg (YIGSR).

19. The vascular repair patch of claim 17, wherein, The first polymer filament layer comprises one or more extracellular matrix compounds in an area amount of 0.5 pg / cm 2 to 100 pg / cm 2 .

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

21. The vascular repair patch of claim 1 or 2, wherein the physical fixation means comprises a plurality of microneedles, wherein the plurality of microneedles are formed from a bioabsorbable material.

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

23. The vascular repair patch of claim 22, wherein the one or more thrombogenic agents are selected from the group consisting of tissue factor, factor VII, factor X, and fibrin.

24. The vascular repair patch of claim 22, wherein, The second polymeric filament layer comprises one or more thrombogenic agents in an area amount of 0.5 pg / cm to 100 pg / cm based on the surface area of the second major surface of the patch 2 to 100 pg / cm 2 .

25. The vascular repair patch of claim 1 or 2, for use in repairing a lesion in a blood vessel wall.

26. 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 against the blood vessel wall.

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

28. The vascular repair patch of claim 1 or 2, provided with indicia to indicate the orientation direction of the parallel oriented filaments.

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

30. Use of a vascular repair patch in the manufacture of a device for a method of treating a vascular defect, wherein the vascular repair patch comprises a polymeric substrate having a first major surface and a second major surface, wherein the substrate comprises at least: (i) a first layer of polymeric filaments adjacent to the first major surface, comprising a plurality of polymeric filaments, wherein the polymeric filaments are oriented in parallel; and (ii) a second layer of polymeric filaments adjacent to the second major surface, comprising a plurality of polymeric filaments, wherein the polymeric filaments are oriented randomly; wherein the polymeric 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 inside of a vessel wall; the method comprising placing the vascular repair patch across the vascular defect such that the vascular repair patch conforms to the inside of a vessel wall; and wherein deploying the vascular repair patch such that the first major surface forms the lumen side of the patch and the second major surface forms the distal lumen side of the patch.

31. The use of claim 30, wherein the vascular repair patch is as defined in any one of claims 1-29.

32. The use of claim 30 or 31, wherein the vascular defect is a tear in a vessel wall.

33. The use of claim 30 or 31, wherein the vascular defect is aortic dissection.

34. The use according to claim 30 or 31, wherein, the vascular repair patch is deployed by an endovascular delivery system.

35. The use according to claim 30 or 31, wherein, the vascular repair patch is deployed by an endovascular delivery system, using a catheter or guide wire to deploy the vascular repair patch.

36. A method of manufacturing a vascular repair patch as defined in any one of claims 1 to 29, 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 layer of polymeric filaments comprising a plurality of polymeric filaments, wherein the polymeric filaments are oriented in parallel; (ii) is a second layer of polymeric filaments comprising a plurality of polymeric filaments, wherein the polymeric filaments are oriented randomly.

37. The method of claim 36, 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.

38. Use of a thrombus forming agent in the form of a vascular repair patch as defined in any one of claims 1 to 29 in the manufacture of a medicament for use in a method of treating a vascular defect, the method comprising placing the thrombus forming agent in the form of a vascular repair patch as defined in any one of claims 1 to 29 across a vascular defect such that the vascular repair patch conforms to the inside of the blood vessel wall; wherein deployment of the vascular repair patch is such that the first major surface forms the lumen side of the patch and the second major surface forms the far-lumen side of the patch.

39. A method of making a vascular repair patch, the method comprising: providing a polymer substrate having first and second major surfaces by electrospinning, the electrospinning comprising dissolving a polymer in a solvent at a concentration of 5% to 15% w / v to form a polymer solution, then placing the polymer solution in a syringe pump and advancing the polymer solution towards a collector at a volumetric flow rate in the range of 500 to 5,000 pL / h, wherein the syringe pump is placed at a distance of 15 to 30 cm from the collector and an electric potential of between 20 to 30 kV is applied between the syringe and the collector; subjecting the polymer substrate to a plasma treatment using oxygen gas or a mixture of oxygen gas and argon gas at a pressure of about 0.15 mbar; and applying one or more extracellular matrix compounds to the first major surface of the polymer substrate and / or applying one or more thrombus forming agents to the second major surface of the polymer substrate, wherein applying one or more extracellular matrix compounds to the first major surface of the polymer substrate is performed by immersing the first major surface of the polymer substrate in an aqueous solution comprising about 100 pg / mL of the one or more extracellular matrix compounds so as to impregnate the first substrate layer with a solution of the one or more extracellular matrix compounds, then drying the impregnated substrate to provide a dispersion of the one or more extracellular matrix compounds in the first substrate layer, applying one or more thrombus forming agents to the second major surface of the polymer substrate is performed by immersing the second major surface of the polymer substrate in an aqueous solution comprising about 100 pg / mL of one or more thrombus forming agents so as to impregnate the second substrate layer with a solution of the one or more thrombus forming agents, then drying the impregnated substrate to provide a dispersion of the one or more thrombus forming agents in the second substrate layer.

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