Vascular stents

Abstract

A vascular stent for placement around the outside of a circulatory anastomosis is disclosed, the vascular stent including a laminate having a biodegradable inner collagen layer and a foraminous outer collagen layer disposed around the biodegradable inner collagen layer. Also disclosed is a method of using the vascular stent in an arteriovenous bypass procedure, and a kit including the vascular stent and instructions for using the vascular stent in an arteriovenous bypass procedure.

Description

[Background technology]

[0001] Neointimal hyperplasia refers to an increase in the number of smooth muscle cells (SMCs) located between the endothelium and the internal elastic lamina of blood vessels. When intimal hyperplasia occurs, de novo thickening of the intimal layer or vessel wall occurs, leading to rapid and progressive narrowing and even occlusion of the vessel (often accompanied by thrombosis). Proliferation of arterial SMCs often occurs when the intima of a vessel is damaged, distorted, or disturbed during surgery. Surgical anastomoses, especially those associated with bypass grafts (anastomosis of a vein or vascular graft to an artery), can commonly result in SMC proliferation and consequent stenosis.

[0002] A significant number of arterial bypass grafts fail, i.e., become occluded within 1-6 months after surgery, although occlusion can occur as long as 2 years after surgery. In these cases, it is often SMC intimal hyperplasia that causes narrowing of the vessel lumen and ultimately total occlusion. SMC intimal hyperplasia occurs most commonly around the more distal (usually venous end) anastomosis and in the "native" vessel wall on the side opposite the anastomosis. SMC intimal hyperplasia can also occur in the proximal arterial anastomosis and in parts of the graft itself.

[0003] Grafts are generally anastomosed to vessels in one of three ways: end-to-end, end-to-side, or side-to-side. Of these techniques, end-to-side and side-to-side are more common than end-to-end.

[0004] International Publication No. WO 2007 / 010295 A1 discloses an external vascular stent having an essentially non-porous outer layer and an inner biodegradable layer, the outer layer being relatively rigid and providing a structural framework, whereas the inner layer degrades relatively quickly.

[0005] When the stent of International Publication No. WO2007 / 010295A1 is placed around the anastomosis, it attracts serous fluid and new microvessels begin to grow, primarily as a result of its internal collagen sponge structure. These microvessels are initially single-walled, thick-walled endothelial cells, but eventually tend to produce large amounts of nitric oxide, which is known to directly inhibit the accumulation of SMCs inside the anastomosis. Therefore, increasing the rate at which microvessels form will decrease SMC accumulation and inhibit neointimal hyperplasia of SMCs, thus increasing the success of vascular bypass grafts. Summary of the Invention [Means for solving the problem]

[0006] According to a first aspect of the present invention there is provided a vascular stent for placement around the outside of a circulatory anastomosis, the vascular stent comprising a laminate having a biodegradable inner collagen (sponge) layer and a perforated outer (dense) collagen (sheet) layer disposed around the biodegradable inner collagen layer.

[0007] When using the prior art stent of International Publication No. WO2007 / 010295A1, the outer collagen layer is so dense that it takes several months to be phagocytosed by macrophage cells circulating in the blood, whereas the inner collagen layer is relatively biodegradable and is ideally phagocytosed within about 1-4 weeks. However, during the first few days (before the inner collagen layer is phagocytosed), the surface area of ​​the inner collagen layer presented to the initial microvessels (and therefore macrophage cells) is relatively small (i.e., only the two ends of the inner collagen layer). Therefore, during the first few days after the surgical placement of the stent, nitric oxide production is limited.

[0008] The use of a porous outer collagen layer in the present invention allows for microvascular ingrowth from the outside of the device, increasing the amount of surface area of ​​the non-porous inner collagen layer that is initially presented to the microvessels and can therefore be readily phagocytosed. This results in enhanced proliferation of nitric oxide producing cells, increasing overall nitric oxide production and improving nitric oxide distribution along the length of the stent. Thus, the porous outer layer reduces SMC accumulation and increases the success rate of arterial bypass grafting compared to the stents of WO2007 / 010295A1.

[0009] Circulatory anastomosis refers to an anastomosis between two blood vessels (e.g., between two veins, between two arteries, between a vein and an artery, or between a blood vessel and a bypass graft, which itself may be of natural or synthetic material). References herein to anastomosis should be understood to refer to circulatory anastomosis.

[0010] By laminated it is meant that the vascular stent is formed with adherent layers (ie, an inner collagen layer and an outer collagen layer).

[0011] Vascular stents may be referred to herein simply as stents, or as external stents or external vascular stents, where the term "external" refers to the stent being placed around the outside (rather than inside) of the blood vessel.

[0012] The inner and / or outer collagen layers may be formed from collagen materials of bovine, porcine, or other natural or artificial origin, and are preferably predominantly collagen type I. The outer collagen layer may be, for example, a collagen membrane of the dermis, pericardium, or peritoneum.

[0013] The outer collagen layer contains a plurality of holes (i.e., through holes or perforations). The holes may be substantially elliptical (e.g., circular) or may have other regular or irregular shapes.

[0014] Preferably, each hole of the plurality of holes has a diameter (ie the distance between opposing sides of the hole) of 0.1 mm to 5.0 mm, more preferably 0.1 mm to 0.5 mm.

[0015] The use of holes of this size allows microvessels, and therefore macrophages, to reach the inner collagen layer while avoiding structural weakness of the outer collagen layer (which acts as a scaffolding element around the anastomosis) and preventing the inner collagen layer from leaking through the holes (during fabrication).

[0016] Preferably, the distance (separation) between adjacent (i.e. nearest) holes is between 1 mm and 10 mm. The holes may be arranged regularly (e.g. in a grid) or irregularly (e.g. with different spacing between pairs of adjacent holes). The hole density is preferably between 1 mm 2 1 to 0.01 per 100 mm 2 The period may be between 1 and 1 piece per prize.

[0017] By using this separation distance (or density), microvascular growth (and therefore nitric oxide production) is evenly distributed along the length of the stent while still maintaining the structural integrity of the outer collagen layer.

[0018] The vascular stent is preferably elongated (i.e., long relative to its width) and may be cut to provide longer and shorter lengths which can then be appropriately positioned around various configurations of vascular anastomoses.

[0019] The profile of the vascular stent may be elliptical (eg, oval or circular) or arcuate in a plane perpendicular to the longitudinal axis of the vascular stent (i.e., the vascular stent may have an elliptical or arcuate cross-section throughout the axial extent of the vascular stent).

[0020] Having an elliptical (circular) profile (i.e., formed as a tube) means that the stent must be implanted through one of the blood vessels during a bypass procedure before the two blood vessels are connected (e.g., during an end-to-end connection).

[0021] The arcuate profile means that the stent can be implanted after the vessel has been ligated, for example by opening the vascular stent (by making a longitudinal cut along the stent) and placing it around the vessel, or by placing the stent on the vessel like a saddle.

[0022] The angle of the arcuate portion may be less than 270°.

[0023] Preferably, the outer collagen layer has a thickness of 0.1 mm to 1.0 mm. This thickness allows the outer collagen layer to be strong enough to support the inner collagen layer and the anastomosis while still being easy to handle and implant. This thickness also helps ensure that the outer layer has an appropriate degradation profile.

[0024] Preferably, the outer collagen layer has a degradation profile such that it is retained for at least 3 months, preferably 3-6 months, after placement in the human or animal body, i.e., the properties (e.g., thickness and material) of the outer collagen layer are selected such that the structural integrity of the outer collagen layer is maintained for at least the first 3 months after placement of the stent in the human or animal body.

[0025] Preferably, the inner collagen layer has a degradation profile such that it is retained for a minimum of 7 days and / or a maximum of 28 days after placement in the human or animal body, i.e., the properties (e.g., thickness and material) of the inner collagen layer are selected such that the structural integrity of the inner collagen layer is maintained during the first 7 days after placement of the stent in the human or animal body, but is completely degraded within 28 days after placement of the stent in the human or animal body.

[0026] One of ordinary skill in the art will recognize that there are many materials and thicknesses that can achieve the desired degradation profile and will select the properties of the inner and outer collagen layers accordingly.

[0027] Preferably, the vascular stent has a length of 55 mm to 65 mm (eg, about 60 mm). The vascular stent may be cut to a shorter length during surgery, if necessary.

[0028] Optionally, the vascular stent may be formed of an elongated portion and a tubular portion protruding from a side of the elongated portion, such that, in use, the tubular portion is positionable around the graft vessel in an end-to-side anastomosis and the elongated portion is positionable around the native vessel in an end-to-side anastomosis. Such vascular stents may be Y- or T-shaped. More disc-shaped ones may be made to cover side-to-side anastomoses.

[0029] The tubular portion is preferably formed from the same inner and outer collagen layers as the elongated portion.

[0030] According to a second aspect of the present invention there is provided a method of using a vascular stent of the first aspect in arteriovenous bypass graft surgery, the procedure optionally including the use of synthetic graft material.

[0031] According to a third aspect of the present invention there is provided a kit comprising a vascular stent of the first aspect and instructions for use of the vascular stent in arteriovenous bypass graft surgery.

[0032] Embodiments of the present invention will now be described in detail with reference to the accompanying drawings. [Brief description of the drawings]

[0033] [Figure 1a] FIG. 1a shows an external stent placed at the end-to-end anastomosis site. [Figure 1b] FIG. 1b shows an external stent placed at the end-to-end anastomosis site. [Figure 2a]FIG. 2a shows a cross-sectional view of the external stent of FIG. 1a. [Figure 2b] FIG. 2b shows a cross-sectional view of the external stent of FIG. 1b. [Figure 3a] FIG. 3a shows the outer layer of the external stent of FIG. 1a or FIG. 1b (not to scale). [Figure 3b] FIG. 3b shows a cross-sectional view of an externally mounted stent of FIG. 1a or FIG. 1b including a perforated outer layer. [Figure 4a] FIG. 4a shows a photograph of the collagen layer (dermis) without perforations. [Figure 4b] FIG. 4b shows an enlarged view of the photograph of FIG. 4b. [Figure 4c] FIG. 4c shows a photograph of the outer layer (dermis) of an external stent with perforations. [Figure 4d] FIG. 4d shows a magnified view of the photograph of FIG. 4c. [Figure 5a] FIG. 5a shows a scale photograph of an example of perforation of the outer collagen layer (dermis). [Figure 5b] FIG. 5b shows a scale photograph of an example of perforation of the outer collagen layer (dermis). [Figure 5c] FIG. 5c shows a scale photograph of an example of perforation of the outer collagen layer (dermis). [Figure 5d] FIG. 5d shows a scale photograph of an example of perforation of the outer collagen layer (dermis). [Figure 5e] FIG. 5e shows a scale photograph of an example of perforation of the outer collagen layer (dermis). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] The present invention provides an improved external vascular stent for supporting vascular junctions (anastomoses). Bypass surgery uses a portion of the patient's own healthy blood vessel (usually a vein) or a synthetic graft to reconnect blood supply when blood flow is restricted (such as due to smooth muscle cell neointimal hyperplasia (SMCNIH) or atherosclerosis). As the reattached vessel heals, it tends to grow excessively with "scar" tissue (SMCNIH) on the inside of the vessel, causing the vessel to constrict at the junction, resulting in reduced blood flow, turbulence, and increased risk of blood clot formation (thrombosis). The external stent device of the present invention inhibits the overgrowth of SMCNIH tissue in the vessel and promotes optimal healing of the joined vessel.

[0035] 1a shows a Y-shaped stent 100 according to the present invention. The stent 100 is placed in an end-to-end configuration around a blood vessel 200 formed of a graft vessel 202 connected to a native vessel 201 at an anastomosis site. The stent 100 has an elongated portion 101 that is placed around the native vessel 101 and a tubular portion 102 that protrudes from the side of the elongated portion 101 and is placed around the graft vessel 202. The stent 100 shown has the tubular portion 102 protruding at an acute angle to the elongated portion 101, although it is possible for the tubular portion 102 to instead protrude at a different angle, such as at a right angle (thereby making the stent T-shaped).

[0036] The illustrated stent 100 also includes slits 103 in the elongated portion 101, such that the elongated portion has an arcuate cross-section when viewed in a plane perpendicular to the longitudinal axis of the elongated portion 101. Although the illustrated stent 100 surrounds a majority of the outer surface of the native vessel 201, the size of the slits 103 (and the resulting angle of the arcuate cross-section) can be varied. For example, the slits can be made much larger such that the elongated portion 101 surrounds only the top half of the native vessel 201, i.e., such that the elongated portion 101 "saddles" the native vessel 101. Due to the arcuate configuration of the elongated portion 101, the stent 100 can be placed around the native vessel 201 without having to cut open the native vessel 101.

[0037] Tubular portion 102 is preferably elliptical (e.g., circular) in cross-section, and graft vessel 202 is preferably passed through tubular portion 102 during the surgical procedure, although tubular portion 102 may alternatively have an arc-shaped cross-section similar to elongated portion 101.

[0038] FIG. 1b shows an alternative tubular stent 100 according to the present invention. In FIG. 1b, the stent is disposed around a blood vessel 200 formed of a graft vessel 202 connected in an end-to-end configuration to a native vessel 201 at an anastomosis site. In this example, the stent 100 includes only an elongated portion 101, and no tubular portion. The stent 100 shown in FIG. 1b does not need to be slit, since the stent 100 can be passed over the native vessel 201 or the graft vessel 202 during the surgical procedure. However, configurations with slits (either pre-cut during device manufacture or cut during use during the procedure) are also envisioned.

[0039] In both Figures 1a and 1b, elongated portion 101 preferably has a length of 55mm to 65mm (e.g. 60mm). In general, once deployed, there should ideally be at least 2cm of overlap in any direction away from the anastomosis line, including over any synthetic grafts used in surgery.

[0040] Figures 2a and 2b show cross-sectional views of the stent 100 shown in Figures 1a and 1b, respectively, Figure 2a is a cross-sectional view taken along section line AA and Figure 2b is a cross-sectional view taken along section line BB.

[0041] As shown in both Figures 2a and 2b, elongated portion 101 has a laminated construction and is formed of an inner collagen layer 104 adhered to a surrounding outer collagen layer 105. Although not shown, tubular portion 102 (if present) generally has the same laminated construction as elongated portion 101.

[0042] The outer collagen layer 105 is relatively stiff and serves as a scaffold to support the anastomosis after surgery, and also as a substrate for application of the inner collagen layer 104 .

[0043] The outer collagen layer 105 is preferably formed from a dermal collagen membrane derived from bovine (certified BSE-free) or porcine, which has been subjected to a virus inactivation treatment. The thickness of the outer collagen layer is preferably 0.1 mm to 1.0 mm.

[0044] In WO 2007 / 010295 A1, the outer layer was essentially non-porous. In contrast, the stent 100 of the present invention features a perforated outer collagen layer 105. As shown in FIG. 3b, only the outer collagen layer 105 is perforated, while the inner collagen layer 104 is not. The use of a perforated outer collagen layer 105 allows for microvascular ingrowth from the outside of the device, increasing the surface area of ​​the inner collagen layer that is initially presented to the microvessels and can therefore be readily phagocytosed. Correspondingly, the inner collagen layer 104 remains non-perforated to maximize the amount of sponge material available for biodegradation. The combination of a perforated outer layer 105 and a non-perforated inner layer 104 ensures that the inner layer 104 biodegrades at a faster rate than the outer layer 105, resulting in a higher success rate of arterial bypass grafting.

[0045] As shown in Figure 3a (not to scale), the perforated outer collagen layer 105 has a plurality of holes 106, preferably having a diameter between 0.1 mm and 5.0 mm. The spacing between adjacent / nearest holes (labeled d in Figure 3) is preferably between 1 mm and 10 mm. The holes 106 may be formed using any suitable process.

[0046] 3b, in one embodiment, the holes 106 extend all the way through the perforated outer layer 105 but do not extend into the non-perforated inner layer 104. The holes 106 may be symmetrically and equidistantly spaced around the circumference of the perforated outer layer as shown, although other arrangements are envisioned.

[0047] Figures 4a and 4b show an exemplary collagen substrate (dermis) without holes, and Figures 4c and 4d show an exemplary collagen substrate (dermis) with holes 106. Further examples of collagen layers with holes suitable for use as the outer collagen layer 105 in the present invention are shown in Figures 5a-5e.

[0048] The outer collagen layer 105 has a degradation profile such that its structure is maintained for a minimum of three months after placement.

[0049] The inner collagen layer 104 is biodegradable (i.e., after placement, it degrades at a faster rate than the outer collagen layer 105) and is disposed within the outer collagen layer 105 such that the inner surface of the outer collagen layer contacts the outer surface of the inner collagen layer. The inner collagen layer 104 has a degradation profile such that the structure is largely retained after placement, ideally for 7 days, and up to 28 days.

[0050] Furthermore, the inner collagen layer 104 has a composition that allows it to adhere well to the outer collagen layer 105 during treatment, and the outer collagen layer 105 has a structure that allows it to adhere well to the inner collagen layer 104 during treatment.

[0051] According to an exemplary embodiment, the collagen material used for the inner collagen layer may be prepared as a suspension in sterile water, which may then be optionally filtered, before being injected into the center of a mold surrounded by the outer collagen layer 105. The resulting stent 100 will have an integral coating of collagen material (inner collagen layer 104) across the elongated portion 101 and the outer collagen layer 105 of the tubular portion 102, ideally with a consistent / uniform thickness and no gaps in the coating.

[0052] Like the outer collagen layer 105, the inner collagen layer 104 is preferably formed from a collagen material of bovine (certified BSE-free) or porcine origin that has preferably been subjected to a viral inactivation treatment.

[0053] The stent 100 of the present invention is a single-use device and is preferably distributed in a sealed, sterile package as part of a kit containing the stent 100 and instructions for use (IFU).

Claims

1. A vascular stent for placement around the outside of a circulatory anastomosis, comprising a laminate having a non-perforated, biodegradable inner collagen layer and a perforated outer collagen layer positioned around the non-perforated, biodegradable inner collagen layer.

2. The vascular stent of claim 1 , wherein the perforated outer collagen layer comprises a plurality of holes.

3. The vascular stent according to claim 2, wherein the diameter of each hole of said plurality of holes is 0.1 mm to 5.0 mm, preferably 0.1 mm to 0.5 mm.

4. The vascular stent according to claim 2 or claim 3, wherein the distance between adjacent holes is 1 mm to 10 mm.

5. 5. The vascular stent of claim 1, wherein the profile of the vascular stent is elliptical or arcuate in a plane perpendicular to the longitudinal axis of the vascular stent.

6. The vascular stent according to any one of claims 1 to 5, wherein the perforated outer collagen layer has a thickness of 0.1 mm to 1.0 mm.

7. 7. The vascular stent of any one of claims 1 to 6, wherein the perforated outer collagen layer has a degradation profile such that it is retained for at least 3 months after placement in the human or animal body.

8. 8. The vascular stent of claim 1, wherein the biodegradable inner collagen layer has a degradation profile such that it is retained for a minimum of 7 days after placement in the human or animal body.

9. 9. The vascular stent according to any one of claims 1 to 8, wherein the biodegradable inner collagen layer has a degradation profile such that it is retained for up to 28 days after placement in the human or animal body.

10. The vascular stent according to any one of claims 1 to 9, wherein said vascular stent has a length of 55 mm to 65 mm.

11. The vascular stent comprises: The elongated part and a tubular portion protruding from a side of the elongated portion; In use, the tubular portion is positionable around a graft vessel in an end-to-side anastomosis and the elongated portion is positionable around a native vessel in the end-to-side anastomosis. A vascular stent according to any one of claims 1 to 10.

12. Use of a vascular stent according to any one of claims 1 to 11 in arteriovenous bypass placement.

13. A vascular stent according to any one of claims 1 to 11; Instructions for use of the vascular stent in an arteriovenous bypass procedure; Kit including:

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