Methods and Devices for Contributing to Improved Stent Graft Fixation and/or Seal

Abstract

The present invention relates to methods and devices to contribute to improved stent graft fixation and/or seal within vessels at treatment sites. More specifically, the present invention relates to methods and devices to contribute to improved stent graft fixation and/or seal within vessels at treatment sites by providing stent grafts and methods of making and using stent grafts with collagen III/thrombin coatings.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent application Ser. No. 10/977,545 filed Oct. 28, 2004 which is incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

The present invention relates to methods and devices to contribute to improved stent graft fixation and/or seal within vessels at treatment sites. More specifically, the present invention relates to methods and devices to contribute to improved stent graft fixation and/or seal within vessels at treatment sites by providing stent grafts and methods of making and using stent grafts with collagen III/thrombin coatings.

BACKGROUND OF THE INVENTION

An aneurysm is a localized dilation of a blood vessel wall usually caused by degeneration of the vessel wall. These weakened sections of vessel walls can burst, causing an estimated 32,000 deaths in the United States each year. Additionally, aneurysm deaths are suspected of being underreported because sudden unexplained deaths, about 450,000 in the United States alone, are often simply misdiagnosed as heart attacks or strokes while many of them may be due to aneurysms.

U.S. surgeons treat approximately 50,000 abdominal aortic aneurysms each year, typically by replacing the abnormal section of vessel with a polymer graft in an open surgical procedure. A less-invasive procedure that has more recently been used is the placement of a stent graft at the aneurysm site. Stent grafts are tubular devices that span the aneurysm site to provide support without replacing a section of the vessel. The stent graft, when placed within a vessel at an aneurysm site, acts as a barrier between blood flow and the weakened wall of a vessel, thereby decreasing pressure on the damaged portion of the vessel. Patients whose multiple medical comorbidities make them excessively high risk for conventional aneurysm repair are candidates for stent grafting.

While stent grafts can represent improvements over previously-used vessel treatment options, there are still risks associated with their use. The most common of these risks is migration of the stent graft due to matrix remodeling and/or hemodynamic forces within the vessel. Stent graft migrations can lead to endoleaks, or leaking of blood into the aneurysm sac between the outer surface of the graft and the inner lumen of the blood vessel which can increase the risk of vessel rupture. Such migrations of stent grafts are especially possible in curved portions of vessels where asymmetrical forces place uneven forces on the stent graft.

Based on the foregoing, one goal of treating aneurysms is to provide stent grafts that do not migrate. To achieve this goal, stent grafts with stainless steel anchoring barbs that engage the vessel wall have been developed. Additionally, endostaples that fix stent grafts more securely to the vessel wall have been developed. While these physical anchoring devices have proven to be effective in some patients, they have not sufficiently ameliorated stent graft migration associated with current treatment methods in all cases.

An additional way to reduce the risk of stent graft migration is to administer to the treatment site, either before, during or relatively soon after implantation, one or more growth factors. The administration of one or more growth factors can be beneficial because, normally, the material of the stent graft does not provide a hospitable environment for cells in the area to grow. As a result, the stent graft rests against the vessel wall and may not be incorporated into the vessel wall. If one or more growth factors are administered immediately before, during or relatively soon after stent graft deployment and implantation, the smooth muscle cells and fibroblasts will be stimulated to proliferate. As these cells proliferate they can grow around the stent graft such that the device becomes physically attached to the vessel wall rather than merely resting against it. This tissue in-growth can help to prevent stent graft migration, although it may not be successful in all circumstances. Therefore, there is still room for improvement in the treatment of aneurysms.

Another approach in the treatment of aneurysms, generally applied to cerebral aneurysms, includes the use of coil embolization. Coils used in this process are generally comprised of platinum and coated with a polymer. They are placed within an aneurysm sac and expected to block blood flow into the aneurysm sac and eventually lead to clot formation, thus shielding the aneurysm sac from the pressure of blood flow. In theory, the more organized clot formation and the more local connective tissue formation that occurs, the more resistant the aneurysm will be to pressure exerted by the general circulation.

Again, while coil embolization has proven beneficial in some patients, it is not successful in all patients. Coil embolization is not always successful because if it fails to sufficiently close off the aneurysm sac from blood flow, a process called “recanalization” occurs. In this process, blood flow moves into the area not completely closed off by clot and connective tissue formation and “reopens” the aneurysm site. Thus, improved aneurysm treatments are still required. The present invention provides methods and devices to further contribute to aneurysm treatment.

SUMMARY OF THE INVENTION

The present invention provides methods and devices to assist in the fixation and/or seal of stent grafts to vessel walls at treatment sites by providing stent grafts with adhesive and/or tissue in-growth promoting coatings. Coatings according to the present invention are created by providing collagen III and thrombin to the surface of stent grafts. The collagen III/thrombin coating can also deliver other bioactive agents including growth factors to promote tissue in-growth at the treatment site. These coatings can contribute to the anchoring of a stent graft to the vessel wall thus contributing to the prevention of stent graft migration. As will be described more fully below, these coatings can also be used to contribute to enhanced adhesion between portions of stent grafts and can also contribute to the maintenance of vessel patency at vessel branches.

Specifically, one embodiment according to the present invention comprises a stent graft comprising a collagen III and thrombin coating wherein the collagen III and thrombin coating covers only a portion of the stent graft and wherein, when implanted at a treatment site, the stent graft has a distal end and a proximal end.

In another embodiment the collagen III and thrombin coating is found at locations selected from the group consisting of at the distal end of the stent graft; at the proximal end of the stent graft; and at the distal end and the proximal end of the stent graft.

In another embodiment the stent graft further comprises an interruption in stent graft material.

In another embodiment the collagen III and thrombin coating is found at a location selected from the group consisting of around the perimeter of the interruption; around the perimeter of the interruption and at the distal end of the stent graft; around the perimeter of the interruption and at the proximal end of the stent graft; around the perimeter of the interruption and at the distal end and the proximal end of the stent graft; at the distal end of the stent graft; at the proximal end of the stent graft; and at the distal end and the proximal end of the stent graft.

In another embodiment the stent graft further comprises a polymer layer between the stent graft and the collagen III and thrombin coating.

In another embodiment the stent graft is a first stent graft in a system further comprising a second stent graft wherein the second stent graft comprises a collagen III and thrombin coating that only covers a portion of the second stent graft and wherein, when implanted at a treatment site, the second stent graft has a distal end and a proximal end and wherein the collagen III and thrombin coating on the second stent graft is found at a location selected from the group consisting of at the distal end of the second stent graft; at the proximal end of the second stent graft; and at the distal end and the proximal end of the second stent graft and wherein, when the stent grafts of the system are implanted at a treatment site, a location of the collagen III and thrombin coating on the first stent graft at least partially overlaps with a location of the collagen III and thrombin coating on the second stent graft.

In another embodiment the stent graft is a first stent graft in a system further comprising a second stent graft wherein the second stent graft comprises a collagen III and thrombin coating that only covers a portion of the second stent graft and wherein, when implanted at a treatment site, the second stent graft has a distal end and a proximal end and wherein the collagen III and thrombin coating on the second stent graft is found at a location selected from the group consisting of around the perimeter of the interruption; around the perimeter of the interruption and at the distal end of the second stent graft; around the perimeter of the interruption and at the proximal end of the second stent graft; around the perimeter of the interruption and at the distal end and the proximal end of the second stent graft; at the distal end of the second stent graft; at the proximal end of the second stent graft; and at the distal end and the proximal end of the second stent graft and wherein, when the stent grafts of the system are implanted at a treatment site, a location of the collagen III and thrombin coating on the first stent graft at least partially overlaps with a location of the collagen III and thrombin coating on the second stent graft.

In another embodiment the stent graft further comprises and releases one or more bioactive agents. In another embodiment the one or more bioactive agents are selected from the group consisting of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), plated-derived epidermal growth factor (PDEGF), basic fibroblast growth factor (BFGF), fibroblast growth factors (FGFs), transforming growth factor-beta (TGF-β), platelet-derived angiogenesis growth factor (PDAF) and autologous platelet gel (APG) including platelet rich plasma (PRP) and platelet poor plasma (PPP).

Embodiments according to the present invention also include methods. In one embodiment according to the methods of the present invention the method comprises providing a stent graft comprising a collagen III and thrombin coating wherein the collagen III and thrombin coating covers only a portion of the stent graft and wherein when implanted at a treatment site the stent graft has a distal end and a proximal end.

In another embodiment of the methods, the collagen III and thrombin coating is found at a location selected from the group consisting of at the distal end of the stent graft; at the proximal end of the stent graft; and at the distal end and the proximal end of the stent graft.

In another embodiment of the methods the stent graft further comprises an interruption in stent graft material.

In another embodiment of the methods the collagen III and thrombin coating is found at a location selected from the group consisting of around the perimeter of the interruption; around the perimeter of the interruption and at the distal end of the stent graft; around the perimeter of the interruption and at the proximal end of the stent graft; around the perimeter of the interruption and at the distal end and the proximal end of the stent graft; at the distal end of the stent graft; at the proximal end of the stent graft; and at the distal end and the proximal end of the stent graft.

In another embodiment of the methods a polymer layer is provided between the stent graft and the collagen III and thrombin coating.

In another embodiment of the methods the stent graft is a first stent graft in a system further comprising a second stent graft wherein the second stent graft comprises a collagen III and thrombin coating that only covers a portion of the second stent graft and wherein, when implanted at a treatment site, the second stent graft has a distal end and a proximal end and wherein the collagen III and thrombin coating on the second stent graft is found at a location selected from the group consisting of at the distal end of the second stent graft; at the proximal end of the second stent graft; and at the distal end and the proximal end of the second stent graft and wherein, when the stent grafts of the system are implanted at a treatment site, a location of the collagen III and thrombin coating on the first stent graft at least partially overlaps with a location of the collagen III and thrombin coating on the second stent graft.

In another embodiment of the methods the stent graft is a first stent graft in a system further comprising a second stent graft wherein the second stent graft comprises a interruption and a collagen III and thrombin coating found at a location selected from the group consisting of around the perimeter of the interruption; around the perimeter of the interruption and at the distal end of the second stent graft; around the perimeter of the interruption and at the proximal end of the second stent graft; around the perimeter of the interruption and at the distal end and the proximal end of the second stent graft; at the distal end of the second stent graft; at the proximal end of the second stent graft; and at the distal end and the proximal end of the second stent graft and wherein, when the stent grafts of the system are implanted at a treatment site, a location of the collagen III and thrombin coating on the first stent graft at least partially overlaps with a location of the collagen III and thrombin coating on the second stent graft.

In another embodiment of the methods the stent graft further comprises and releases one or more bioactive agents. In another embodiment of the methods the one or more bioactive agents are selected from the group consisting of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), plated-derived epidermal growth factor (PDEGF), basic fibroblast growth factor (BFGF), fibroblast growth factors (FGFs), transforming growth factor-beta (TGF-β), platelet-derived angiogenesis growth factor (PDAF) and autologous platelet gel (APG) including platelet rich plasma (PRP) and platelet poor plasma (PPP).

In another embodiment the methods comprise providing a stent graft comprising a collagen III and thrombin coating wherein the collagen III and thrombin coating covers only a portion of the stent graft and wherein, when implanted at a treatment site, the stent graft has a distal end and a proximal end and wherein the collagen III and thrombin coating is found at a location selected from the group consisting of the distal end of the stent graft; the proximal end of the stent graft; and the distal end and the proximal end of the stent graft and positioning the stent graft at a treatment site wherein the collagen III and thrombin coating contributes to the fixation and/or seal of the stent graft to the vessel wall at the treatment site.

In another embodiment the methods comprise providing a stent graft comprising an interruption in stent graft material and a collagen III and thrombin coating wherein the collagen III and thrombin coating covers only a portion of the stent graft and wherein, when implanted at a treatment site, the stent graft has a distal end and a proximal end and wherein the collagen III and thrombin coating is found at a location selected from the group consisting of around the perimeter of the interruption; around the perimeter of the interruption and at the distal end of the stent graft; around the perimeter of the interruption and at the proximal end of the stent graft; around the perimeter of the interruption and at the distal end and the proximal end of the stent graft; and positioning the stent graft at a treatment site wherein the interruption is found at the opening of a vessel branch and the collagen III and thrombin coating contributes to the fixation and/or seal of the stent graft to the vessel wall at the treatment site.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts a schematic diagram of representative stent grafts deployed at a treatment site that can be used to contribute to stent graft fixation and/or seal in accordance with the present invention.

FIG. 2 depicts a schematic diagram of representative stent grafts deployed at a treatment site that can be used to contribute to adhesion between different portions of stent grafts in accordance with the present invention.

FIGS. 3 and 4 depict schematic diagrams of representative stent grafts deployed at treatment sites that can be used to contribute to stent graft fixation and/or seal at vessel branches in accordance with the present invention.

FIG. 5 depicts the distal end of an injection and delivery catheter that can be used in accordance with the present invention.

DEFINITION OF TERMS

Prior to setting forth embodiments according to the present invention, it may be helpful to an understanding thereof to set forth definitions of certain terms that will be used hereinafter. Unless otherwise explained, 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 belongs. The singular terms “a,” “an,” and “the” include plural referents unless context clearly indicates otherwise. Similarly, the word “or” is intended to include “and” unless the context clearly indicates otherwise. The term “comprises” means “includes.”

Aneurysm: As used herein “aneurysm” shall include a weak section of an artery wall in an animal.

Abdominal aortic aneurysm: As used herein “abdominal aortic aneurysm” shall include a weak section of an artery wall in the abdominal section of the aorta of an animal.

Animal: As used herein “animal” shall include mammals, fish, reptiles and birds. Mammals include, but are not limited to, primates, including humans, dogs, cats, goats, sheep, rabbits, pigs, horses and cows.

Drug(s): As used herein “drug” shall include any bioactive compound or composition having a therapeutic effect in an animal. Exemplary, non-limiting examples include small molecules, peptides, proteins, hormones, DNA or RNA fragments, genes, cells, genetically-modified cells, endothelialization factors, matrix metalloproteinase inhibitors and autologous platelet gel.

Stent graft: As used herein “stent graft” shall include a tube comprised of fabric, metal, composite, and/or derivations and combinations of these materials, that reinforces a weakened portion of a vessel (in one instance, an aneurysm).

Endoleak: As used herein “endoleak” refers to the presence of blood flow past the seal between the end of a stent graft and the vessel wall (Type I), and into the aneurysmal sac, when all such flow should be contained within the stent graft's lumen.

Migration: As used herein “migration” refers to displacement of a stent graft from its intended implantation site.

Placed or implanted stent graft: As used herein “placed stent graft” or “implanted stent graft” shall include a surgically placed or implanted stent graft, either by invasive or non-invasive techniques.

Bioactive agents: As used herein, “bioactive agents” include any agent or combination of agents that can promote cell growth and/or adhesion and includes, without limitation, collagen 1, collagen III, thrombin, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), plated-derived epidermal growth factor (PDEGF), fibroblast growth factors (FGFs), transforming growth factor-beta (TGF-β), platelet-derived angiogenesis growth factor (PDAF) and autologous platelet gel (APG) including platelet rich plasma (PRP) and platelet poor plasma (PPP).

Interruption: As used herein, the term “interruption” includes an absence of stent graft material in the wall of a stent graft that allows blood flow into a vessel branch that would otherwise be impeded by the presence of stent graft material at a treatment site. This absence of stent graft material can occur in any shape and wherever necessary along the length of a stent graft to prevent the impedance of blood flow into a vessel branch. An interruption in a mid section of a stent graft is sometimes referred to as a branch opening or window. An interruption at an end of a stent graft is sometimes referred to as a scallop and includes a noticeable change in the geometric end pattern (construction) of the stent graft, i.e., a square (or oblique) ended circular cylinder pattern, that is altered by the absence of stent graft material at a location of a branch vessel, to reduce, if not eliminate, blood flow restriction from the main vessel to that particular branch vessel.

DETAILED DESCRIPTION

Embodiments according to the present invention include methods and devices that are useful in reducing the risk of implantable stent graft migration and/or endoleak. More specifically, methods and devices that promote implantable stent graft attachment to blood vessel luminal walls are provided. One embodiment provides methods and devices useful for minimizing post-implantation stent graft migration following deployment at an aneurysmal treatment site and is also useful in preventing or minimizing post-implantation endoleak following stent-graft deployment at an aneurysmal treatment site. Another embodiment provides methods and devices that can be used to contribute to enhanced adhesion between portions of stent grafts and can also contribute to the maintenance of vessel patency at vessel branches.

As discussed above, an aneurysm is a swelling, or expansion of a vessel lumen at a defined point and is generally associated with a vessel wall defect. Aneurysms are often multi-factorial asymptomatic vessel diseases that if left unchecked can result in spontaneous rupture, often with fatal consequences. One method to treat aneurysms involves a highly invasive surgical procedure where the affected vessel region is removed and replaced with a synthetic graft that is sutured in place. However, this procedure is extremely risky and generally only employed in patients who can be expected to survive the associated surgical trauma. Feeble patients are not candidates for these aneurysmal surgeries, and, before the development of stent grafts, remained untreated and at continued risk for sudden death.

In contrast to the described invasive surgical procedures, stent grafts can be implanted with a cut down procedure or percutaneously using minimally invasive procedures. Essentially, a catheter having a stent graft compressed and fitted into the catheter's distal end is advanced through an artery to the aneurysmal site. The stent graft is then deployed within the vessel lumen juxtaposed to the weakened vessel wall forming an inner liner that insulates the aneurysm from the body's hemodynamic forces thereby reducing the risk of rupture. The size of the stent graft is matched to the treatment site's lumen diameter and aneurysm length. Moreover, branched grafts are commonly used to treat abdominal aortic aneurysms that are located near the iliac branch.

While stent grafts provide a number of benefits, stent graft migration can cause a problem, and tissue in-growth and/or cell adhesion at contact areas between the stent graft and vessel wall have been proposed as methods to reduce this risk. Embodiments according to the present invention provide a mechanism to further stimulate tissue in-growth at the ends of a stent graft and other strategic locations by providing a stent graft with collagen III and thrombin coating on its surface. By providing such collagen III and thrombin coatings, these embodiments also provide mechanisms to contribute to enhanced adhesion between different portions of a stent graft and to contribute to the maintenance of vessel patency at a vessel branch.

Collagen, a major component of the extracellular matrix, is in some forms a fibrous protein that provides tensile strength to tissues. It strengthens blood vessels and plays an important role in tissue development. Collagen can provide a unique ligand for platelets during endothelialization and tissue in-growth due to the fact that it both causes platelet activation and supports adhesion thus leading to platelet aggregate formation.

Collagen exists in several different forms. Collagen I is composed of 2 α1(I) and one α2(I) chains while collagen III is a homotrimeric procollagen comprised of three identical pro-α (III) chains (NCBI Protein Sequence Listing Accession Number PO2461). Collagen III is found co-localized with collagen I in blood vessels, tissues and skin. While collagen I is more abundant than collagen III, collagen III appears first at wound sites and initiates hemostatic processes. Collagen III can also demonstrate superior adhesion strength, larger surface area and higher hemostatic activity than collagen. Thus, collagen III provides an important method to stimulate adhesion and tissue in-growth at implantable medical device implantation sites.

Thrombin is a pluripotent serine protease that also plays a central role in hemostasis following tissue injury by converting soluble plasma fibrinogen into an insoluble fibrin clot and by promoting platelet aggregation (Chambers et al., J. Biol. Chem. 275(45):35584-35591, Nov. 10, 2000). In addition to these procoagulant effects, thrombin also influences a number of cellular responses that play important roles in subsequent inflammatory and tissue repair processes. Thrombin influences the recruitment and trafficking of inflammatory cells and is a potent mitogen for a number of cell types, including endothelial cells, fibroblasts, and smooth muscle cells. Thrombin also promotes the production and secretion of extracellular matrix proteins and influences tissue remodeling processes. There is also increasing in vivo evidence that the pro-inflammatory and profibrotic effects of thrombin play an important role in vascular repair.

Most of the cellular effects elicited by thrombin are mediated via a family of widely expressed G-protein-coupled receptors that are activated by limited proteolytic cleavage of the N-terminal extracellular domain. Once thrombin has interacted with its receptor, it exerts its cellular effects either directly or via the induction and release of secondary mediators, including classical growth factors, pro-inflammatory cytokines, and vasoactive peptides and amines.

Due to these complementary effects of collagen III and thrombin, together they can provide a mechanism to stimulate fixation and/or seal of stent grafts at treatment sites. In one embodiment according to the present invention, a stent graft is provided “pre-loaded” into a delivery catheter. In the embodiment depicted in FIG. 1, the stent graft 100 has a body section 101 and a leg section 108. In an exemplary non-limiting stent graft deployment protocol, the body portion 101 of stent graft 100 is fully deployed through the right iliac artery 114 to an aneurysm site 104 through a first delivery catheter (not shown). The body section 101 of stent graft 100 has a proximal end 102. The leg section 108 of stent graft 100 is deployed in a second delivery catheter (not shown) through the left iliac artery 116 to a secondary aneurysm site 104′. The leg section 108 grafts the secondary aneurysm site 104′ and also anchors the stent graft 100 in the iliac artery. The body section 101 and the leg section 108 of the stent graft 100 are joined with an overlap 106 between the two sections. In the embodiment depicted in FIG. 1, three portions 105 of the stent graft 100 are coated with a collagen III/thrombin coating. This coating can enhance stent graft fixation and/or seal at a treatment site by promoting cell adhesion and tissue in-growth. The collagen III/thrombin coating can be, without limitation, Fibrogen and Zymogenetics' (San Francisco, Calif. and Seattle, Wash. respectively) recombinant collagen III/thrombin products.

As stated, in the embodiment depicted in FIG. 1, stent graft 100 comprises a body section 101 and a leg section 108. In additional embodiments, other stent graft configurations can include, but are not limited to, a body section 101 alone, a tubular stent graft (similar to stent graft 304 depicted in FIG. 3), a stent graft with an interruption (similar to stent graft 302 depicted in FIG. 3) or a plurality of stent grafts or stent graft sections. For the purposes of the present disclosure, when not mentioned in direct relation to a section thereof (i.e. a body section of a stent graft), “stent graft” must be read to encompass any type of whole stent graft and/or sections thereof.

FIG. 2 depicts an alternative embodiment according to the present invention. In this embodiment, the portions of the stent graft body section 101 and leg section 108 that contact each other 120, 110 are coated with a collagen III/thrombin coating. In one embodiment the coating is found on the outer surface of leg section 108 and the inner surface of body section 101. In another embodiment this configuration can be reversed. In further embodiments the coating can be on the inner surface and/or the outer surface of a stent graft or stent graft section. “Inner surface” refers to the portion of a stent graft facing blood flow. “Outer surface” refers to the portion of a stent graft facing a vessel wall.

Using the coatings according to the present invention in the manner depicted in FIG. 2 can contribute to enhanced adhesion between these portions 120, 110 of the stent graft after they are joined at a treatment site. For example, in the embodiment depicted in FIG. 2, portions 120, 110 contribute to enhanced adhesion between themselves and as a result between stent graft sections 101 and 108. In one embodiment, for example, a portion of a stent graft comprising a polymer fiber (such as, without limitation, polyethylene terephthalate can be coated with a polymer which is subsequently overlayed with collagen III/thrombin coating. When polymers are used in embodiments according to the present invention, any suitable biocompatible polymer can be used. Non-limiting examples of such polymers include biodegradable biocompatible polymers including, without limitation, polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polymrethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, chitin, and chitosan and non-biodegradable biocompatible polymers including, without limitation, cellulose acetates (including cellulose diacetate), ethylene vinyl alcohol copolymers, hydrogels (e.g., acrylics), polyacrylonitrile, polyvinylacetate, cellulose acetate butyrate, nitrocellulose, copolymers of urethane/carbonate, copolymers of styrene/maleic acid, and mixtures thereof. The presently described embodiment can enhance adhesion between different portions of stent grafts at an aneurysmal treatment site. This enhanced adhesion creates a more robust seal between these portions of the stent graft thus reducing the likelihood of a break in the seal followed by stent graft migration and endoleak. As shown in FIG. 2, the depicted embodiment also includes collagen III/thrombin coatings 105 at its ends thus further contributing to enhanced stent graft 100 fixation and/or seal.

In addition to contributing to stent graft fixation and/or seal as previously described, stent grafts according to the present invention also can contribute to stent graft fixation and/or seal at vessel branches. For example, when a stent graft that will be implanted at a vessel branch is created, it may be advantageous to have an area of the stent graft material that is cut away or “scalloped” creating an interruption in stent graft material to ensure that blood flow to the branched vessel is not blocked by stent graft material. This interruption, however, can negatively affect the adherence of a stent graft to a vessel wall due in part to lost surface area on the stent graft and also to a break in an otherwise continuous seal between the main vessel and the stent graft. To help compensate for the loss of a continuous seal, in one embodiment according to the present invention, the area around an interruption on a stent graft is coated with a collagen III/thrombin coating. In addition to contributing to stent graft fixation overall, this feature can help to maintain vessel branch patency by reducing the likelihood that the interruption in the stent graft material will migrate away from the opening of the vessel branch.

As depicted in FIG. 3, a stent graft 302 with an interruption 300 is found within an artery. In the embodiment depicted in FIG. 3, the interruption 300 is near the mid section of stent graft 302 and could also be referred to as a branch opening or window. A collagen III/thrombin coating 105 is found on portions of stent graft around the interruption 300. These portions of the coating can contribute to fixation and/or seal around the opening of the vessel branch which can help to maintain vessel patency at this site. Note also that in the depicted embodiment, while not required, additional collagen III/thrombin coatings 105 are found at the ends of each of stent grafts 302 and 304. Thus, in various embodiments according to the present invention collagen III/thrombin coatings can be strategically placed to enhance fixation and/or seal at different portions of the stent graft as needed or desired. FIG. 4 depicts a stent graft 402 with an interruption in stent graft material 400 found at the proximal end 404 of the stent graft 402. This type of interruption 400 appears as a noticeable change in the geometric end pattern (construction) of the stent graft 402 that is altered by the absence of stent graft material to reduce, if not eliminate, blood flow restriction from the main vessel to a vessel branch and is sometimes referred to as a scallop. The stent graft 402 depicted in FIG. 4 also includes a collagen III/thrombin coating 105 found on the distal end 406 and the proximal end 404 of the stent graft 402 as well as around the interruption 400.

In another embodiment according to the present invention, a stent graft comprising a collagen III/thrombin coating is pre-loaded into a delivery catheter such as that depicted in FIG. 5. Other stent graft delivery catheters known to persons skilled in the art are also useful in deploying the stent grafts. Stent graft body section 101 is radially compressed to fill the stent graft chamber 218 in the distal end 202 of delivery catheter 200. In the depicted embodiment, the stent graft chamber is a retractable sheath. In one embodiment, catheter 200 has two injection ports 208 and 210 (and associated lumens) for delivering drugs of choice to the treatment site. In these embodiments, drugs such as, without limitation, growth factors can be injected through either or both of injection ports 208 and 210. In another embodiment, one of the ports 208 or 210 can be an injection (delivery) port and the other can be an exit (drain or evacuation) port. In this embodiment, drugs can be introduced at the treatment site through one port and its associated lumen and displaced blood or other liquids at the treatment site can exit the area through the second port and associated lumen. This feature is especially beneficial at aneurysm treatment sites where increased internal pressure at the treatment site can increase the risk of vessel rupture. Stent graft body section 101 is then deployed to the treatment site as depicted in FIGS. 1, 2 and/or 3. Stent leg section 108, if necessary, is delivered to the treatment site using a second delivery catheter.

Adhesion and tissues in-growth can also be stimulated by inclusion of, without limitation, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). The discussion of these factors is for exemplary purposes only, as those of skill in the art will recognize that numerous other growth factors have the potential to induce cell proliferation. Co-pending U.S. patent application Ser. No. 10/977,545, filed Oct. 28, 2004 which is hereby incorporated by reference for all it contains regarding growth factors, discloses injecting autologous platelet gel (APG) into the aneurysmal sac and/or between an implanted stent graft and the vessel wall to induce cell migration and/or proliferation around the stent graft to prevent stent graft migration and resulting endoleak. The development of genetically-engineered growth factors also is anticipated to yield more potent growth factors. Additionally it may be possible to identify small molecule drugs that can induce cell migration and/or proliferation. Thus, the stent grafts of the present invention can improve tissue in-growth through providing substances that promote inflammatory responses near the ends of the stent graft, and in some embodiments further by providing and releasing one or more bioactive agents at one or more ends or along the length of the stent graft.

The field of medical device coatings is well established and methods for coating stent grafts with drugs, with or without added polymers, are well known to those of skill in the art. Non-limiting examples of coating procedures include spraying, dipping, waterfall application, heat annealing, etc. The amount of coating applied to a stent graft can vary depending upon the desired effect of the compositions contained within the coating. The coating may be applied to the entire stent graft or to a portion of the stent graft. Thus, various drug coatings applied to stent grafts are within the scope of embodiments according to the present invention.

Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification are approximations that may vary depending upon the desired properties sought to be obtained. Notwithstanding that the numerical ranges and parameters are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

The terms “a” and “an” and “the” and similar referents used are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided herein is intended to better illuminate embodiments according to the invention.

Groupings of alternative elements or embodiments according to the invention disclosed herein are not to be construed as limitations. Each group member may be referred to individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

Embodiments of this invention are described herein. Of course, variations on those embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description unless otherwise indicated herein or otherwise clearly contradicted by context.

Furthermore, numerous references have been made to patents and printed publications throughout this specification. Each of the above cited references and printed publications are herein individually incorporated by reference in their entirety.

Claims

1. A stent graft comprising a collagen III and thrombin coating wherein said collagen III and thrombin coating covers only a portion of said stent graft and wherein, when implanted at a treatment site, said stent graft has a distal end and a proximal end.

2. A stent graft according to claim 1, wherein said collagen III and thrombin coating is found at locations selected from the group consisting of at said distal end of said stent graft; at said proximal end of said stent graft; and at said distal end and said proximal end of said stent graft.

3. A stent graft according to claim 1, wherein said stent graft further comprises an interruption in stent graft material.

4. A stent graft according to claim 3, wherein said collagen III and thrombin coating is found at a location selected from the group consisting of around the perimeter of said interruption; around the perimeter of said interruption and at said distal end of said stent graft; around the perimeter of said interruption and at said proximal end of said stent graft; around the perimeter of said interruption and at said distal end and said proximal end of said stent graft; at said distal end of said stent graft; at said proximal end of said stent graft; and at said distal end and said proximal end of said stent graft.

5. A stent graft according to claim 1, further comprising a polymer layer between said stent graft and said collagen III and thrombin coating.

6. A stent graft according to claim 2, wherein said stent graft is part of a system comprising a first stent graft and a second stent graft and wherein said second stent graft comprises a collagen III and thrombin coating that only covers a portion of said second stent graft and wherein when implanted at a treatment site said second stent graft has a distal end and a proximal end and wherein said collagen III and thrombin coating on said second stent graft is found at a location selected from the group consisting of at said distal end of said second stent graft; at said proximal end of said second stent graft; and at said distal end and said proximal end of said second stent graft and wherein, when said stent grafts of said system are implanted at a treatment site, a location of said collagen III and thrombin coating on said stent graft according to claim 2 at least partially overlaps with a location of said collagen III and thrombin coating on said second stent graft.

7. A stent graft according to claim 4, wherein said stent graft is part of a system comprising a first stent graft and a second stent graft and wherein said second stent graft comprises a collagen III and thrombin coating that only covers a portion of said second stent graft and wherein when implanted at a treatment site said second stent graft has a distal end and a proximal end and wherein said collagen III and thrombin coating on said second stent graft is found at a location selected from the group consisting of around the perimeter of said interruption; around the perimeter of said interruption and at said distal end of said second stent graft; around the perimeter of said interruption and at said proximal end of said second stent graft; around the perimeter of said interruption and at said distal end and said proximal end of said second stent graft; at said distal end of said second stent graft; at said proximal end of said second stent graft; and at said distal end and said proximal end of said second stent graft and wherein, when said stent grafts of said system are implanted at a treatment site, a location of said collagen III and thrombin coating on said stent graft according to claim 4 at least partially overlaps with a location of said collagen III and thrombin coating on said second stent graft.

8. A stent graft according to claim 1, wherein said stent graft further comprises and releases one or more bioactive agents.

9. A stent graft according to claim 8, wherein said one or more bioactive agents are selected from the group consisting of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), plated-derived epidermal growth factor (PDEGF), fibroblast growth factors (FGFs), basic fibroblast growth factor (bFGF), transforming growth factor-beta (TGF-β), platelet-derived angiogenesis growth factor (PDAF) and autologous platelet gel (APG) including platelet rich plasma (PRP) and platelet poor plasma (PPP).

10. A method comprising providing a stent graft comprising a collagen III and thrombin coating wherein said collagen III and thrombin coating covers only a portion of said stent graft and wherein when implanted at a treatment site said stent graft has a distal end and a proximal end.

11. A method according to claim 10, wherein said collagen III and thrombin coating is found at a location selected from the group consisting of at said distal end of said stent graft; at said proximal end of said stent graft; and at said distal end and said proximal end of said stent graft.

12. A method according to claim 10, wherein said stent graft further comprises an interruption in stent graft material.

13. A method according to claim 12, wherein said collagen III and thrombin coating is found at a location selected from the group consisting of around the perimeter of said interruption; around the perimeter of said interruption and at said distal end of said stent graft; around the perimeter of said interruption and at said proximal end of said stent graft; around the perimeter of said interruption and at said distal end and said proximal end of said stent graft; at said distal end of said stent graft; at said proximal end of said stent graft; and at said distal end and said proximal end of said stent graft.

14. A method according to claim 10, further comprising a polymer layer between said stent graft and said collagen III and thrombin coating.

15. A method according to claim 11, wherein said stent graft is a first stent graft in a system further comprising a second stent graft wherein said second stent graft comprises a collagen III and thrombin coating that only covers a portion of said second stent graft and wherein when implanted at a treatment site said second stent graft has a distal end and a proximal end and wherein said collagen III and thrombin coating on said second stent graft is found at a location selected from the group consisting of at said distal end of said second stent graft; at said proximal end of said second stent graft; and at said distal end and said proximal end of said second stent graft and wherein, when said stent grafts of said system are implanted at a treatment site, a location of said collagen III and thrombin coating on said first stent graft according at least partially overlaps with a location of said collagen III and thrombin coating on said second stent graft.

16. A method according to claim 13, wherein said stent graft is a first stent graft in a system further comprising a second stent graft wherein said second stent graft comprises an interruption in stent graft material and a collagen III and thrombin coating found at a location selected from the group consisting of around the perimeter of said interruption; around the perimeter of said interruption and at said distal end of said second stent graft; around the perimeter of said interruption and at said proximal end of said second stent graft; around the perimeter of said interruption and at said distal end and said proximal end of said second stent graft; at said distal end of said second stent graft; at said proximal end of said second stent graft; and at said distal end and said proximal end of said second stent graft and wherein, when said stent grafts of said system are implanted at a treatment site, a location of said collagen III and thrombin coating on said first stent graft at least partially overlaps with a location of said collagen III and thrombin coating on said second stent graft.

17. A method according to claim 10, wherein said stent graft further comprises and releases one or more bioactive agents.

18. A method according to claim 10, wherein said one or more bioactive agents are selected from the group consisting of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), plated-derived epidermal growth factor (PDEGF), fibroblast growth factors (FGFs), basic fibroblast growth factor (bFGF), transforming growth factor-beta (TGF-β), platelet-derived angiogenesis growth factor (PDAF) and autologous platelet gel (APG) including platelet rich plasma (PRP) and platelet poor plasma (PPP).

19. A method comprising providing a stent graft comprising a collagen III and thrombin coating wherein said collagen III and thrombin coating covers only a portion of said stent graft and wherein, when implanted at a treatment site, said stent graft has a distal end and a proximal end and wherein said collagen III and thrombin coating is found at a location selected from the group consisting of said distal end of said stent graft; said proximal end of said stent graft; and said distal end and said proximal end of said stent graft and positioning said stent graft at a treatment site wherein said collagen III and thrombin coating contributes to the fixation and/or seal of said stent graft to the vessel wall at said treatment site.

20. A method according to claim 19 wherein said stent graft further comprises an interruption in stent graft material and wherein said collagen III and thrombin coating is found at a location selected from the group consisting of around the perimeter of said interruption; around the perimeter of said interruption and at said distal end of said stent graft; around the perimeter of said interruption and at said proximal end of said stent graft; around the perimeter of said interruption and at said distal end and said proximal end of said stent graft; and positioning said stent graft at a treatment site wherein said interruption is found at the opening of a vessel branch and said collagen III and thrombin coating contributes to the fixation and/or seal of said stent graft to the vessel wall at said treatment site.