CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority to U.S. Provisional Patent Application No. 63/396,552, filed August 9, 2022, and to U.S. Provisional Patent Application No. 63/396,492, filed August 9, 2022, the entire contents of both of which are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

[0002] Surgical stents are known for implantation, for instance into an artery or vein, and may be used in treating a patient to reinforce or repair the vein or artery, as well as to secrete drugs or other active agents. Currently known stents suffer from disadvantages which are addressed by the novel and inventive stent and related methods described herein.

[0003] Additionally, islet cell transplantation is a novel experimental therapeutic procedure for the treatment of type 1 diabetes and chronic pancreatitis. The procedure includes the transplantation of autologous or allogeneic beta cells (pancreatic islet cells) into a host to provide endogenous insulin production. Despite major advances, islet cell transplantation has demonstrated limited success with multicenter cohort studies demonstrating an insulin dependence rate ranging from 25%-50% post-transplantation.

[0004] The major factors described in the role of islet failure include failed engraftment, immunosuppression, and scarce donor supply. Failed engraftments often require alternative islet transplant sites and local therapy to increase vascularization. Among other things, the innovation described herein targets at least failed islet engraftment and may reduce the need for systemic immunosuppression. BRIEF SUMMARY OF THE INVENTION

[0005] In some aspects, the present disclosure provides an implantable vascular device comprising a tubular stent component comprising an internal bore; a graft component disposed at least partially within the internal bore of the tubular stent component, wherein the graft component comprises an outer cylindrical wall made of a semipermeable membrane material and an inner lumen made of a semipermeable membrane material, wherein the semipermeable membrane material has a selected or preselected permeability, and wherein the graft component is configured with a compartment to encapsulate cells between the outer cylindrical wall and the inner lumen, and wherein the inner lumen is configured to permit blood flow longitudinally therethrough; and one or more support members providing a fixed position between the tubular stent component and the graft component, wherein the one or more support members optionally provides a collapsible fixed position. The implantable vascular device may further comprise cells between the outer cylindrical wall and the inner lumen. The cells may be pancreatic, hepatic, renal, gastric, thyroid, adrenal, pituitary, parathyroid, hypothalamus, ovary, or testis cells which may be bovine, porcine, murine, rattus, equine, or human cells. The cells may preferably be pancreatic islet cells. The cells may be derived from stem cells, be genetically engineered cells, autogenic, allogenic, induced pluripotent stem cells, xenograft, or are from universal cell lines, or are a combination thereof. The device may optionally further comprise at least one small molecule supplement which may be embedded into a layer or part of the structure of the device components, such as in a scaffold, for instance a scaffold associated with the cells.

[0006] In some aspects, the present disclosure provides an implantable vascular device comprising a tubular stent component comprising an internal bore; a graft component disposed at least partially within the internal bore of the tubular stent component, wherein the graft component comprises an insulin-generating bioscaffold; and one or more support members providing a fixed position between the tubular stent component and the graft component, wherein the one or more support members optionally provide a collapsible fixed position. The implantable vascular device may further comprise an inner lumen, wherein the inner lumen permits blood flow longitudinally through the insulin-generating bioscaffold. The insulin-generating bioscaffold may comprise decellularized pancreatic tissue or a 2D or 3D printed tissue seeded with transplanted islet cells; at least one of autogenic, allogenic, induced pluripotent stem cells, xenograft, or universal cell lines; or cells, wherein at least a majority of the cells are pancreatic islet cells. The insulin-generating bioscaffold may be vascularized, a hydrogel, or a decellularized tissue.

[0007] In some aspects, the present disclosure provides an implantable vascular device comprising a tubular stent component; a graft component disposed at least partially within the internal bore of the tubular stent component, wherein the graft component comprises an insulin-generating hydrogel, wherein the insulin-generating hydrogel comprises an inner lumen, wherein the inner lumen permits blood flow longitudinally therethrough; and one or more support members providing a fixed position between the tubular stent component and the graft component, wherein the one or more support members optionally provide a collapsible fixed position. The insulingenerating hydrogel may be in the form of a sheet coiled around a longitudinal axis of the tubular stent; may comprise a member selected from the group consisting of growth factors, antithrombotics, anticoagulants, immunosuppressives, and mixtures thereof; and may be porous or microporous. The insulin-generating hydrogel may further comprise a semipermeable membrane material.

[0008] As described herein, the collapsible fixed position may allow the tubular stent component to contract in a radial direction so that the outer diameter of the device is reduced as compared to its fully expanded position. The one or more support members may have a bias providing a radial force in an outward direction on the tubular stent component and supporting an expanded position for the tubular stent component. For instance, the support members may be flexible and attached in a way that they are flexed or provided with hinges or hingelike structures to provide a bias towards an expanded position, but the support members

[0009] The semipermeable membrane material of the implantable vascular devices described herein may comprise regenerated cellulose and/or polyurethane films and/or may be configured with a plurality of pores having a diameter in the range of from about 0.001 pm to about 0.4 pm, wherein the plurality of pores allows for flow of oxygen and/or glucose and/or flow of insulin, and wherein the plurality of pores prevents cells and antibodies from traversing the semipermeable membrane material. The implantable vascular devices described herein may further comprise an immunosuppressive material embedded in the graft component, attached to the graft component, attached to the tubular stent component, or a combination thereof; and/or one or more antithrombotic dispensing components which are optionally in the form of one or more flow lumens disposed between the tubular stent component and the graft component and/or within the graft component.

[0010] The tubular stent component may be coated or embedded with a pharmaceutical composition, and the pharmaceutical composition may be an anticoagulant. The tubular stent component may be self-expanding and may comprise a covering layer, wherein the covering layer comprises polydimethylsiloxane (PDMS), collagen, albumin, fibrin, alginate, graphene, nylon (polyamides), dacron (polyesters), polystyrene, polypropylene, poly(acrylic acids), poly(methacrylic acids), polyvinyl compounds (e.g., polyvinyl chloride, polyvinyl acetate), polycarbonate (PC), poly(alkylene oxides), polyvinylpyrrolidone (PVP), polytetrafluorethylene (PTFE, teflon), thermanox (TPX), polymers of hydroxy acids, such as polylactic acid (PLA), polyglycolic acid (PGA), and polylactic acid-glycolic acid (PLGA), polyorthoesters, polyanhydrides, polyphosphazenes, polyhydroxyalkanoates, or a combination thereof.

[0011] The implantable vascular device may be configured for securement in apposition to an interior blood vessel wall. The implantable vascular device may further comprise a support ring connected to the tubular stent component, the support ring wrapped around an outer surface of a ring-shaped support member, the ring-shaped support member connected to the graft component, and the implantable vascular device may further comprise a ring-shaped rubber seal, wherein the support ring wraps around the outer surface of the ring-shaped rubber seal, wherein the ring-shaped rubber seal is self-sealing after a puncture with a needle, wherein the rubber seal is configured to retain the cells between the outer cylindrical wall and the inner lumen. The implantable vascular device may further comprise a conical receiving member having an attachment end attached to at least one longitudinal end of the implantable vascular device, the conical receiving member having a bore therethrough and a distal end of the conical receiving member having a diameter larger than the attachment end.

[0012] The implantable vascular device may further comprise at least one hook. The inner lumen may comprise an inflow cone. The implantable vascular device may further comprise an internal stent disposed at least partially within the internal bore of the tubular stent component. The implantable vascular device may be bidirectional. [0013] Tn some aspects, the present disclosure provides a method of using an implantable vascular device, wherein the method comprises implanting one or more implantable vascular devices disclosed herein into one or more fixed positions with respect to one or more inner blood vessel walls of a subject. The method may further comprise reseeding the cells after implantation. Reseeding may comprise using a needle to deliver additional cells between the outer cylindrical wall and the inner lumen through the rubber seal. The method may further comprise removing the implantable vascular device from the one or more fixed positions with respect to one or more inner blood vessel walls of the subject, wherein removing the implantable vascular device comprises engaging the implantable vascular device with a catheter comprising a snare; engaging the snare with the at least one hook; and pulling the snare thereby engaging the walls of the catheter with the one or more support members thereby collapsing the stent component.

[0014] The implantable vascular device may be implanted into a vein or artery selected from the group consisting of: the main portal vein of the liver, branches of the main portal vein, the main hepatic vein, hepatic vein branches, splenic vein, mesenteric veins, a peripheral vein, the femoral axillary, brachial veins, brachial vein tributaries, brachial vein branches, superior mesenteric artery, inferior mesenteric artery, splenic artery, celiac artery, superior mesenteric artery branches, inferior mesenteric artery branches, a peripheral artery, a femoral artery, radial artery, ulnar artery, brachial artery, axillary artery, popliteal artery or a branch or tributary thereof. The subject may have type 1 diabetes or type 2 diabetes.

[0015] In some aspects, the present disclosure provides a method of implanting an implantable vascular device described herein in a subject, the method comprising sheathing the implantable vascular device in a delivery device and subsequently unsheathing the implantable vascular device from the delivery device at a desired position with respect to one or more inner blood vessel walls of a subject. The delivery device may implant the implantable vascular device into the main portal vein of the liver or branches of the main portal vein of the liver, including portions of the main portal vein of the liver that are inside of the liver or outside of the liver. Unsheathing the vascular device may allow the tubular stent component to expand.

[0016] The methods may further comprise suturing the implantable vascular device to the one or more inner blood vessel walls. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Non-limiting embodiments of the present invention will be described by way of example with reference to the accompanying figures, which are schematic and are not intended to be drawn to scale. In the figures, each identical or nearly identical component illustrated is typically represented by a single numeral. For purposes of clarity, not every component is labeled in every figure, nor is every component of each embodiment of the invention shown where illustration is not necessary to allow those of ordinary skill in the art to understand the invention.

[0018] FIG. 1 shows a lateral view of an embodiment of this disclosure.

[0019] FIG. 2 shows a top view of an embodiment similar to that of Fig. 1.

[0020] FIG. 3 shows a perspective cross-sectional view of an embodiment similar to that of Fig. 1.

[0021] FIG. 4 shows a perspective view of another embodiment of this disclosure.

[0022] FIG. 5 shows a partial side view of certain features of an embodiment of this disclosure.

[0023] FIG. 6 shows a partial elevated view of an embodiment similar to that of Fig. 5.

[0024] FIG. 7 shows another partial elevated view of an embodiment similar to that of Fig. 5.

[0025] FIG. 8 shows a side view of another embodiment of this disclosure.

[0026] FIG. 9 shows a side view of an embodiment similar to Fig. 8, but in a different position.

[0027] FIG. 10 shows a side view of another embodiment of this disclosure.

[0028] FIG. 11 shows a top view of an embodiment similar to that of Fig. 10.

[0029] FIG. 12 shows a perspective cross-sectional view of an embodiment similar to that of Fig. 10.

[0030] FIG. 13 shows a side view of another embodiment of this disclosure. [0031] FTG. 14 shows a top view of an embodiment similar to that of Fig. 13.

[0032] FIG. 15 shows a perspective cross-sectional view of an embodiment similar to that of Fig. 13.

[0033] FIG. 16 shows a side view of another embodiment of this disclosure.

[0034] FIG. 17 shows a cross-sectional view of certain components in an embodiment similar to that of Fig. 13-15.

[0035] FIG. 18 shows a cross-sectional view of certain components in an embodiment similar to that of Figs. 10-12.

[0036] FIG. 19 shows results from an in vitro circuit glucose perfusion experiment with 40 mM glucose resulting in the production of insulin from an embodiment of a device over a twelve hour period.

[0037] FIG. 20 shows results from an in vitro two-day perfusion Glucose Stimulated Insulin Secretion (GSIS) experiment with high glucose (HG; 28 mM) and low glucose (LG; 2.8 mM) conditions over two days on the same device. All timepoints have been corrected for the reading of the blank wells.

DETAILED DESCRIPTION OF THE INVENTION

[0038] Before the present invention is described in further detail, it is to be understood that the invention is not limited to the particular embodiments described. It is also understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. The scope of the present invention will be limited only by the claims. As used herein, the singular forms "a", "an", and "the" include plural embodiments unless the context clearly dictates otherwise.

[0039] It should be apparent to those skilled in the art that many additional modifications beside those already described are possible without departing from the inventive concepts. In interpreting this disclosure, all terms should be interpreted in the broadest possible manner consistent with the context. Variations of the term "comprising" should be interpreted as referring to elements, components, or steps in a non-exclusive manner, so the referenced elements, components, or steps may be combined with other elements, components, or steps that are not expressly referenced. Embodiments referenced as "comprising" certain elements are also contemplated as "consisting essentially of and "consisting of those elements. When two or more ranges for a particular value are recited, this disclosure contemplates all combinations of the upper and lower bounds of those ranges that are not explicitly recited. For example, recitation of a value of between 1 and 10 or between 2 and 9 also contemplates a value of between 1 and 9 or between 2 and 10. Further, as used herein, ranges that are between two particular values should be understood to expressly include those two particular values. For example, “between 0 and 1” means “from 0 to 1” and expressly includes 0 and 1 and anything falling inside these values. Also, as used herein “about” means ±20% of the stated value, and includes more specifically values of ±10%, ±5%, ±2%, ±1%, and ±0.5% of the stated value. Common usage of the phrase “at least X” is to be understood to refer to a value of X and greater. For example, “at least one” (or “at least 1”) may refer to 1, 2, 3, 4... ad infinitum.

[0040] Type 1 diabetes mellitus (T1DM) is an endocrine disease characterized by elevated blood glucose levels due to autoimmune destruction of insulin producing pancreatic beta cells. Chronic hyperglycemia causes devastating multisystem injury and costed the United States healthcare system an estimated $327 billion in 2018. The majority of T1DM patients rely on exogenous insulin to achieve normoglycemia, which is patient-dependent and morbid treatment paradigm. Islet cell transplantation involves the direct transplantation of islet cells via the portal vein. However, current methods of islet cell transplantation have demonstrated limited success in helping patients achieve long term insulin freedom due to the need for toxic immunosuppression, failed islet cell engraftment from hypoxia, and a shortage of suitable donor cells. Here we propose several embodiments of a novel vascular implant device (interchangeably referred to as a stent graft or stent graft device) and methods of use thereof designed to facilitate cell transplantation. By housing the cells intravascularly within this novel stent graft, this device will address the challenges of vascular engraftment and help to prevent cell injury and death related to ischemia. Several embodiments are detailed hereafter, though, in general and without limitation, the cells will be housed within a semi-permeable cellular chamber that will allow the diffusion of glucose, insulin, oxygen, and cellular waste but be impermeable to large immunoglobulins and immune cells.

[0041] Recently, both xenograft and embryonic stem cell derived islet cells have successfully been transplanted in clinical trials, representing an increase in donor islet supply. We believe that our innovation is well suited to capitalize on these advances as the graft could be seeded with any islet cell lineage.

[0042] At least some of the innovative concepts described herein were the result of the inventors’ aim to utilize cellular macro-encapsulation to immunoisolate islet cells within an endovascular intraportal stent graft. In at least one way to practice some of the innovative concepts, the inventors aimed to graft islet cells that are able to survive, sense glucose, and secrete insulin while housed within a semipermeable membrane with a pore size that prevents diffusion of human leukocytes and large immunoglobulins. In particular, experiments demonstrating successful murine isolated islet function and glucose stimulated insulin secretion (GSIS) across an expanded polytetrafluoroethylene (ePTFE) membrane with a pore size selectively impermeable to mediators of cellular immunity (0.22 micrometer, for example).

[0043] Some embodiments of the present disclosure utilize cellular macro-encapsulation to immunoisolate islet cells within an endovascular intraportal stent graft in which islet cells are able to survive, sense glucose, and secrete insulin while housed within a semipermeable membrane with a pore size that prevents diffusion of human leukocytes and large immunoglobulins, to the work described herein at least reflects determining the optimal membrane for immunoisolation and demonstrating successful murine isolated islet function and glucose stimulated insulin secretion (GSIS) across a selected pore size that at least prevents diffusion of human leukocytes and large immunoglobulins. This inquisition and the related work and experimentation resulted in at least the devices and methods described in the present disclosure.

[0044] Vascular implant devices are provided herein.

[0045] In a first embodiment, shown in FIGs. 1-3, the vascular implant device comprises a tubular stent component 5 comprising an internal bore 10; a graft component 15 disposed at least partially within the internal bore 10 of the tubular stent component 5, wherein the graft component 15 comprises an outer cylindrical wall 20 made of a semipermeable membrane material and an inner lumen 25 made of a semipermeable membrane material, wherein the semipermeable membrane material has a selected permeability, and wherein the graft component 15 is configured to encapsulate cells between the outer cylindrical wall 20 and the inner lumen 25 (this may be referred to as a “cell compartment” or “cell chamber”), and wherein the inner lumen 25 permits blood flow 41 longitudinally therethrough; and one or more support members 30 providing a fixed position between the tubular stent component 5 and the graft component 15, wherein the one or more support members 30 optionally provide a collapsible fixed position, for instance via hinges or the flexibility of the support members 30 themselves. The one or more support members 30 may be referred to as “struts”. The collapsibility of the one or more support members 30 may at least provides the benefit of positioning the graft component 15 centrally in the internal bore 10 as well as enhancing retrievability of the vascular implant device which is described herein. Briefly, when a retrieval device (a catheter 115, for example) engages the vascular implant device, the walls 125 of the catheter 115 engage the one or more support members 30 causing them to compress or collapse and become encompassed (or enveloped) by the catheter 115, as is depicted in FIGS 8 and 9. These benefits may apply to the one or more support members 30 throughout the disclosure. The cell compartment may be enclosed as to encapsulate cells within the compartment while retaining connection to the rest of the device. The cell compartment may comprise a tube for reseeding or other purposes. In some embodiments, the vascular implant device further comprises cells between the outer cylindrical wall 20 and the inner lumen 25. That is, the cells may be encapsulated in the cell chamber or compartment of the vascular implant device. In some embodiments, the cells are pancreatic, hepatic, renal, gastric, thyroid, adrenal, pituitary, parathyroid, hypothalamus, ovary, or testis cells. In some embodiments, the cells are bovine, porcine, murine, rattus, equine, or human. In some embodiments, the cells are pancreatic islet (or “beta”) cells. In some embodiments, the cells are derived from stem cells, are genetically engineered cells, or are a combination thereof. In some embodiments, the cells are autogenic, allogenic, induced pluripotent stem cells, xenograft, or are from universal cell lines, and some embodiments optionally further comprise at least one small molecule supplement. Some embodiments comprise about 100,000 to about 15,000,000 cells, or 500,000 to 10,000,000, or 1,000,000 to 5,000,000 cells. The number of cells may correlate to about 0.5 to about 10 mL of volume of cells. Without being limited to any particular theory, a healthy adult male the number of islet cells is approximately 3-15 million with a total volume of 0.5-2 mL and, in some embodiments, only a quarter of islet cell volume is needed to be free of exogenous insulin. In some embodiments, the vascular implant device further comprises at least one pharmaceutical composition between the outer cylindrical wall 20 and the inner lumen 25, and, in some embodiments, the at least one pharmaceutical composition comprises a prolonged drug release agent.

[0046] In a second embodiment, shown in FIGs. 10-12 the vascular implant device comprises a tubular stent component 5 comprising an internal bore 10; a graft component 15 disposed at least partially within the internal bore 10 of the tubular stent component 5, wherein the graft component 15 comprises an insulin-generating bioscaffold 35; and one or more support members 30 providing a fixed position between the tubular stent component 5 and the graft component 15, wherein the one or more support members 30 optionally provide a collapsible fixed position. In some embodiments, the insulin-generating bioscaffold 35 comprises a semipermeable membrane material. In some embodiments, the vascular implant device further comprises an inner lumen 25, wherein the inner lumen 25 permits blood flow 41 longitudinally through the insulin-generating bioscaffold 35. In some embodiments, the insulin-generating bioscaffold 35 comprises decellularized pancreatic tissue or a 2D- or 3D-printed tissue seeded with transplanted islet cells. Decellularized tissues may refer to natural scaffolds derived from tissues or organs, in which the cellular and nuclear contents are eliminated, but the tridimensional (3D) structure and composition of the extracellular matrix (ECM) are preserved. Such scaffolds retain biological activity, are biocompatible and do not show immune rejection upon allogeneic or xenogeneic transplantation. An increased number of reports suggest that decellularized tissues/organs are promising candidates for clinical applications. A 2D-printed tissue, for example, may be a sheet. In some embodiments, the insulin-generating bioscaffold 35 comprises at least one of autogenic, allogenic, induced pluripotent stem cells, xenograft, or universal cell lines. In some embodiments, the insulingenerating bioscaffold 35 comprises cells, wherein at least a majority of the cells are pancreatic islet cells. In some other embodiments, the cells are pancreatic, hepatic, or renal cells. In some embodiments, the cells are bovine, porcine, murine, rattus, equine, or human. In some embodiments, the cells are pancreatic islet cells. In some embodiments, the cells are derived from stem cells, are genetically engineered cells, or are a combination thereof. In some embodiments, the cells are autogenic, allogenic, induced pluripotent stem cells, xenograft, or are from universal cell lines. In some embodiments, the insulin-generating bioscaffold 35 is vascularized. In some embodiments, for example, one embodiment shown in FIG. 18, the graft component does not comprise an inner lumen, and therefore blood flow 41 must flow through the vascularization 45 of the graft component. Vascularization 45 may comprise a 3D-printed vascular tree inside of the bioscaffold, one method for which is called SWIFT printing or sacrificial ink writing into functional tissues. Methods of providing vascularization 45 may be found in at least Primo and Mata (“3D Patterning within Hydrogels for the Recreation of Functional Biological Environments”, Advanced Functional Materials, February 2021) and Skylar-Scott, et al (“Biomanufacturing of organ-specific tissues with high cellular density and embedded vascular channels”, Science Advances, September 2019), the contents of both of which are incorporated in their entireties herein. Vascularization 45 at least provides small channels weaving through the hydrogel which act as small vessels to carry blood through and throughout the bioscaffold. Vascularization 45 in some embodiments may at least provide imunnoisolation, that is as long as the hydrogel is impermeable to cellular and large protein components of the immune system. In some embodiments, the insulin-generating bioscaffold 35 is a hydrogel. In some embodiments, the insulin-generating bioscaffold 35 is a decellularized tissue. “Generating” as used herein may be used interchangeably with “producing”, “secreting”, and the like. That is “insulin-generating” indicates the element is capable of making insulin in at least some capacity. In general, and without limitation, insulin generation is intended to provide a host (or subject; that is a subject implanted with the device) endogenous insulin production. In some embodiments, the bioscaffold comprises collagen (including collagen subtypes), laminin, the like, or combinations thereof.

[0047] In a third embodiment, shown in FIGs. 13-15 the vascular implant device comprises a tubular stent component 5; a graft component 15 disposed at least partially within the internal bore 10 of the tubular stent component 5, wherein the graft component 15 comprises an insulingenerating hydrogel 40, wherein the insulin-generating hydrogel 40 comprises an inner lumen 25, wherein the inner lumen 25 permits blood flow 41 longitudinally therethrough; and one or more support members 30 providing a fixed position between the tubular stent component 5 and the graft component 15, wherein the one or more support members 30 optionally provide a collapsible fixed position. In some embodiments, the insulin-generating hydrogel 40 is in the form of a sheet coiled around a longitudinal axis of the tubular stent. In some embodiments, support ring 50s described herein are placed around the outer diameter of the hydrogel to prevent it from unrolling. In some embodiments, the hydrogel comprises spacers 130 (that is, a material intended to create space between layers due mostly to its volume) between layers of hydrogel. The spacers 130 at least allow blood to flow between the hydrogel layers thus increasing surface area for diffusion. Tn some embodiments, the insulin-generating hydrogel 40 comprises growth factors, antithrombotics, anticoagulants, immunosuppressive agents, or combinations thereof. Examples of immunosuppressive agents include, but are not limited to, immunosuppressive agents such as tacrolimus, everolimus, or sirolimus. In some embodiments, the insulin-generating hydrogel 40 is porous or microporous. In some embodiments, the insulin-generating hydrogel 40 further comprises a semipermeable membrane material.

[0048] One aspect of the current disclosure features a smaller diameter within the inner lumen 25 of the graft component 15 of the device and centrally placed as the flow velocity is highest in the center of the vessel. Conversely, blood flow 41 is slowest along the vessel wall due to friction of the fluid with vessel wall (faster flow in the center), thus placing the inner component walls 125 too peripherally increases the risk of thrombosis by disrupting the slower flow near the periphery of the vessel where flow is already slowed and disrupted. In some embodiments, the device centers the inner component so that it is only disrupting the fastest moving blood at the center of the vessel to minimize thrombosis due to flow disrupt! on/stagnati on. At the time of this filing and to the best of the Applicant’s knowledge, there are currently no dual lumen stents or stent grafts (covered stents) that utilize an outer and inner component to create two distinct flow lumens through the stent. The graft component 15 may be described as tubular or referred to as a “graft tube” due to certain embodiments’ shape.

[0049] In some embodiments, the graft component 15 comprises non-biologically active means of composition release. The composition may be a pharmaceutical composition and/or pharmaceutical agent. The composition may be embedded into the device. Examples of compositions include, but are not limited to, biologic agents, immunotherapeutic agents, slow- release drugs (for applications such as anti-arrhythmic medications, anti-epileptic drugs, metabolic medications, and the like). This embodiment particularly favors any composition (such as a drug or medication) that would benefit from slow and/or extended release.

[0050] It is important to note that the embodiments described herein are not limited to the use of islet cells — nor limited to other cell types — or active ingredients. For example, small molecule pharmaceuticals or larger biologies such as proteins, or combinations of the foregoing, including with or without islet cells, may be provided in the device, and said embodiments may be utilized in the methods described herein. Such pharmaceuticals, biologies, and other agents may be provided on or embedded in a scaffold, coating or layer, for instance inside the cell compartment and in contact with the cells, or adjacent to the cell compartment, hydrogel 40, or graft component 15

[0051] In some embodiments, the vascular implant device further comprises at least one small molecule supplement, and, in some embodiments, the at least one small molecule supplement is bound, fixed, and/or embedded into the vascular implant device. It is understood that “at least one small molecule” does not refer to a singular molecular unit but rather at least one species or type of small molecule. The at least one small molecule supplement may include, but is not limited to, wnt agonists, egf, noggin, r-spondin, valproic acid, the like, and combinations thereof. In some embodiments, the at least one small molecule supplement is/are added to the vascular transplant device with the cells and/or bioscaffold. “Small molecule supplement” is at least intended to refer to small molecules added to the device to support the seeded cells and/or bioscaffold. In some instances, the small molecule supplement may be referred to as a “small molecule cocktail” or “support milieu”. In particular, stem cell lines may preferably require a support milieu, however, even islet cells may need a support system beyond a scaffold. In embodiments such that the cell compartment comprises small molecules, the device may comprise a scaffold for small molecule support and/or a restrictive layer to ensure the small molecule supplement does not leak.

[0052] In some embodiments, the semipermeable membrane material comprises regenerated cellulose and/or polyurethane films. In some embodiments, the semipermeable membrane material is configured with a plurality of pores having a diameter in the range of from about 0.001 pm to about 0.4 pm, wherein the plurality of pores allows for flow of oxygen and/or glucose and/or flow of insulin, and wherein the plurality of pores prevents cells and antibodies from traversing the semipermeable membrane material. In some embodiments, the semipermeable membrane material has a pre-selected permeability. Pre-selection of permeability may be made using any number of various factors including, but not limited to, pore size, surface area, membrane material, and permissible size. In some embodiments, the semipermeable membrane material is connected directly to support rings 50 described herein or directly to the stent component. In some embodiments, the pore size of the semipermeable membrane material is sufficiently small to permit the diffusion across the semipermeable membrane material of only oxygen, glucose, hormones, and cellular waste. In some embodiments, the pore size is sufficiently small to permit the diffusion across the semipermeable membrane material of compositions smaller than about 50 kDa, for one example. Tn general, and without limitation to any particular embodiments, the semipermeable membrane or material allows for the free exchange of glucose, insulin, and/or cellular waste but is impermeable to the cellular elements and large proteins of the human immune system. In general, and without limitation, the graft component 15 may be described as “immunoisolated” due to some embodiments’ properties of protecting the graft component 15 and, in particular, any insulin-generating compositions (including cells or tissue or tissues) from a subject’s immune system. At least one benefit of this aspect is the reduction of the need for systemic immunosuppression in a subject implanted with the device.

[0053] In some embodiments, the tubular stent component 5 comprises a material selected from the group comprising a metal, a polymer, a composite, a ceramic, or a combination thereof.

[0054] In some embodiments, the vascular implant device further comprises an immunosuppressive material embedded in the graft component 15, attached to the graft component 15, attached to the tubular stent component 5, or a combination thereof. In some embodiments, the immunosuppressive material is an immunosuppressive drug, and, in some embodiments, the immunosuppressive drug is Sirolimus. In some embodiments, the tubular stent component 5 is coated or embedded with a pharmaceutical composition. The pharmaceutical composition or compositions described herein may include, but is/are not limited to, anticoagulants, antithrombotics, statins, beta blockers, angiotensins, ACE inhibitors, anti-arrythmics, antiplatelets, nitrates, diuretics, anti-resorptive medications for osteoporosis, anti-epileptic and anti- convulsive medications, cholinesterase inhibitors which may be useful for the treatment of dementia and neurocognitive disorders or other conditions, and calcium-channel blockers. In some embodiments, the graft component 15 comprises a pharmaceutical composition. In some embodiments, the tubular stent component 5 is self-expanding. As described elsewhere in this disclosure, self-expansion is at least beneficial in that it provides stable positional support in everchanging vessels. In some embodiments, the tubular stent component 5 is rigid, and, in some embodiments, the graft component 15 is rigid. In some embodiments, the tubular stent component 5 comprises a covering layer, wherein the covering layer comprises polydimethylsiloxane (PDMS), collagen, albumin, fibrin, alginate, graphene, nylon (polyamides), dacron (polyesters), polystyrene, polypropylene, poly(acrylic acids), poly(methacrylic acids), polyvinyl compounds (e.g., polyvinyl chloride, polyvinyl acetate), polycarbonate (PC), poly(alkylene oxides), polyvinylpyrrolidone (PVP), polytetrafluorethylene (PTFE, teflon), thermanox (TPX), polymers of hydroxy acids, such as polylactic acid (PLA), polyglycolic acid (PGA), and polylactic acid- glycolic acid (PLGA), polyorthoesters, polyanhydrides, polyphosphazenes, polyhydroxyalkanoates, or a combination thereof.

[0055] In some embodiments, the tubular stent component 5 is self-expanding and/or is constructed in a way that allows the tubular stent component 5 to have a bias towards an expanded disposition (or arrangement) but is such that the diameter of the tubular stent component may be compressed into a smaller diameter, for example by application of a mechanical force, for example by the methods described elsewhere in the present disclosure. The bias towards the larger diameter allows for self-expansion and may also allow the stent to apply outward radial force to the vessel wall. This is beneficial in the event of varying vessel diameter or pressure. For example, if the vessel swells or changes diameter. Veins are known to change in diameter based on volume in the vessel. In some embodiments, the tubular stent component comprises a wire frame or chain link configuration. One example of the means by which the tubular stent component is self-expanding may be found in U.S. Patent 7,300,456 the entire disclosure of which is incorporated herein by reference thereto. Comparatively, some embodiments of the present disclosure comprise one or more support members wherein the one or more support members are flexible or are attached in way that an outer stent portion may be compressed to a smaller cylindrical radius. The one or more support members may provide or assist in providing the bias to an expanded position. This difference at least provides a mechanism by which the stent may be retrieved from a subject that is previously undisclosed . In some embodiments, the one or more support members may comprise hinges, for example, providing collapsibility, and, in some embodiments, the hinges are connected to one or both or the support ring and/or the tubular stent component.

[0056] In some embodiments, the vascular implant device further comprises one or more antithrombotic dispensing components which are optionally in the form of one or more flow lumens disposed between the tubular stent component 5 and the graft component 15 and/or within the graft component 15.

[0057] In some embodiments, the vascular implant device is configured for securement in apposition to an interior blood vessel wall (including at least arteries and veins). That is, the device may be configured to be longer or shorter to achieve adequate apposition to the vessel wall to prevent migration of the device within the vessel. [0058] Tn some embodiments, the tubular stent component 5 is connected to the graft component 15 with stops, tabs, clasps, friction hold, or combinations thereof.

[0059] In some embodiments, the vascular implant device further comprises a support ring 50 connected to the tubular stent component 5, the support ring 50 wrapped around an outer surface of a ring-shaped support member, the ring-shaped support member connected to the graft component 15. In some embodiments, the support ring 50 connects to the one or more support members 30 by a connecting feature selected from the group comprising crimping 52 the one or more support members 30 to the support ring 50, coiling 51 an extension of the one or more support member around the support ring 50, and embedding the one or more support members to the support ring 50. In some embodiments, wherein the support ring 50 is made of rubber. Alternatives for rubber may include, but is not limited to, silicone, nitrile, vinyl, and neoprene.

[0060] In some embodiments, the vascular implant device comprises a ring-shaped rubber seal 55, wherein the support ring 50 wraps around the outer surface of the ring-shaped rubber seal 55, wherein the ring-shaped rubber seal 55 is self-sealing after a puncture with a needle 60, wherein the rubber seal is configured to retain the cells between the outer cylindrical wall 20 and the inner lumen 25.

[0061] In some embodiments, for instance as shown in FIG 4, the vascular implant device further comprises a conical receiving member 65 having an attachment end attached to at least one longitudinal end of the vascular implant device, the conical receiving member 65 having a bore 80 therethrough and a distal end of the conical receiving member 65 having a diameter larger than the attachment end.

[0062] Referring to FIGs 4-9, in some embodiments, the vascular implant device further comprises at least one hook 90, preferably attached at one or both longitudinal ends of the device. The hook 90 may alternatively or additionally be a loop, snare 120, or the like. The hook 90 is intended to at least act to provide retrievability of the device from with a vessel. However, the hook 90 may provide mobility, dexterity, security, and/or additional benefits to the device not described herein. [0063] In some embodiments, the length of the vascular implant device is between about 10 mm and about 1000 mm, or about 50 mm to about 800 mm, or about 100 mm to about 500 mm. In some embodiments, the outer diameter of the vascular implant device is between about 2 mm and about 40 mm, or about 5 mm to about 30 mm, or about 10 mm to about 20 mm. The diameter of the tubular stent component 5 is sensitive to size because it supports deployment in vasculature. The length of the tubular stent component 5 has been minimized to prevent unnecessary coverage of side branches of veins. However, length of the tubular stent component 5 must remain long enough to maintain apposition with the vessel wall and prevent the device from migrating. Additionally, length minimization is an important consideration because an exceedingly long outer stent may make the vessel exceedingly stiff which could cause kinking of the vessel or erosion of the vessel wall. In some embodiments, the length of the tubular stent component 5 may be between about 5 mm to about 10 cm depending on the patient’s anatomy.

[0064] In some embodiments, the inner lumen 25 comprises an inflow cone 105. The inflow cone 105 at least provides the benefit of capturing blood and/or directing the blood into orifices of a vascular tree or vascularization.

[0065] In some embodiments, the vascular implant device further comprises an internal stent 106, which may be disposed at least partially within the internal bore 10 of the tubular stent component 5. One embodiment of the internal stent is shown in FIG. 16.

[0066] In some embodiments, the vascular implant device is bidirectional. Herein, “bidirectional” as it pertains to the configuration of the vascular implant device refers to the bilateral nature of the device. That is, in some embodiments, the device comprises elements that are configured on one end or side of the device, as shown in FIGs. 4, 8, and 9. However, it is possible that the device is configured to comprise elements that are configured on both ends or sides of the device. That is, the device would be configured to be capable of implantation into a vessel in either direction while retaining functionality. Exemplary bidirectional embodiments are shown, without limitation, in FIGs. 1, 3, 10, 12, 13, 15, and 16.

[0067] Methods of using the various embodiments of the vascular implant device described herein are provided. In some embodiments, the method comprises implanting one or more vascular implant devices into one or more fixed positions with respect to one or more inner blood vessel walls 125 of a subject. The subject may be from any number of species including, but not limited to, those commonly referred to as humans, monkeys, dogs, cats, cows, pigs, and sheep. Some embodiments of the method may utilize technologies presently available. One preferred system for delivering the vascular implant devices described herein may be those described in U.S. Patent 11,311,397, the entire contents of which are hereby incorporated by reference.

[0068] In some embodiments, the method further comprises reseeding the cells and/or reloading a pharmaceutical composition after implantation, and, in some embodiments, reseeding and/or reloading comprises using a needle 60 to deliver additional cells and/or pharmaceutical composition between the outer cylindrical wall 20 and the inner lumen 25 through the rubber seal. A device that may be utilized in this method is described in US2010/0217117, the entire contents of which are incorporated herein by reference.

[0069] In some embodiments, the method further comprises removing the vascular implant device. “Remove” and “retrieve” may alternatively be used herein. Retrieval of the device may be performed using a catheter 115-based delivery system which would remove both components much like an IVC filter is retrieved. In some embodiments, the device comprises a phalange with hook for docking of a reseeding apparatus and engagement of retrieval catheter 115s. IVC filters are known in the art and may be used herein, one of which is described in U.S. Patent 7,534,251, the entire contents of which are hereby incorporated by reference. Exemplary embodiments of reseeding the device are shown, without limitation, in FIGs. 5-7. In some embodiments, removing the vascular implant device comprises engaging the vascular implant device with a catheter 115 comprising a snare 120; engaging the snare 120 with the at least one hook 90; and pulling the snare 120 thereby engaging the walls 125 of the catheter 115 with the one or more support members 30 thereby collapsing the stent component. Pulling the snare 120 is just one exemplary means by which the snare 120 engages the hook 90, activating pressure on the walls 125 of the catheter 115; other means of engagement may be considered. Exemplary embodiments of device removal are shown, without limitation, in FIGs. 8 and 9. In some embodiments, the vascular implant device is implanted and removed in a direction opposite the direction the vascular implant device was implanted.

[0070] In some embodiments of the method, the vascular implant device is implanted into vein or artery selected from the group consisting of: the main portal vein of the liver, branches of the main portal vein of the liver, the main hepatic vein, hepatic vein branches, splenic vein, mesenteric veins, a peripheral vein, the femoral axillary, brachial veins, brachial vein tributaries, brachial vein branches, splenic artery, celiac artery, superior mesenteric artery, superior mesenteric artery branches, inferior mesenteric artery, inferior mesenteric artery branches, a peripheral artery, a femoral artery, radial artery, ulnar artery, brachial artery, axillary artery, popliteal artery or a branch or tributary thereof. In some embodiments, the vascular implant device is implanted in a fashion selected from percutaneous endovascular, transvenous transhepatic, transjugular, transarterial, transvenous trans-splenic access, and combinations thereof In some embodiments, the vascular implant device is implanted in the hepatic portal vein through hepatic parenchyma, hepatic tract dilation, an intraportal stent, or a hepatic venous stent. In some embodiments, the vascular implant device is implanted with a microneedle. Microneedles (MNs) have been studied for their suitability in increasing endovascular drug delivery, a study of which can be found in Lee, et al (“Microneedle drug eluting balloon for enhanced drug delivery to vascular tissue”, Journal of Controlled Release, May 2020), and their use in delivering stents and drug eluting balloons; their utility in present disclosure should be considered.

[0071] In some embodiments of the method, the subject has a pancreatic disease and/or a metabolic disease. In some embodiments, the subject has diabetes and/or chronic pancreatitis, and, in some embodiments, the subject has type 1 diabetes, and, in some embodiments, the subject has type 2 diabetes. The immuno-isolating feature of the devices described herein may expand islet transplant to the insulin-dependent type 2 diabetes mellitus (T2DM) population. Islet transplantation is currently not performed in T2DM because the limited success of islet transplant may not justify the cost of immunosuppressive therapy for these patients. In some embodiments, the method further comprises treating the subject with a treatment for a pancreatic disease and/or a metabolic disease or syndrome, and, in some embodiments, the method further comprises treating the subject with insulin. In some embodiments, the method further comprises treating the subject with at least one pharmaceutical composition, and, in some embodiments, the at least one pharmaceutical composition is an anticoagulant, antithrombotic, immunosuppressive, or a combination thereof.

[0072] In some embodiments, the method comprises implanting two or more vascular implant devices into two or more fixed positions with respect to two or more inner blood vessel walls 125 of the subject.

[0073] Methods of implanting one or more of the various vascular implant devices described herein are provided. In some embodiments, the method comprises sheathing the vascular implant device in a delivery device and subsequently unsheathing the vascular implant device from the delivery device at a desired position with respect to one or more inner blood vessel walls 125 of a subject.

[0074] In some embodiments, the delivery device implants the vascular implant device into the main portal vein of the liver or branches of the main portal vein of the liver, including portions of the main portal vein of the liver that are inside of the liver, as well as portions of the main portal vein of the liver that are outside of the liver. Tn some embodiments, the delivery device implants the vascular implant device percutaneous endovascularly, transvenous transhepatically, transjugularly, transarterially, or by transvenous trans-splenic access. In some embodiments, the delivery device implants the vascular implant device in the hepatic portal vein through hepatic parenchyma, hepatic tract dilation, an intraportal stent, or a hepatic venous stent. In some embodiments, the delivery device comprises a radioopaque marker. A radioopaque marker allows for a practitioner to confirm the position of the delivery device while in vivo. In some embodiments, the delivery device is a catheter 115. In some embodiments, the delivery device implants the implantable vascular transplantation device with a microneedle.

[0075] In some embodiments, the method of implanting one or more of the various vascular implant devices further comprises suturing the implantable vascular transplantation device to the one or more inner blood vessel walls 125.

[0076] In some embodiments, unsheathing the vascular transplantation device allows the tubular stent component 5 to expand. As discussed throughout the present disclosure, the self-expansion feature of the vascular implant devices described herein provides numerous benefits, at least including varying positional support for the vascular implant device in a vessel.

[0077] No admission is made that any reference, including any non-patent or patent document cited in this specification, constitutes prior art. In particular, it will be understood that, unless otherwise stated, reference to any document herein does not constitute an admission that any of these documents forms part of the common general knowledge in the art in the United States or in any other country. Any discussion of the references states what their authors assert, and the applicant reserves the right to challenge the accuracy and pertinence of any of the documents cited herein. All references cited herein are fully incorporated by reference, unless explicitly indicated otherwise. The present disclosure shall control in the event there are any disparities between any definitions and/or description found in the cited references.

[0078] The following examples are meant only to be illustrative and are not meant as limitations on the scope of the invention or of the appended claims. EXAMPLES

Example 1: Determination of insulin production in stent graft prototype using a closed perfusion system

[0079] Problem

[0080] Diabetes is a multisystem endocrine disorder characterized by elevated blood glucose levels impacting multiple organ systems. Diabetes mellitus occurs as a result of either a lack of insulin due to autoimmune destruction of insulin producing pancreatic beta cells in type 1 diabetes (T1DM) or as resistance to chronically elevated insulin levels in type 2 diabetes (T2DM). ^{4, 6} Chronic hyperglycemia caused by poorly controlled diabetes can often result in devastating multisystem injury; including renal failure, blindness, painful neuropathy, impaired wound healing, limb loss, and life-threatening infections. ⁵ Exogenous insulin therapy is the mainstay of treatment for both T1DM and T2DM, but exogenous insulin therapy involves frequent blood glucose checks, self-administered insulin injections, and dependence on patient adherence. ^1,2 Pancreatic transplantation of human islet cells has been performed to restore endogenous insulin production, but there has been limited success in the primary goal of achieving long term freedom from exogenous insulin after transplantation. Major challenges related to pancreatic transplantation include ensuring successful immunosuppression to prevent graft rejection, islet attrition related to vascular engraftment, and a limited availability of donor islet cells suitable for transplantation. ^7,8 In clinical practice, islet transplantation is mostly performed in academic transplant centers in a select group of T1DM patients.

[0081] The current method of islet cell transplantation involves intravascular injection of islet clusters through the portal vein into the hepatic parenchymal bed. These islet emboli are known to result in islet ischemia, which is a major contributor to early graft failure.1 Approximately 60% of transplanted cells die within 3 days of transplantation. ² In addition to physiologic stress and hypoxia, islet cells are targeted by the immune system for destruction. Significant immunosuppression is needed to avoid rejection, but many immunosuppressive medications are also intrinsically toxic to islet cells. ² Despite advances in immunotherapy, the need for immunosuppression remains a barrier to more widespread use of islet cell transplantation. [0082] Significant efforts have been made investigating the immuno-isolation of islets cells with microencapsulation and microencapsulation devices to evade host immune defenses and eliminate the need for immunosuppression. Immunoisolation through cellular microencapsulation was first described by Chang in the 1960s, ^2,3 and immunoisolation ofislet cells was first described by Chick, et. al., in the 1970s. ⁴ In the 1990’s, Monaco developed a vascular arteriovenous shunt with a semipermeable hollow fiber membrane which was designed to be anastomosed to the iliac vasculature. ⁵ These shunts were transplanted into pancreatectomized canines and significantly reduced canine exogenous insulin requirements but did not result in freedom from exogenous insulin. Graft thrombosis was cited as a major reason for graft failure. ⁶ Of note, these experiments were performed before the invention of novel antiplatelet and anticoagulant medications and before the development of modem endovascular techniques. Additionally, the iliac vasculature is not the anatomic or physiologic vascular bed of islet cells, and the insulin produced from within the arteriovenous shunt bypassed physiologic first-pass hepatic insulin metabolism and modulation.

[0083] There are many experimental immuno-isolated islet cell devices that have been described for the treatment of type I diabetes.

[0084] We describe here a self-expanding islet cell-containing endovascular device designed for delivery to the portal circulation to protect islet cells from the host immune system and promote islet cell survival through free exchange of oxygen, glucose, and insulin with the host circulation.

[0085] Successful immunoisolation would drastically increase the access of T1DM patients to islet cell transplantation. ' Successful development and clinical deployment of this device would also encourage prospective use of this device in insulin dependent T2DM patients.

[0086] The major factors described in the role ofislet failure is categorized into failed engraftment, immunosuppression, and scarce donor supply. Our innovation targets failed islet engraftment and may reduce the need for systemic immunosuppression.

[0087] Proposed Solution [0088] One embodiment of a device that addresses the problem is a fully retrievable, re-seedable immunoisolated endovascular stent that provides anatomic insulin delivery to allow patients with inadequate insulin levels to achieve freedom from exogenous insulin therapy without needing immunosuppressive medications. Examples of said patients include those with type 1 diabetes, type 2 diabetes, and/or chronic pancreatitis. Given insulin’s important role in altering liver metabolism and hepatic modification of insulin, the device may be designed and installed to secrete insulin directly to the liver (for instance, the portal venous or mesenteric venous branch). The hepatic venous branch would also represent a favorable delivery site due to ease of access. The novel biologic endograft may be seeded with other endocrine cell types to act as secretory organoids for a broad array of endocrine disorders.

[0089] Methods

[0090] Fifteen BALB-C mice were sacrificed and islet isolation was performed resulting in approximately -1500 islet cells. The islets were instilled with cell culture media into the vascular implant device composed of thermally bonded PTFE with a pore size of 0.22 pm. The seeded stent graft was placed in an oxygenated perfused circuit with a perfusion pressure of 24-28 mmHG. Triplicate outflow measurements were obtained every 3 hours for a 12 hour period and insulin ELISA tests were performed of the samples. At a concentration of 40 mM of glucose within the acellular perfusate, insulin was produced and detected within the perfusion circuit throughout the 12-hour period.

[0091] The device used in this first Example is merely one example. Devices described in Examples 3 and 4 and elsewhere in the present disclosure can realistically be substituted for the device used in the present Example.Results

[0092] Circuit glucose perfusion of 40 mM resulted in the detection of insulin in the system over a twelve-hour period (FIG. 19). This at least indicates that islet cells in the system were able to functionally produce insulin in the stent device described herein.

[0093] Discussion [0094] The results show promise for using islet cell-comprising stents in insulin -depl eted systems. In particular, this device could be used in treating patients with diabetes (including type 1 diabetes and type 2 diabetes), for example, in place of or in combination with insulin administration. Other metabolic and non-metabolic diseases can be considered. In particular, cells other than pancreatic islet cells could be used in the graft to produce proteins or compounds other than insulin. Additionally, the stent could be a valuable tool in delivering pharmaceutical compounds or other medical compositions vascularly.

References for Example 1

[0095] 1. Siwakoti, P. et al. (2022) Challenges with cell-based therapies for type 1 diabetes mellitus,” Stem Cell Reviews and Reports [Preprint],

[0096] 2. Bornstein, S.R., Ludwig, B. and Steenblock, C. (2022) “Progress in islet transplantation is more important than ever,” Nature Reviews Endocrinology, 18(7),

[0097] 3. Carlsson, P.-O. etal. (2018) “Transplantation of macroencapsulated human islets within the bioartificial pancreas pAir to patients with type 1 diabetes mellitus,” American Journal of Transplantation, 18(7), pp. 1735-1744.

[0098] 4. Lanza, R.P., Sullivan, SJ. and Chick, W.L. (1992) “Perspectives in diabetes, islet transplantation with Immunoisolation,” Diabetes, 41(12), pp. 1503-1510.

[0099] 5. Type 1 diabetes treatment: Bioartificial pancreas: Beta-02 Technologies Ltd. Vertex presents new data from VX-880 phase 1/2 clinical trial at the American Diabetes Association 82nd Scientific sessions (2022) Vertex Pharmaceuticals.

[00100] 6 Chick, W.L. et al. (1977) “Artificial pancreas using living beta cells: Effects on glucose homeostasis in diabetic rats,” Science, 197(4305), pp. 780-782.

[00101] 7. MONACO, A N T.H.O.N.Y.P. et al. (1991) “Transplantation of islet allografts and xenografts in totally pancreatectomized diabetic dogs using the hybrid artificial pancreas,” Annals of Surgery, 214(3), p. 339. [00102] 8. Haque O, Pendexter CA, Cronin SEI, Raigani S, de Vries RJ, Yeh H, Markmann JF, Uygun K. Twentyfour hour ex-vivo normothermic machine perfusion in rat livers. Technology (Singap World Sci). 2020 Mar-Jun;8(l-2):27-36. doi: 10.1142/s2339547820500028. Epub 2020 Nov 5. PMID: 34307768; PMCID: PMC8300916.

[00103] The results from the first Example provided a proof of principle and these early positive results achieved with this first Example encouraged further development of the device and methods. This further development work led to the results described below.

Example 2: Perfusion Glucose Stimulated Insulin Secretion (GSIS) analysis of stent graft device

[00104] Similarly to Example 1, a prototypical stent graft’s insulin-producing capacity was determined using a closed perfusion system.

[00105] Methods

[00106] Reagents

[00107] Low Glucose Harvest and Culture Media comprised Glucose free DMEM (Sigma Aldrich), 2.8mM dextrose (Diluted from stock D50, Sigma Aldrich), 10% Fetal Bovine Serum, 5% Penicillin Streptomycin (Sigma Aldrich), and 5% HEPES (Sigma Aldrich). Low Glucose Perfusion Media (2.8 mM glucose) comprised Glucose free DMEM (Sigma Aldrich), 2.8mM dextrose (Diluted from stock D50, Sigma Aldrich), 10% Bovine Serum Albumin, 5% Penicillin Streptomycin (Sigma Aldrich), and 5% HEPES (Sigma Aldrich). High Glucose Perfusion Media (28 mM glucose) comprised Glucose free DMEM (Sigma Aldrich), 28 mM dextrose (Diluted from stock D50, Sigma Aldrich), 10% Bovine Serum Albumin, 5% Penicillin Streptomycin (Sigma Aldrich), and 5% HEPES (Sigma Aldrich). Priming Solution (Glucose Free) comprised Lactated Ringers Solution and 10% BSA (Sigma). Priming Media (Glucose Free) comprised Glucose free DMEM (Sigma Aldrich).

[00108] Analysis was performed using an ELISA Kit for Mouse Insulin (Invitrogen EMINS). [00109] Islet Harvest can be performed by any preferred method as known in the art. Here we describe one such method used in the present Example.

[00110] Pancreas Isolation

[00111] Thaw 4mL of 6x DL Liberase (collagenase) enzyme and dilute with 20 mL HBSS to make lx DL Liberase. Load 2.5mL of IX Liberase into syringes, leave 2mL of lx Liberase in the pancreas collection tube. Anesthetize mouse, euthanize by cervical dislocation, then spray abdomen with alcohol. Place the mouse in dorsal recumbency with the head toward you. Use a large pair of scissors to cut an abdominal flap, pulling the skin and abdominal wall caudally to expose the abdominal contents. Move the intestines to your left and locate the gall bladder and bile duct. Clamp the common bile duct where it enters the duodenum, just distal to where the pancreatic duct joins it. Cannulate the common bile duct with a 30g needle 60 just distal to where the cystic duct and the common hepatic duct join, and infuse 2-2.5mL of collagenase in HBSS into the pancreas via the bile duct. Excise the pancreas by carefully pulling it away from surrounding tissues. Place pancreas into 50 mL collection tube with 2 mL Liberase and leave on ice until isolation is finished.

[00112] Pancreas Digestion

[00113] Once all pancreases have been isolated and placed into collection tube, place tubes into 37.4°C water bath for 16 minutes. At 16 minutes, remove the tubes from the water bath and quench with media (up to 25mL mark on tube). Shake tube vigorously 6 times up and down. Hold tube up to lamp to make sure tissue is completely digested and few to no large tissue pieces are visible. If several chunks still persist, repeat shaking. Once digestion is complete, fill tube up to 50 mL with media before spinning.

[00114] Washing:

[00115] Centrifuge tube @ 1300rpm for 1 min. Carefully aspirate off supernatant. Add 10 mL of media to tube and shake with cap on to break up pellet. Wet tea strainer with media before placing into a new tube. Pour islets and media through the tea strainer into the tube. Pipet lOmL of new media to rinse any islets off of the tea strainer. Add lOmL of media to old tube and shake to rinse walls 125 and capture any remaining islets. Pour through strainer in new tube. Repeat rinsing to fill new tube with 50mL of media. Centrifuge islets @ 1300rpm for 1 min. Aspirate supernatant carefully to avoid disrupting the pellet. Add lOmL of media and shake to fully break up the pellet.

[00116] Add 40mL of media to fill tube. Centrifuge islets @ 1300rpm for 1 min. Aspirate supernatant carefully to avoid disrupting the pellet. Make sure to aspirate as much/all media if possible.

[00117] Islet Purification:

[00118] Adjust electronic pipet setting to draw up and release at “slow” . Add 1 OmL of 1.11 gradient solution to pellet and pulse vortex to break up pellet. Checking under the lamp to make sure there are no visible clumps. Slowly pipet lOmL of media carefully downside of tube on top of heavy gradient solution and islets layer. * Two distinct layers should be visible if done correctly. Before centrifuging, make sure to balance tubes carefully and decrease acceleration to 2 and deceleration to 0. Centrifuge @ 2000rpm for 18 min with decreased acceleration and deceleration described above. Wet transfer pipet with fresh media to avoid losing islets in pipet. Carefully remove islets from interface between the heavy layer and media layer, making sure to suck up as much as possible. Be careful not to suck up to high to avoid losing islets. Place islets from interface into fresh tube. Once all islets have been picked up from interface, fdl tube to 50mL with media. Centrifuge at 1300rpm for 1 min with fast acceleration and deceleration. Carefully aspirate supernatant without disturbing pellet. Break pellet by tapping. Once pellet has been fully resuspended, fdl tube up to 50mL with serum free media. Centrifuge at 1300rpm for 1 min with fast acceleration and deceleration. Carefully aspirate supernatant without disturbing pellet. Resuspend pellet with 200ul of media using a lOOOmL pipet. Fill a 60 x 15mm petri dish with enough media to cover the bottom, and also the top. Transfer islets in 200ul to top of petri dish. Make sure to wash out 50mL tube with 200ul to collect any residual islets left. Carefully swirl petri dish without spilling contents to collect islets in the middle of the petri dish top. Briefly view under microscope to see purity. If purity is >80%, transferring islets into another petri dish would be enough to get high pure islets. If purity is <80%, follow the steps. Place a 70 pm mesh upside down in the petri dish bottom and wet it with media. Using a 1 mb micropipette carefully suck up 200ul at a time of islets and pipet onto mesh strainer so that islets are captured on strainer and all smaller tissue will pass through into petri dish. Once all islets have been pipetted onto strainer, quickly flip strainer over and place right side up into a fresh petri dish with media. Pipet media through mesh to release all islets stuck to bottom of strainer into the petri dish. Swirl and observe purity under microscope.

[00119] Overnight Culture

[00120] Islets were cultured overnight in Low Glucose Culture Media at 37 C

[00121] Islet Seeding

[00122] After culturing the islets overnight, the islets were washed with fresh Low Glucose Perfusion Media and were seeded into the graft suspended in Low Glucose Perfusion Media. Device protypes were created using 0.22 micrometer PTFE and polystyrene discs with thermally bonded (130° C) polyurethane adhesive. The islets were drawn up from the culture dish into a lee syringe attached to a butterfly needle 60 with 10 cm of tubing. After the suspension was drawn up the syringe was positioned vertically for 5 mins to allow the islets to settle in a dependent position at the lowest part of the tubing/syringe to minimize seeding excess media into the graft. Approximately 500 cc of islet and media suspension were infused into each cell chamber through the 27G butterfly needle 60 penetrating the seeding membrane. After cell seeding the device graft was submerged in Low Glucose Perfusion Media and kept @ 37° C for 1 hour. All cell handling was performed under sterile conditions using standard cell culture techniques.

[00123] Perfusion GSIS

[00124] Perfusate circulation was carried out using a roller pump system (Masterflex L/S, Vernon Hills, IL) with two separate sets of tubing delivering perfusate into and out of the 50 mL perfusion reservoir. The system was consistently kept at a temperature of 37° C via a water bath (PolyScience, Niles, Illinois, USA), continuously pumping heated water through the doublejacketed Oxygenator (Radnoti, Covina, CA, USA). Perfusate oxygen concentration was maintained within a close range of 500 mmHg using a 95% 02/5% CO2 gas cylinder (Airgas, Radnor, PA, USA). The flow rate was kept at 30mL/min. Samples were collected from a port placed in series and distal to the tubing draining out the large tubing (Masterflex L/S precision pump tubing size 36) in which the prototype device was connected in series in a closed system. The perfusion circuit was sterilized by autoclaving and set up in a biosafety cabinet. The circuit was primed with 40 cc of Priming Media for 1 hour. Priming media was drained from the circuit. Device prototype was placed inside of the tubing of the perfusion circuit. Perfusion was resumed with 40 cc of new Low Glucose Perfusion Media.

[00125] Sample Collection:

[00126] lee of perfusion media was removed from the circuit just prior to resuming perfusion (TO timepoint, before the stent has touched the media). Followed by additional samples taken 1 minute after resuming perfusion, as well as 1,2,3 hours after resuming perfusion. After the 3 ^rd hour time point the Low Glucose Perfusion Media was drained from the circuit. With the stent still in the circuit, the perfusate was changed to 40 cc Priming Solution for 15 mins to remove any residual Low Glucose Perfusion Media. After washing with Priming Solution, this solution was replaced with 40 cc Priming Media, which was run through the circuit for another 15 mins. The circuit was drained and perfusion was immediately resumed with High Glucose Perfusion Media

[00127] Sample Collection

[00128] lee of perfusion media was removed from the circuit just prior to resuming perfusion (TO timepoint, before the stent has touched the media). Followed by additional samples taken 1 minute after resuming perfusion, as well as 1,2,3 hours after resuming perfusion. After the 3 ^rd hour time point the High Glucose Perfusion Media was drained from the circuit.

[00129] Overnight Perfusion

[00130] With the stent still in the circuit, perfusion was resumed with Priming Solution for 15 mins to remove any residual High Glucose Perfusion Media. After washing with Priming Solution, this solution was replaced with Priming Media, which was run through the circuit for another 15 mins. The circuit was drained and Priming Media was replaced with Low Glucose Perfusion Media. The graft was kept in the perfusion circuit with Low Glucose Perfusion Media overnight.

[00131] Day 2 Perfusion GSIS [00132] Low Glucose perfusion media from overnight run was removed from the circuit. The circuit was primed with lOOcc of Priming Solution for 15 mins. The circuit was primed with 40 cc of Priming Media for 15 mins. Priming media was drained from the circuit. The device was placed inside of the tubing of the perfusion circuit. Perfusion was resumed with 40 cc of new Low Glucose Perfusion Media.

[00133] Sample Collection

[00134] lee of perfusion media was removed from the circuit just prior to resuming perfusion (TO timepoint, before the stent has touched the media). Followed by additional samples taken 1 minute after resuming perfusion, as well as 1,2,3 hours after resuming perfusion. After the 3 ^rd hour time point the Low Glucose Perfusion Media was drained from the circuit. With the stent still in the circuit, perfusion was resumed with Priming Solution for 15 mins to remove any residual Low Glucose Perfusion Media. After washing with Priming Solution, this solution was replaced with Priming Media, which was run through the circuit for another 15 mins. The circuit was drained and perfusion was immediately resumed with High Glucose Perfusion Media.

[00135] Sample Collection

[00136] lee of perfusion media was removed from the circuit just prior to resuming perfusion (TO timepoint, before the stent has touched the media). Followed by additional samples taken 1 minute after resuming perfusion, as well as 1,2,3 hours after resuming perfusion. After the 3 ^rd hour time point the High Glucose Perfusion Media was drained from the circuit.

[00137] Post-GSIS Storage

[00138] At the completion of day 2 GSIS the vascular implant devices were fixed in formalin or frozen in liquid nitrogen and stored at -80° C.

[00139] ELISA

[00140] Insulin ELISA was performed for quantitative analysis of the samples using mouse insulin kit. [00141] This machine perfusion setup provided continuous pulsatile flow of oxygenated and warmed perfusion media maintained at 8-12mmHg of hydrostatic pressure. The fact that there is continuous pulsatile flow or perfusion is quite distinct from a standard cell culture or culture conditions where the media is stagnant.

[00142] Results

[00143] A two-day perfusion GSIS is shown in FIG. 20 with high glucose (HG) and low glucose (LG) conditions . The islet cell device in the system responded in a statistically significant fashion on the second day of the experiment, with increased concentration insulin after 3 hours at Day 2 High Glucose compared to 3 hours at Day 2 Low glucose (p=0.02; alpha =0.05). These findings are depicted in FIG. 20. It is possible that the device in the system requires a rest period after placement in the system before the engrafted islet cells are glucose-concentration responsive, as statistically significant concentration dependent insulin release was attained on Day 2 (FIG. 20).

[00144] Discussion

[00145] Similarly to Example 1 above, the results shown here show promise for using islet cellcomprising stents in insulin-depleted systems. In particular, this device could be used in treating patients with diabetes (including type 1 diabetes and type 2 diabetes), for example, in place of or in combination with insulin administration. Other metabolic and non-metabolic diseases can be considered. In particular, cells other than pancreatic islet cells could be used in the graft to produce proteins or compounds other than insulin. Additionally, the stent could be a valuable tool in delivering pharmaceutical compounds or other medical compositions vascularly.

Example 3: A hybrid double-layered biologic stent graft and potential delivery system

[00146] Problem

[00147] Islet cell transplantation is a novel experimental therapeutic procedure for the treatment of type I diabetes and chronic pancreatitis where autologous or allogeneic beta cells (pancreatic islet cells) are transplanted into a host to provide endogenous insulin production. Despite major advances, islet cell transplantation has demonstrated limited success with multicenter cohort studies demonstrating an insulin dependence rate ranging from 25%-50% post-transplantation. ¹ ' ² The major factors described in the role of islet failure is categorized into failed engraftment, immunosuppression, and scarce donor supply. Our innovation targets failed islet engraftment and may reduce the need for systemic immunosuppression.

[00148] Proposed Solution

[00149] We propose a hybrid double-layered biologic stent graft. One embodiment of the stent graft is described here. The stent graft comprises a metal stent frame and PTFE covering layer (endovascular stent graft) which houses a vascularized bioscaffold of decellularized pancreatic tissue ³ or 3D printed tissues ⁴ seeded with transplanted islet cells. Transplanted islet cells could be autogenic, allogenic, IPSC, xenograft, or potential future universal cell lines. The stent graft may be embedded with immunosuppressive drugs such as Sirolimus (part of the Edmonton protocol for islet cell transplant and currently used in endovascular drug coated balloons and stents). We favor a transvenous intrahepatic stent placed in a transjugular fashion across the hepatic and portal veins through hepatic parenchyma, an intraportal stent, or a hepatic venous stent to prevent islet cell attrition from arterial pressures. An intraportal/intrahepatic venous stent is favored over a systemic venous stent to promote vascularization and to lower the risk of in-stent thrombosis. In one proposed embodiment, the stent graft has an approximately 10 mm x 40 mm outer diameter.

[00150] One exemplary system for delivering such a stent graft is described here. We propose percutaneous intrajugular access and an over the wire dilation of the hepatic tract via transjugular approach. Further we propose delivering the stent graft device containing the double-layered biologic stent-biograft, with subsequent deployment via unsheathing.

[00151] References for Example 3

[00152] 1. Kuna, V., Kvamstrom, N., Elebring, E. and Holgersson, S., 2018. Isolation and Decellularization of a Whole Porcine Pancreas. Journal of Visualized Experiments, (140). [00153] 2. Skylar-Scott, M., Uzel, S., Nam, L , Ahrens, I , Truby, R , Damaraju, S. and Lewis, J., 2019. Biomanufacturing of organ-specific tissues with high cellular density and embedded vascular channels. Science Advances, 5(9).

[00154] 3. Barton FB, Rickels MR, Alejandro R, et al. Improvement in outcomes of clinical islet transplantation: 1999-2010. Diabetes Care. 2012;35: 1436-1445.

[00155] 4. Beilin MD, Barton FB, Heitman A, et al. Potent induction immunotherapy promotes long- term insulin independence after islet transplantation in type 1 diabetes. Am J Transplant. 2012;12: 1576-1583.

[00156] 5 Gamble, A., Pepper, A., Bruni, A. and Shapiro, A., 2018. The journey of islet cell transplantation and future development. Islets, 10(2), pp.80-94.

Example 4: An immuno-isolated islet cell portal venous stent graft and delivery mechanism

[00157] Problem

[00158] Islet cell transplantation is a novel experimental therapeutic procedure for the treatment of type 1 diabetes and chronic pancreatitis where autologous or allogeneic beta cells (pancreatic islet cells) are transplanted into a host to provide endogenous insulin production. Despite major advances, islet cell transplantation has demonstrated limited success with multicenter cohort studies demonstrating an insulin dependence rate ranging from 25%-50% post-transplantation. ¹ ' ² The major factors described in the role of islet failure is categorized into failed engraftment, immunosuppression, and scarce donor supply. Our innovation targets failed islet engraftment and may reduce the need for systemic immunosuppression.

[00159] Proposed Solution

[00160] We propose an immuno-isolated islet cell portal venous stent graft. One embodiment of the stent graft is described here. The stent graft comprises an 1. outer component comprising a vessel wall apposition (bare metal portal venous stent), 2. an inner component comprising an immuno-isolated semi-permeable stent graft, and 3. An islet cell component housing stem-cell derived islet cells. Islet cells are housed between two layers of semipermeable membranes (regenerated cellulose, polyurethane films). This design would allow for an inflow of oxygen and glucose to the islet cells and outflow of insulin to the portal vein but would be impermeable to immune cells and large antibodies. This "tube" of islet cells allows for blood flow 41 along the inner and outer walls 125 of the "tube" maximizing surface area for diffusion. These stent grafts may be embedded with immunosuppressive medications (Sirolimus) if needed for additional immune protection. The stent graft comprises antithrombotic flow lumens between the outer bare metal stent component and sealed inner islet cell component and within the inside of the inner component.

[00161] One exemplary mechanism for delivering such a stent graft is described herein. We propose delivery into the main portal vein or main portal vein branches via percutaneous endovascular access with a transvenous transhepatic or transvenous trans-splenic access. A delivery system comprising a handle where the device is loaded onto a sheath with a radioopaque marker to confirm position and using a screw gear based handle to unfurl the self-expanding device from a straight position to an outswept position. The inner chamber (islet containing semipermeable chamber) will never change in volume. The use of support guidewires will also be necessary.

[00162] Retrieval of the device may be performed using a catheter-based delivery system which would remove both components much like an IVC filter is retrieved. An embodiment of the device possesses a phalange with hook for docking of the reseeding apparatus and engagement of the retrieval catheter 115s.

[00163] References for Example 4

[00164] 1. Kuna, V., Kvamstrbm, N., Elebring, E. and Holgersson, S., 2018. Isolation and Decellularization of a Whole Porcine Pancreas. Journal of Visualized Experiments, (140).

[00165] 2. Skylar-Scott, M., Uzel, S., Nam, L , Ahrens, J., Truby, R., Damaraju, S. and Lewis, J., 2019. Biomanufacturing of organ-specific tissues with high cellular density and embedded vascular channels. Science Advances, 5(9). [00166] 3 Barton FB, Rickels MR, Alejandro R, et al. Improvement in outcomes of clinical islet transplantation: 1999-2010. Diabetes Care. 2012;35: 1436-1445.

[00167] 4. Beilin MD, Barton FB, Heitman A, et al. Potent induction immunotherapy promotes long- term insulin independence after islet transplantation in type 1 diabetes. Am J Transplant. 2012;12: 1576-1583.

[00168] 5 Gamble, A., Pepper, A., Bruni, A. and Shapiro, A., 2018. The journey of islet cell transplantation and future development. Islets, 10(2), pp.80-94.

Example 5: A proposed method of reseeding cells in a vascular implant device

[00169] Cells can be seeded into some embodiments of the vascular implant device. While we believe there is novelty in at least these embodiments alone, we believe there to be novelty in at least the capability of the devices to be re-seeded (or “reseeded”) with cells. This can be performed outside of a subject implanted with the device or while the device is still inside the subject. One such method of reseeding the device with cells while the device is in the subject is proposed here.

[00170] First, several embodiments of the vascular implant device are described herein. For this example, we want to highlight some embodiments of the device as follows. The device comprises a stent that is self-expanding, thus it will continue to apply outward radial force to the vessel wall even if the vessel swells or changes diameter (veins are well known to change in diameter based on volume in the vessel). The stent is uncovered; thus blood is able to flow in-between the struts/fibers of the stent. We have designed the outer stent to be uncovered to prevent blocking flow through side branches of the vessel. In other words, because there are openings between the woven struts of the stent, if the outer stent is placed in a position where the outer stent covers a branch vessel, blood will still be able to flow out of the branch vessel through the struts of the outer stent. The uncovered outer stent can be made of metals such as steel, platinum, nickel, titanium, cobalt-chromium alloys, nickel -titanium alloy (Nitinol), platinum, and tantalum alloys materials commonly used for self-expanding stents), however it is possible that this outer stent could be made from plastic polymers. The diameter of the outer stent ranges from 6 mm to 15 mm which supports deployment in the main portal vein, right portal, or left portal vein. The length of the bare metal outer stent has been minimized to prevent unnecessary coverage of side branches, while remaining long enough to maintain apposition with the vessel wall and preventing the device from migrating. We have also minimized the length of the outer stent as an exceedingly long outer stent may make the vessel exceedingly stiff which could cause kinking of the vessel or erosion of the vessel wall. In some embodiments of the device, the outer stent may be as short as 5 mm or as long as 10 cm depending on the patient’s anatomy.

[00171] Additionally, the device comprises dual flow lumens. To our knowledge there are currently no dual lumen stents or stent grafts (covered stents) that utilize an outer and inner component to create two distinct flow lumens through the stent. The inner component is designed to create as smaller lumen in the center of the outer stent. This creates a larger flow chamber around the outside of the inner component compared to the smaller lumen of the second component. We designed the inner component to be of smaller diameter and centrally placed as the flow velocity is highest in the center of the vessel. We have avoided putting the inner component walls 125 near the outer component walls 125 because the blood flow 41 is slowest along the vessel wall due to friction of the fluid with vessel wall (faster flow in the center), thus placing the inner component walls 125 too peripherally increases the risk of thrombosis by disrupting the slower flow near the periphery of the vessel, where flow is already slowed and disrupted. Our device centers the inner component so that it is only disrupting the fastest moving blood at the center of the vessel to minimize thrombosis due to flow disruption/stagnation.

[00172] Further, the device comprises within the inner component a cell-containing chamber. The inner component of the device is comprised of a semipermeable material which allows for free exchange of glucose, insulin, and cellular waste but impermeable to the cellular elements and large proteins of the human immune system. In some embodiments the inner component is composed of PTFE, nylon, biopolymers natural hydrophilic polymers including polysaccharides, nylon, polymeric hydrogels, artificial hydrogels.

[00173] Further, the device comprises a hook 90 at the top of the device that can be snare 120d (snaring a hook 90ed device is a common endovascular technique, for example, retrieval of an IVC filter). Once the hook 90 has been snare 120d, the user can advance the retrieval or re-seeding catheter 115 along the snare 120 wire to engage the device. In the case of the re-seeding catheter 115, the catheter 115 engages the stent with the catheter 115 inside of a rubber "engagement rim". Below the rim is a black o-ring called the "support ring 50” which has a “seeding membrane", which may be a rubber spacer that separates the membranes of the cell chamber. The rubber reseeding membrane can be punctured by a needle 60 and "re-seal" when the needle 60 is removed (this is analogous to the rubber caps on medication vials that can be punctured multiple times). The re-seeding catheter 115 has two lumens, one lumen for the snare 120 and a guidewire to go through and a peripheral lumen "infusion lumen" that houses a mobile hypodermic that can be advanced out of the end of the catheter 115 to penetrate the seeding membrane; thus the new islet cells can be infused inside of the cell chamber. The orientation of the catheter 115 lumens is such that when catheter 115 engages the stent, the peripherally located infusion lumen is lined up so that the infusion needle 60 can be advanced directly across the seeding membrane in a controlled fashion.

[00174] Exemplary embodiments of reseeding methods are shown, without limitation, in FIGs. 5- 7.

[00175] This technique may alternatively or additionally be used to retrieve the device from a subject some time after implantation of the device.

Additional Examples

[00176] 1. An implantable vascular device, comprising: a tubular stent component comprising an internal bore; a graft component disposed at least partially within the internal bore of the tubular stent component, wherein the graft component comprises an outer cylindrical wall made of a semipermeable membrane material and an inner lumen made of a semipermeable membrane material, wherein the semipermeable membrane material has a selected permeability, and wherein the graft component is configured to encapsulate cells between the outer cylindrical wall and the inner lumen, and wherein the inner lumen permits blood flow longitudinally therethrough; and one or more support members providing a fixed position between the tubular stent component and the graft component, wherein the one or more support members optionally provide a collapsible fixed position.

[00177] 2. An implantable vascular device, comprising: a tubular stent component comprising an internal bore; a graft component disposed at least partially within the internal bore of the tubular stent component, wherein the graft component comprises an insulin-generating bioscaffold; and one or more support members providing a fixed position between the tubular stent component and the graft component, wherein the one or more support members optionally provide a collapsible fixed position.

[00178] 3. An implantable vascular device, comprising: a tubular stent component; a graft component disposed at least partially within the internal bore of the tubular stent component, wherein the graft component comprises an insulin-generating hydrogel, wherein the insulin-generating hydrogel comprises an inner lumen, wherein the inner lumen permits blood flow longitudinally therethrough; and one or more support members providing a fixed position between the tubular stent component and the graft component, wherein the one or more support members optionally provide a collapsible fixed position

[00179] 4. The implantable vascular device of case 1, further comprising cells between the outer cylindrical wall and the inner lumen.

[00180] 5. The implantable vascular device of case 4, wherein the cells are pancreatic, hepatic, renal, gastric, thyroid, adrenal, pituitary, parathyroid, hypothalamus, ovary, or testis cells.

[00181] 6. The implantable vascular device of case 4 or 5, wherein the cells are bovine, porcine, murine, rattus, equine, or human. [00182] 7 The implantable vascular device of any one of cases 4-6, wherein the cells are pancreatic islet cells.

[00183] 8. The implantable vascular device of any one of cases 4-7, wherein the cells are derived from stem cells, are genetically engineered cells, or are a combination thereof, the device optionally further comprising at least one small molecule supplement.

[00184] 9. The implantable vascular device of any one of cases 4-8, wherein the cells are autogenic, allogenic, induced pluripotent stem cells, xenograft, or are from universal cell lines, optionally further comprising at least one small molecule supplement.

[00185] 10. The implantable vascular device of any one of cases 4-9, comprising from 100,000- 15,000,000 cells.

[00186] 11. The implantable vascular device of case 2, wherein the insulin-generating bioscaffold comprises a semipermeable membrane material.

[00187] 12. The implantable vascular device of case 2 or 11, further comprising an inner lumen, wherein the inner lumen permits blood flow longitudinally through the insulin-generating bioscaffold.

[00188] 13. The implantable vascular device of cases 2, 11, or 12, wherein the insulingenerating bioscaffold comprises decellularized pancreatic tissue or a 2D or 3D printed tissue seeded with transplanted islet cells.

[00189] 14. The implantable vascular device of any one of cases 2 and 11-13, wherein the insulin-generating bioscaffold comprises at least one of autogenic, allogenic, induced pluripotent stem cells, xenograft, or universal cell lines.

[00190] 15. The implantable vascular device of any one of cases 2 and 11-14, wherein the insulin-generating bioscaffold comprises cells, wherein at least a majority of the cells are pancreatic islet cells.

[00191] 16. The implantable vascular device of any one of cases 2 and 11-15, wherein the insulin-generating bioscaffold is vascularized. [00192] 17. The implantable vascular device of any one of cases 2 and 11 -16, wherein the insulin-generating bioscaffold is a hydrogel.

[00193] 18. The implantable vascular device of any one of cases 2 and 11-16, wherein the insulin-generating bioscaffold is a decellularized tissue.

[00194] 19. The implantable vascular device of case 3, wherein the insulin-generating hydrogel is in the form of a sheet coiled around a longitudinal axis of the tubular stent.

[00195] 20. The implantable vascular device of case 3 or 19, wherein the insulin-generating hydrogel comprises a member selected from the group consisting of growth factors, antithrombotics, anticoagulants, immunosuppressives, and mixtures thereof.

[00196] 21. The implantable vascular device of case 3, 19, or 20, wherein the insulin-generating hydrogel is porous or microporous.

[00197] 22. The implantable vascular device of any one of cases 3 and 19-21, wherein the insulin-generating hydrogel further comprises a semipermeable membrane material.

[00198] 23. The implantable vascular device of any one of cases 1, 4-11, and 22, wherein the semipermeable membrane material comprises regenerated cellulose and/or polyurethane fdms.

[00199] 24. The implantable vascular device of any one of cases 1, 4-11, 22, and 23, wherein the semipermeable membrane material is configured with a plurality of pores having a diameter in the range of from about 0.001 pm to about 0.4 pm, wherein the plurality of pores allows for flow of oxygen and/or glucose and/or flow of insulin, and wherein the plurality of pores prevents cells and antibodies from traversing the semipermeable membrane material.

[00200] 25 The implantable vascular device of any one of the preceding cases, wherein the tubular stent component comprises a material selected from the group comprising a metal, a polymer, a composite, a ceramic, or a combination thereof.

[00201] 26. The implantable vascular device of any one of the preceding cases, further comprising an immunosuppressive material embedded in the graft component, attached to the graft component, attached to the tubular stent component, or a combination thereof. [00202] 27. The implantable vascular device of any one of the preceding cases, further comprising one or more antithrombotic dispensing components which are optionally in the form of one or more flow lumens disposed between the tubular stent component and the graft component and/or within the graft component.

[00203] 28. The implantable vascular device of any one of the preceding cases, wherein the tubular stent component is coated or embedded with a pharmaceutical composition.

[00204] 29. The implantable vascular device of case 28, wherein the pharmaceutical composition is an anticoagulant.

[00205] 30. The implantable vascular device of any one of the preceding cases, wherein the tubular stent component is self-expanding.

[00206] 31. The implantable vascular device of any one of cases 1-29, wherein the tubular stent component is rigid.

[00207] 32. The implantable vascular device of any one of the preceding cases, wherein the graft component is rigid.

[00208] 33. The implantable vascular device of any one of the preceding cases, wherein the tubular stent component comprises a covering layer, wherein the covering layer comprises polydimethylsiloxane (PDMS), collagen, albumin, fibrin, alginate, graphene, nylon (polyamides), dacron (polyesters), polystyrene, polypropylene, poly(acrylic acids), poly(methacrylic acids), polyvinyl compounds (e.g., polyvinyl chloride, polyvinyl acetate), polycarbonate (PC), poly(alkylene oxides), polyvinylpyrrolidone (PVP), polytetrafluorethylene (PTFE, teflon), thermanox (TPX), polymers of hydroxy acids, such as polylactic acid (PLA), polyglycolic acid (PGA), and polylactic acid-glycolic acid (PLGA), polyorthoesters, polyanhydrides, polyphosphazenes, polyhydroxyalkanoates, or a combination thereof.

[00209] 34. The implantable vascular device of any one of the preceding cases, wherein the implantable vascular device is configured for securement in apposition to an interior blood vessel wall. [00210] 35. The implantable vascular device of any one of the preceding cases, wherein the tubular stent component is connected to the graft component with stops, tabs, clasps, friction hold, or combinations thereof.

[00211] 36. The implantable vascular device of any one of the preceding cases, further comprising a support ring connected to the tubular stent component, the support ring wrapped around an outer surface of a ring-shaped support member, the ring-shaped support member connected to the graft component.

[00212] 37. The implantable vascular device of case 36, wherein the support ring connects to the one or more support members by a connecting feature selected from the group comprising crimping the one or more support members to the support ring, coiling an extension of the one or more support members around the support ring, and embedding the one or more support members to the support ring.

[00213] 38. The implantable vascular device of case 36 or 37, further comprising a ring-shaped rubber seal, wherein the support ring wraps around the outer surface of the ring-shaped rubber seal, wherein the ring-shaped rubber seal is self-sealing after a puncture with a needle, wherein the rubber seal is configured to retain the cells between the outer cylindrical wall and the inner lumen, and wherein the implantable vascular device is the implantable vascular device of any one of cases 4-10.

[00214] 39. The implantable vascular device of any one of cases 36-38, wherein the support ring is made of rubber.

[00215] 40. The implantable vascular device of any one of the preceding cases, further comprising a conical receiving member having an attachment end attached to at least one longitudinal end of the implantable vascular device, the conical receiving member having a bore therethrough and a distal end of the conical receiving member having a diameter larger than the attachment end.

[00216] 41. The implantable vascular device of any one of the preceding cases, wherein the implantable vascular device further comprises at least one hook. [00217] 42. The implantable vascular device of any one of the preceding cases, wherein the length of the implantable vascular device is between about 10 mm and about 1000 mm.

[00218] 43. The implantable vascular device of any one of the preceding cases, wherein the outer diameter of the implantable vascular device is between about 2 mm and about 40 mm.

[00219] 44. The implantable vascular device of any one of the preceding cases, wherein the inner lumen comprises an inflow cone.

[00220] 45. The implantable vascular device of any one of the preceding cases, further comprising an internal stent disposed at least partially within the internal bore of the tubular stent component.

[00221] 46. The implantable vascular device of any one of the preceding cases, wherein the implantable vascular device is bidirectional.

[00222] 47. A method of using an implantable vascular device, wherein the method comprises: implanting one or more implantable vascular devices of any one or more of the preceding cases into one or more fixed positions with respect to one or more inner blood vessel walls of a subject.

[00223] 48. The method of case 47, further comprising reseeding the cells after implantation, wherein the at least one implantable vascular device is from of any one of cases 1, 4-10, and 38.

[00224] 49. The method of case 48, wherein reseeding comprises using a needle to deliver additional cells between the outer cylindrical wall and the inner lumen through the rubber seal, wherein the at least one implantable vascular device is from case 38.

[00225] 50. The method of any one of cases 47-49, further comprising removing the implantable vascular device.

[00226] 51. The method of case 50, wherein removing the implantable vascular device comprises engaging the implantable vascular device with a catheter comprising a snare; engaging the snare with the at least one hook; and pulling the snare thereby engaging the walls of the catheter with the one or more support members thereby collapsing the stent component; wherein the at least one implantable vascular device is the device of case 41.

[00227] 52. The method of case 50, wherein the at least one implantable vascular device is the device of case 46 and wherein the implantable vascular device is implanted and removed in a direction opposite the direction the implantable vascular device was implanted.

[00228] 53. The method any one of cases 47-52, wherein the implantable vascular device is implanted into a vein or artery selected from the group consisting of: the main portal vein of the liver, branches of the main portal vein, the main hepatic vein, hepatic vein branches, splenic vein, mesenteric veins, a peripheral vein, the femoral axillary, brachial veins, brachial vein tributaries, brachial vein branches, superior mesenteric artery, inferior mesenteric artery, splenic artery, celiac artery, superior mesenteric artery branches, inferior mesenteric artery branches, a peripheral artery, a femoral artery, radial artery, ulnar artery, brachial artery, axillary artery, popliteal artery or a branch or tributary thereof.

[00229] 54. The method any one of cases 47-53, wherein the implantable vascular device is implanted in a fashion selected from percutaneous endovascular, transvenous transhepatic, transjugular, transarterial, transvenous trans-splenic access, and combinations thereof.

[00230] 55. The method any one of cases 47-54, wherein the implantable vascular device is implanted in the hepatic portal vein through hepatic parenchyma, hepatic tract dilation, an intraportal stent, or a hepatic venous stent.

[00231] 56. The method of any one of cases 47-55, wherein the implantable vascular device is implanted with a microneedle.

[00232] 57. The method of any one of cases 47-56, wherein the subject has a pancreatic disease and/or a metabolic disease.

[00233] 58. The method of case 57, wherein the subject has diabetes.

[00234] 59. The method of case 58, wherein the subject has type 1 diabetes or type 2 diabetes. [00235] 60. The method of any one of cases 47-59, comprising implanting two or more implantable vascular device of any one of cases 1-44 into two or more fixed positions with respect to two or more inner blood vessel walls of the subject.

[00236] 61. The method of any one of cases 47-60, further comprising treating the subject with a treatment for a pancreatic disease and/or a metabolic disease or syndrome.

[00237] 62. The method of any one of cases 47-61, further comprising treating the subject with insulin.

[00238] 63. A method of implanting the implantable vascular device of any one of cases 1-46 in a subject, the method comprising sheathing the implantable vascular device in a delivery device and subsequently unsheathing the implantable vascular device from the delivery device at a desired position with respect to one or more inner blood vessel walls of a subject.

[00239] 64. The method of case 63, wherein the delivery device implants the implantable vascular device into the main portal vein of the liver or branches of the main portal vein of the liver, including portions of the main portal vein of the liver that are inside of the liver or outside of the liver.

[00240] 65. The method of case 63 or 64, wherein the delivery device implants the implantable vascular device percutaneous endovascularly, transvenous transhepatically, transjugularly, transarterially, or by transvenous trans-splenic access.

[00241] 66. The method of any one of cases 63-65, wherein the delivery device implants the implantable vascular device in the hepatic portal vein through hepatic parenchyma, hepatic tract dilation, an intraportal stent, or a hepatic venous stent.

[00242] 67. The method of any one of cases 63-66, wherein the delivery device comprises a radioopaque marker.

[00243] 68. The method of any one of cases 63-67, wherein the delivery device is a catheter.

[00244] 69. The method of any one of cases 63-68, wherein the delivery device implants the implantable vascular device with a microneedle. [00245] 70. The method of any one of cases 47-69, further comprising suturing the implantable vascular device to the one or more inner blood vessel walls.

[00246] 71. The method of any one of cases 63-69, wherein unsheathing the vascular device allows the tubular stent component to expand.