Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
  • A61F2/02—Prostheses implantable into the body
  • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
  • A61F2/06—Blood vessels
  • A61F2/07—Stent-grafts
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
  • A61F2/02—Prostheses implantable into the body
  • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
  • A61F2/06—Blood vessels
  • A61F2/07—Stent-grafts
  • A61F2002/075—Stent-grafts the stent being loosely attached to the graft material, e.g. by stitching
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
  • A61F2/95—Instruments specially adapted for placement or removal of stents or stent-grafts
  • A61F2002/9528—Instruments specially adapted for placement or removal of stents or stent-grafts for retrieval of stents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
  • A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
  • A61F2250/0067—Means for introducing or releasing pharmaceutical products into the body

Definitions

• 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.
• 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.
• autologous or allogeneic beta cells pancreatic islet cells
• islet cell transplantation has demonstrated limited success with multicenter cohort studies demonstrating an insulin dependence rate ranging from 25%-50% post-transplantation.
• 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.
• 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.
• 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.
• 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.
• 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
• 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.
• 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
• 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.
• 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.
• 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.
• 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.
• 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.
• the methods may further comprise suturing the implantable vascular device to the one or more inner blood vessel walls.
• FIG. 1 shows a lateral view of an embodiment of this disclosure.
• FIG. 2 shows a top view of an embodiment similar to that of Fig. 1.
• FIG. 3 shows a perspective cross-sectional view of an embodiment similar to that of Fig. 1.
• FIG. 4 shows a perspective view of another embodiment of this disclosure.
• FIG. 5 shows a partial side view of certain features of an embodiment of this disclosure.
• FIG. 6 shows a partial elevated view of an embodiment similar to that of Fig. 5.
• FIG. 7 shows another partial elevated view of an embodiment similar to that of Fig. 5.
• FIG. 8 shows a side view of another embodiment of this disclosure.
• FIG. 9 shows a side view of an embodiment similar to Fig. 8, but in a different position.
• FIG. 10 shows a side view of another embodiment of this disclosure.
• FIG. 11 shows a top view of an embodiment similar to that of Fig. 10.
• FIG. 12 shows a perspective cross-sectional view of an embodiment similar to that of Fig. 10.
• FIG. 13 shows a side view of another embodiment of this disclosure.
• FTG. 14 shows a top view of an embodiment similar to that of Fig. 13.
• FIG. 15 shows a perspective cross-sectional view of an embodiment similar to that of Fig. 13.
• FIG. 16 shows a side view of another embodiment of this disclosure.
• FIG. 17 shows a cross-sectional view of certain components in an embodiment similar to that of Fig. 13-15.
• FIG. 18 shows a cross-sectional view of certain components in an embodiment similar to that of Figs. 10-12.
• 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.
• 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.
• GSIS Glucose Stimulated Insulin Secretion
• ranges that are between two particular values should be understood to expressly include those two particular values.
• “between 0 and 1” means “from 0 to 1” and expressly includes 0 and 1 and anything falling inside these values.
• “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.
• Type 1 diabetes mellitus 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.
• 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.
• 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.
• this device 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.
• 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.
• 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.
• 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.
• 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.
• GSIS glucose stimulated insulin secretion
• Vascular implant devices are provided herein.
• 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.
• a retrieval device a catheter 115, for example
• 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.
• 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.
• 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.
• the cells are pancreatic, hepatic, renal, gastric, thyroid, adrenal, pituitary, parathyroid, hypothalamus, ovary, or testis cells.
• the cells are bovine, porcine, murine, rattus, equine, or human.
• the cells are pancreatic islet (or “beta”) cells.
• the cells are derived from stem cells, are genetically engineered cells, or are a combination thereof.
• 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.
• 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.
• 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.
• the insulin-generating bioscaffold 35 comprises a semipermeable membrane material.
• 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.
• 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 may be a sheet.
• the insulin-generating bioscaffold 35 comprises at least one of autogenic, allogenic, induced pluripotent stem cells, xenograft, or universal cell lines.
• the insulingenerating bioscaffold 35 comprises cells, wherein at least a majority of the cells are pancreatic islet cells.
• the cells are pancreatic, hepatic, or renal cells.
• the cells are bovine, porcine, murine, rattus, equine, or human.
• the cells are pancreatic islet cells.
• 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.
• 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.
• vascularization 45 may be found in at least Primo and Mata (“3D Patterning within Hydrogels for the Adventure 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.
• 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.
• 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.
• the insulin-generating hydrogel 40 is in the form of a sheet coiled around a longitudinal axis of the tubular stent.
• support ring 50s described herein are placed around the outer diameter of the hydrogel to prevent it from unrolling.
• 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.
• the insulin-generating hydrogel 40 comprises growth factors, antithrombotics, anticoagulants, immunosuppressive agents, or combinations thereof.
• immunosuppressive agents include, but are not limited to, immunosuppressive agents such as tacrolimus, everolimus, or sirolimus.
• the insulin-generating hydrogel 40 is porous or microporous.
• the insulin-generating hydrogel 40 further comprises a semipermeable membrane material.
• 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.
• 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.
• the graft component 15 may be described as tubular or referred to as a “graft tube” due to certain embodiments’ shape.
• 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.
• 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.
• islet cells nor limited to other cell types — or active ingredients.
• 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
• 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.
• 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.
• 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.
• the small molecule supplement may be referred to as a “small molecule cocktail” or “support milieu”.
• stem cell lines may preferably require a support milieu, however, even islet cells may need a support system beyond a scaffold.
• the device may comprise a scaffold for small molecule support and/or a restrictive layer to ensure the small molecule supplement does not leak.
• the semipermeable membrane material comprises regenerated cellulose and/or polyurethane films.
• 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.
• 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.
• the semipermeable membrane material is connected directly to support rings 50 described herein or directly to the stent component.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• the immunosuppressive material is an immunosuppressive drug, and, in some embodiments, the immunosuppressive drug is Sirolimus.
• the tubular stent component 5 is coated or embedded with a pharmaceutical composition.
• 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.
• the graft component 15 comprises a pharmaceutical composition.
• the tubular stent component 5 is self-expanding.
• the tubular stent component 5 is rigid, and, in some embodiments, the graft component 15 is rigid.
• 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
• PDMS polydimethylsiloxane
• collagen e.g., albumin, fibrin, alginate, graphene
• 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.
• 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.
• 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 .
• 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.
• 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.
• 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.
• the tubular stent component 5 is connected to the graft component 15 with stops, tabs, clasps, friction hold, or combinations thereof.
• 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.
• 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.
• the support ring 50 is made of rubber. Alternatives for rubber may include, but is not limited to, silicone, nitrile, vinyl, and neoprene.
• 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.
• 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.
• 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.
• the hook 90 may provide mobility, dexterity, security, and/or additional benefits to the device not described herein.
• 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.
• 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.
• 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.
• the length of the tubular stent component 5 may be between about 5 mm to about 10 cm depending on the patient’s anatomy.
• 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.
• 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.
• an internal stent 106 is shown in FIG. 16.
• the vascular implant device is bidirectional.
• “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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• the vascular implant device is implanted and removed in a direction opposite the direction the vascular implant device was implanted.
• 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.
• the vascular implant device is implanted in a fashion selected from percutaneous endovascular, transvenous transhepatic, transjugular, transarterial, transvenous trans-splenic access, and combinations thereof
• 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.
• the vascular implant device is implanted with a microneedle.
• Microneedles 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.
• the subject has a pancreatic disease and/or a metabolic disease.
• 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.
• T2DM insulin-dependent type 2 diabetes mellitus
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• the delivery device is a catheter 115.
• the delivery device implants the implantable vascular transplantation device with a microneedle.
• 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.
• unsheathing the vascular transplantation device allows the tubular stent component 5 to expand.
• 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.
• Example 1 Determination of insulin production in stent graft prototype using a closed perfusion system
• 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.
• 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.
• 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.
• Proposed Solution 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.
• 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.
• 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
• 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.
• the results show promise for using islet cell-comprising stents in insulin -depl eted systems.
• 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.
• cells other than pancreatic islet cells could be used in the graft to produce proteins or compounds other than insulin.
• the stent could be a valuable tool in delivering pharmaceutical compounds or other medical compositions vascularly.
• 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.
• Example 2 Perfusion Glucose Stimulated Insulin Secretion (GSIS) analysis of stent graft device
• Example 2 Similarly to Example 1, a prototypical stent graft’s insulin-producing capacity was determined using a closed perfusion system.
• 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).
• Islet Harvest was performed by any preferred method as known in the art. Here we describe one such method used in the present Example.
• pancreases 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.
• 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.
• Islets were cultured overnight in Low Glucose Culture Media at 37 C
• 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.
• 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.
• lee of perfusion media was removed from the circuit just prior to resuming perfusion (TO timepoint, before the stent has touched the media).
• TO timepoint before the stent has touched the media.
• additional samples taken 1 minute after resuming perfusion, as well as 1,2,3 hours after resuming perfusion.
• the Low Glucose Perfusion Media was drained from the circuit.
• the perfusate was changed to 40 cc Priming Solution for 15 mins to remove any residual Low Glucose Perfusion Media.
• 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
• lee of perfusion media was removed from the circuit just prior to resuming perfusion (TO timepoint, before the stent has touched the media).
• TO timepoint before the stent has touched the media.
• additional samples taken 1 minute after resuming perfusion, as well as 1,2,3 hours after resuming perfusion.
• the Low Glucose Perfusion Media was drained from the circuit.
• Priming Solution for 15 mins to remove any residual Low Glucose Perfusion Media.
• Priming 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.
• lee of perfusion media was removed from the circuit just prior to resuming perfusion (TO timepoint, before the stent has touched the media).
• TO timepoint before the stent has touched the media.
• additional samples taken 1 minute after resuming perfusion, as well as 1,2,3 hours after resuming perfusion.
• the High Glucose Perfusion Media was drained from the circuit.
• Insulin ELISA was performed for quantitative analysis of the samples using mouse insulin kit.
• 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.
• FIG. 20 A two-day perfusion GSIS is shown in FIG. 20 with high glucose (HG) and low glucose (LG) conditions .
• HG high glucose
• LG low glucose
• 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).
• Example 1 the results shown here show promise for using islet cellcomprising stents in insulin-depleted systems.
• 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.
• cells other than pancreatic islet cells could be used in the graft to produce proteins or compounds other than insulin.
• 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
• 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.
• autologous or allogeneic beta cells pancreatic islet cells
• 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.
• 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).
• the stent graft has an approximately 10 mm x 40 mm outer diameter.
• Example 4 An immuno-isolated islet cell portal venous stent graft and delivery mechanism
• 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.
• autologous or allogeneic beta cells pancreatic islet cells
• 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.
• 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.
• 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
• the use of support guidewires will also be necessary.
• 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.
• Example 5 A proposed method of reseeding cells in a vascular implant device
• 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.
• 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.
• 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.
• the outer stent may be as short as 5 mm or as long as 10 cm depending on the patient’s anatomy.
• the device comprises dual flow lumens.
• dual lumen stents or stent grafts covered stents
• 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.
• 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.
• the inner component is composed of PTFE, nylon, biopolymers natural hydrophilic polymers including polysaccharides, nylon, polymeric hydrogels, artificial hydrogels.
• 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).
• a hook 90ed device is a common endovascular technique, for example, retrieval of an IVC filter.
• the user can advance the retrieval or re-seeding catheter 115 along the snare 120 wire to engage the device.
• 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.
• This technique may alternatively or additionally be used to retrieve the device from a subject some time after implantation of the device.
• 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.
• 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.
• 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
• 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.
• 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.
• 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.
• tubular stent component comprises a material selected from the group comprising a metal, a polymer, a composite, a ceramic, or a combination thereof.
• 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.
• 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.
• 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
• PDMS polydimethylsiloxane
• collagen collagen
• albumin
• 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.
• 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.
• 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.
• the implantable vascular device of any one of the preceding cases wherein the implantable vascular device further comprises at least one hook.
• the length of the implantable vascular device is between about 10 mm and about 1000 mm.
• 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.
• a method of using an implantable vascular device comprising: 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.
• 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.
• 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.
• 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.
• a method of implanting the implantable vascular device of any one of cases 1-46 in a subject 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.

Landscapes

• Health & Medical Sciences (AREA)
• Heart & Thoracic Surgery (AREA)
• Life Sciences & Earth Sciences (AREA)
• Cardiology (AREA)
• Oral & Maxillofacial Surgery (AREA)
• Transplantation (AREA)
• Engineering & Computer Science (AREA)
• Biomedical Technology (AREA)
• Gastroenterology & Hepatology (AREA)
• Pulmonology (AREA)
• Animal Behavior & Ethology (AREA)
• Vascular Medicine (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Prostheses (AREA)
• Materials For Medical Uses (AREA)
• Media Introduction/Drainage Providing Device (AREA)

Applications Claiming Priority (3)

Publications (1)

Family

ID=89852496

Family Applications (1)

Country Status (3)

Family Cites Families (6)

• 2023
  • 2023-08-09 EP EP23853506.6A patent/EP4568616A2/de active Pending
  • 2023-08-09 WO PCT/US2023/071910 patent/WO2024036199A2/en not_active Ceased
  • 2023-08-09 CA CA3264527A patent/CA3264527A1/en active Pending

Also Published As

Similar Documents

Legal Events