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
  • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. 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
  • 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
  • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
  • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
  • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
  • A61F2/91—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
  • A61L31/02—Inorganic materials
  • A61L31/022—Metals or alloys
• • 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
  • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
  • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
  • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
  • A61F2/91—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
  • A61F2/915—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other
• • 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
  • A61F2/0077—Special surfaces of prostheses, e.g. for improving ingrowth
  • A61F2002/0086—Special surfaces of prostheses, e.g. for improving ingrowth for preferentially controlling or promoting the growth of specific types of cells or tissues
• • 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
  • A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
  • A61F2210/0014—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof using shape memory or superelastic materials, e.g. nitinol
• • 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
  • A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
  • A61F2210/0076—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof multilayered, e.g. laminated structures
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2400/00—Materials characterised by their function or physical properties
  • A61L2400/16—Materials with shape-memory or superelastic properties

Definitions

• This invention pertains generally to implantable devices, and more particularly to an implantable medical device, and surface treatments for the same, for treating peripheral artery disease (PAD).
• PAD peripheral artery disease
• Lower extremity peripheral arterial disease is characterized by the accumulation of atherosclerotic plaque in the arteries of the legs.
• PAD commonly presents with intermittent claudication, which can be lifestyle-limiting, but may also present as chronic or acute limb ischemia and ultimately require amputation.
• the prevalence of symptomatic PAD increases with age and is as high as 8% of the general population in persons over 70.
• -1 million endovascular procedures for PAD were performed in the United States, representing a 5 -fold increase from a decade earlier and -70% of the total PAD interventions. Due to the aging of our population, endovascular procedures to treat PAD are increasing, with an estimated 2 million procedures performed annually by 2020. Unfortunately, current endovascular treatments are often associated with poor outcomes and new endovascular devices need to be considered for the aging population
• One endovascular device for treating PAD is the Viabahn endoprosthesis from Gore. This device uses a self-expandable Nitinol stent backbone lined
• ePTFE polytetrafluoroethylene
• FIG. 1 shows images taken of a stented sheep iliac artery three months after stenting. Due to the image magnification, only two struts 10 of a stent 5 are shown adjacent the iliac artery lining 12.
• An ePTFE stent liner 12 is on the luminal side of struts 10. Struts 10 are thus ab luminal with regard to ePTFE stent liner 12. Given the impermeability of ePTFE stent liner 12, intercellular communication between any luminal endothelial layer on a luminal surface 14 of ePTFE stent liner 12 and an artery wall 15 is impossible. Luminal surface 14 is thus chronically exposed and acellular. This endothelialization failure on luminal surface 14 greatly increases the risk of thrombosis. In contrast, a neointima 11 has proliferated around struts 10.
• neointimal hyperplasia NASH
• ePTFE stent liner 12 prevents neointima 11 from invading the vessel lumen, the proliferation of neointima 11 on struts 10 is undesirable and increases the probability of restenosis.
• the relatively thick and impermeable ePTFE barrier while preventing smooth muscle cell proliferation (i.e. a beneficial attribute), also prevents nutrient exchange and paracrine communication between intima and media that are key features of normal vessel physiology.
• a stent cover is provided that inhibits smooth muscle cell migration and resulting neointimal hyperplasia while promoting a healthy luminal endothelial lining.
• the stent cover comprises micro-patterned-thin-film nitinol (MTFN) forming a cylinder for enclosing and covering stent struts or truss members.
• the micro-pattern comprises a plurality of fenestrations in the thin- film nitinol that are large enough to allow sufficient intercellular communication yet are small enough to inhibit neointimal hyperplasia.
• the stent cover extends in a longitudinal dimension from a proximal end to a distal end.
• each fenestration there is a corresponding longitudinal dimension or extent across each fenestration.
• the blood flow within the stented vessel flows generally in the longitudinal dimension.
• These dimensions exist whether each fenestration comprises a similar polygon or are instead irregular.
• the transverse and longitudinal dimensions for each fenestration do not exceed a critical dimension so as to inhibit neointimal hyperplasia.
• This maximum or critical dimension is comparable to the dimensions of a smooth muscle cell. In one embodiment, the maximum dimension is 10 microns. More generally, the maximum dimension is that which prevents or at least substantially inhibits migration of smooth muscle cells through the fenestrations such as 25 microns or less.
• the micro-patterned thin film stent cover is quite advantageous as compared to conventional ePTFE barriers.
• the fenestrations promote endothelialization on the luminal surface of the stent cover.
• the micro-patterned- thin-film stent cover thus inhibits thrombosis.
• the fenestrations enable endothelialization of the luminal surface and thus inhibit thrombosis
• the fenestrations also prevent neointimal hyperplasia on the stent cover luminal surface because the fenestration dimensions are too small to permit smooth muscle cell migration through the fenestrations.
• the resulting cellular communication between the endothelial lining on the stent cover luminal surface and the vessel wall adjacent to the stent cover abluminal surface is believed to inhibit hyperplasia on the abluminal surface of the stent cover.
• the neointimal proliferation (neointimal 11 of Figure 1) on the abluminal surface of conventional ePTFE barriers is plainly undesirable.
• micro-patterned thin-film stent cover is markedly thinner than conventional ePTFE barriers and thus resists restenosis resulting from flow
• FIG. 1 shows an image taken from an ePTFE covered stent after 3 months in a sheep iliac artery.
• FIG. 2A illustrates an assembled view of a PAD stent in accordance with the present invention.
• FIG. 2B illustrates an exploded view of the PAD stent of FIG. 1.
• FIG. 3 A shows a schematic diagram of an implanted stent with MTFN covering of the present invention and its effect on "edge effect" stenosis.
• FIG. 3B shows a schematic diagram of an implanted stent with ePTFE covering and its effect on "edge effect” stenosis.
• FIG. 4 shows a schematic diagram of an implanted stent with MTFN covering of the present invention and effect on SMC (smooth muscle cell) migration.
• FIG. 5 shows a schematic diagram of an implanted stent with MTFN covering of the present invention and resulting endothelial monolayer.
• FIG. 6 is a graph showing the influence of treatment time on the wetting angle of the MTFN film of the present invention.
• FIG. 7 shows SEM images of four MTFN sheets, each with different micro patterns of fenestrations in accordance with the present invention.
• FIG. 8A and FIG. 8B show optical microscopy images of two films having diamond pattern fenestrations with dimensions of 7.5 ⁇ x 10 ⁇ and 45 ⁇ x 60 ⁇ , respectively.
• FIG. 9A through FIG. 9C show molecular analysis of the
• FIG. 9A showing total thrombus
• FIGS. 9B and 9C showing fibrin and platelet deposition, respectively.
• FIG. 10A through FIG. IOC show images of the effects of surface wettability and the endothelial monolayer in vitro after 1 week for contact angles of 0 ,
• FIG. 11 shows a representative image of a vessel wall treated with the stent of FIG. 8A having 7.5 ⁇ xlO ⁇ perforations.
• FIG. 12 shows the contralateral iliac artery treated with the stent covering of FIG. 8B having 45 ⁇ x 60 ⁇ perforations.
• FIG. 13 shows a graph of neointimal area for various fenestration sizes.
• FIG. 14A through FIG. 14C show images of the wall of an artery treated with a 45 ⁇ x 60 ⁇ stent covering at low magnification, medium magnification, and high magnification respectively.
• FIG. 15A shows images of HAECs grown on un-patterned TFN.
• FIG. 15B (scale bar 100 ⁇ ) and FIG. 15C (scale bar 50 ⁇ ) show HAECs grown on MTFN with a lattice pattern.
• FIG. 2 through FIG. 15C the apparatus generally shown in FIG. 2 through FIG. 15C. It will be appreciated that the apparatus may vary as to configuration and as to details of the parts, and that the method may vary as to the specific steps and sequence, without departing from the basic concepts as disclosed herein.
• FIG. 2A and FIG. 2B illustrate assembled and exploded views
• Stent 20 generally comprises a micro-patterned-thin- film nitinol (MTFN) cover 22 that is disposed around a collapsible truss 24.
• truss 24 may comprise a plurality of undulating wire segments or stent struts 28 that are coupled to anchor points 26 that allow the truss 24 to be compressed in a collapsed configuration (not shown) to a delivery location.
• struts 28 may comprise nitinol.
• the MTFN sheet 22 generally forms an extremely low profile (e.g.
• FIG. 3A shows a portion of an MTFN stent cover 22 contacting a vessel wall 21.
• the stent struts on the luminal side of MTFN stent cover 22 are not illustrated in FIG. 3 A.
• stent cover 22 comprises thin- film nitinol, it presents an insignificant barrier to the blood flow direction as indicated by arrow F. This lack of flow restriction inhibits restenosis of the stented vessel. In contrast, the much greater thickness of conventional ePTFE stent liner 12 as shown in FIG. 3B presents a much greater obstruction to blood flow as indicated by flow separation zone F s .
• MTFN stent cover 22 promotes endothelialization 30 on its luminal surface 23 to inhibit thrombosis whereas luminal surface 14 of conventional ePTFE stent liner 12 is acellular and thus promotes thrombosis.
• FIG. 4 An example fenestration 40 in MTFN stent cover 22 is shown in FIG. 4.
• the longitudinal and transverse dimensions across fenestration 40 are small enough to prevent migration of smooth muscle cells 32 in the stented vessel wall through fenestration 40 (i.e., from an abluminal surface 42 of MTFN stent cover 22 to the luminal surface 44).
• these dimensions in one embodiment do not exceed 10 microns with 1 micron precision.
• endothelial cells 34 on luminal surface 44 do not get invaded by smooth muscle cells 32 such that neointimal hyperplasia is prevented while still allowing for intercellular communication through the graft's thickness.
• the MTFN stent covers disclosed herein may include a surface treatment to increase hydrophilicity. This increased hydrophilicity is illustrated symbolically in FIG. 5 by dotted line 51.
• the resulting chemical modification of stent surfaces such as luminal surface 44 facilitates growth of a robust endothelial monolayer 34.
• MTFN stent cover 22 is processed to specific dimensions and composition to promote adaptation within the patient's body.
• Nitinol or Nickel Titanium, is an equiatomic (1 atom Ni, 1 atom Ti) shape memory alloy, and is commonly used in endo vascular devices in the form of bulk Nitinol (>100 microns thick).
• MTFN stent cover 22 of the present invention comprises thin film nitinol (TFN) that is fabricated in sheets approximately 5 ⁇ thick via sputter deposition that has only recently become available for practical uses.
• TFN thin film nitinol
• MTFN stent cover 22 may be generated using a "hot-target" sputter deposition process, detailed in International Application No.
• TFN thin-film nitinol
• a semiconductor substrate may be patterned using a deep reactive ion etching (DRIE) process to create a patterned substrate.
• DRIE deep reactive ion etching
• Nitinol is then sputtered onto the patterned substrate.
• the bottoms of the etched trenches in the substrate also receive a sputtered layer of nitinol, those areas are separated from the nitinol deposited on the non-trenched portions of the patterned substrate by the vertical trench walls produced by the DRIE process.
• the nitinol film When the nitinol film is then released from the patterned substrate, the nitinol film will then have fenestrations corresponding to where the trenches were produced on the patterned substrate.
• the use of the DRIE-patterned substrate is quite advantageous because of its relatively tight tolerance - for example, the trench shapes (and thus the resulting fenestrations in the patterned thin-film nitinol) may have a tolerance of a 1 micron or less. In contrast, wet etching techniques typically have much coarser tolerances. Since the fenestrations disclosed herein are relatively small (e.g., having longitudinal and transverse dimensions of 10 microns or less), it is advantageous to employ the DRIE process discussed in the '430 application. However, it will be appreciated that nitinol may be sputtered onto an un-patterned substrate such that the fenestrations are subsequently formed using conventional wet- etching techniques in alternative embodiments.
• stent cover 22 is cylindrical. To form such a three-dimensional structure from the nitinol sheet, the longitudinal edges of the sheet are sealed together along a seam 23 as shown in FIG. 2B. It will thus be appreciated the stent cover length (the longitudinal extent of a stent cover) depends upon the longitudinal length of the initial thin-film nitinol sheet that is then sealed along its longitudinal edges to form seam 23.
• the initial thin-film nitinol sheet will have some transverse length along its proximal and distal edges. It is this transverse length for the initial thin-film nitinol sheet that determines the stent cover lumen diameter.
• nitinol could be sputtered onto a patterned tubular mandrel and then released from the mandrel to produce stent cover 22. In such embodiments, there would be no intermediate stage of forming a planar sheet and then sealing the sheet into a tubular structure.
• nitinol may be sputtered onto a patterned planar substrate.
• a sacrificial layer such as a chromium layer may then be deposited along a swath of the sputtered nitinol and then additional nitinol sputtered onto this sacrificial layer and the initially-deposited nitinol outside of the area covered by the sacrificial layer.
• a "layer cake" nitinol sheet results that has sealed edges (nitinol deposited on nitinol) and also nitinol layers that are separated by the sacrificial layer. This sacrificial layer is exposed in the fenestrations of the nitinol layers and may thus be etched away.
• a three-dimensional (i.e., tubular) structure results that needs no sealing along any longitudinal edges despite the use of planar substrates. Additional details regarding the manufacture of such a tubular thin- film nitinol structure may be found in U.S. Patent No. 6,790,298, the contents of which are incorporated by reference in their entirety.
• the MTFN stent cover 22 of the present disclosure generally has a thickness of less than 50 microns, and preferably has a thicknesses ranging from about 0.1 microns to about 30 microns.
• the thin films may have a thickness ranging from about 0.1, 1, 2, 4, 5, 10, 15, 20, 25, 30 or 50 microns to about 4, 5, 10, 15, 20, 25, or 30 microns. More preferably, the thin films may have a thickness of from about 4 microns to about 12 microns.
• a stent truss 24 (FIG. 2B) with the thin memory metal film of the present disclosure results in a minimal and inconsequential increase in the size of the overall device.
• MTFN can be manufactured in films of from about 5 to about 8 ⁇ thickness, so that covering a stent with MTFN adds very little bulk to the devices.
• the stent struts can have a thickness in the range of, for example, about 2 ⁇ , 4 ⁇ , 6 ⁇ , 7 ⁇ , 10 ⁇ , 17 ⁇ , 18 ⁇ , or 20 ⁇ .
• Both truss 24 and MTFN stent cover 22 can be produced in a range of shapes and sizes.
• thin memory metal alloy films can be made square or rectangular e.g. when laid flat, the sheet can have the appearance of a rectangle with a longer longitudinal dimension and a shorter transverse dimension. Each dimension of such a square or rectangle can be selected from a wide range.
• the width (the transverse dimension) of such a square or rectangle may be in the range of, for example, about 0.5 mm, 1 mm, 3 mm, 5 mm, 10 mm, 16 mm, 20 mm, 25 mm, 30 mm, or 40 mm.
• the width is generally a function of the internal diameter of the lumen to be treated.
• the length (longitudinal dimension) of such a square or rectangle may be in the range of, for example, about 0.5 mm, 2 mm, 5 mm, 15 mm, 20 mm, mm, 50 mm, or 100 mm. Generally, the length is a function of the size of the region to be treated.
• Adjacent sides of sheet 22 need not be perpendicular.
• the sheet 22 can have a form that is not an endless loop; for example, the sheet can have two distal edges as ends of the sheet, bounding the length dimension.
• Thin memory metal alloy films may be made in a wide variety of shapes other than square or rectangular.
• thin memory metal alloy films may be made to resemble other polygons, circles, ovals, crescents, or an arbitrary shape.
• the sheet 22 comprises a generally rectangular thin film sheet wrapped into a generally tubular shape having a longitudinal and radial direction.
• the two distal edges of the sheet define two ends of the tubular shape and meet or overlap.
• the sheet has a compacted form with a first internal diameter and a deployed form with a second internal diameter larger than the first internal diameter such that the sheet contacts the lumen wall at a radius equal to or slightly larger than the radius of the lumen.
• Another advantage of MTFN sheet 22 of the present invention is the ability to control its surface characteristics by chemical treatment.
• the MTFN sheet 22 is treated in accordance with the methods disclosed in the '430 application, which includes removal of the film's native surface oxide layer with a buffered oxide etchant, followed by passivation in nitric acid (FINOs) and submersion in hydrogen peroxide (H 2 O 2 ).
• This process produces a TiO layer (e.g., lOOnm thick) and allows charged hydroxyl groups to attach to the surface as confirmed with high resolution transmission electron microscopy (HRTEM).
• HRTEM transmission electron microscopy
• the negative charge mimics the negative charge of the vascular endothelium and can be manipulated to facilitate rapid endothelialization (see FIGS. 1 OA- IOC described in further detail below).
• FIG. 6 shows the influence of treatment time on the wetting angle of the sheet 22.
• untreated TFN has a wetting contact angle of 65
• the sheet 22 treated for 15 hours in H 2 0 2 has a contact angle of 0 (i.e. a super- hydrophilic surface).
• This treatment modifies the surface characteristics (i.e. negative charge and TiO layer) to achieve contact angles ranging from 0 to 65 , which can be used to vary the characteristics of the stent 20.
• MTFN stent cover 22 Another significant advantage of MTFN stent cover 22 is the ability to precisely control permeability (i.e. porosity) and geometry.
• DRIE deep reactive ion etching
• the '430 application may be used to produce relatively small fenestrations with high precision (tolerance of 1 micron or less).
• fenestrations having the maximum dimensions of, for example, 25 microns or less, or even 10 microns or less, to inhibit smooth muscle migration through the fenestrations is achievable.
• Examples of four different fabricated MTFN sheets are shown in FIG.
• a sheet 50 may comprise a plurality of oval slots 52
• a sheet 60 may comprise a pattern of circular holes 62
• a sheet 70 may comprise thin diamond-shaped borders 72 separating the fenestrations in a "chain-link fence" fashion
• a sheet 80 may comprise a plurality of diamond-shaped fenestrations 82.
• FIG. 8A is an optical microscopy image of a sheet 90 having diamond-shaped fenestrations 92 with a longitudinal dimension of 10 microns across each fenestration 92 and a transverse dimension across each fenestration 92 of 7.5 microns (7.5 ⁇ xlO ⁇ ).
• FIG. 8B is an optical microscopy image of a sheet 94 having diamond-shaped fenestrations 96 having dimensions of 45 ⁇ x 60 ⁇ .
• Each fenestration 92 is smaller than a smooth muscle cell (SMC) 32 (see FIG. 4), allowing the sheet 90 to act as a filter that prevents SMC migration onto the stent luminal surface and the resulting NIH, but still permits exchange of nutrients and cell-to-cell signaling molecules through fenestrations 92.
• SMC smooth muscle cell
• FIG. 9A through FIG. 9C are graphs of the results from molecular analysis of the hemocompatibility of TFN as compared to ePTFE.
• FIG. 9A shows the total thrombus deposition for the ePTFE control and the two TFN examples whereas FIGS. 9B and 9C show fibrin and platelet deposition, respectively, for those devices.
• the devices were placed in a whole blood circulation model at a wall shear rate simulating a moderate arterial stenosis for 3 hours.
• MTFN stent 20 of the present disclosure will have a reduced incidence of both acute and late -term thrombosis as compared to ePTFE counterparts.
• HAECs Human Aortic Endothelial Cells (HAECs, Lonza, Switzerland) were cultured on the TFN samples for 1, 3, and 7 days. After each test time, samples were stained with AlexaFluor 488 phalloidin (f-actin specific) and DAPI (nucleus).
• FIG. 10A through FIG. IOC Representative images of the effects of surface wettability and the endothelial monolayer in vitro after 1 week are shown in FIG. 10A through FIG. IOC,
• an MTFN sheet 22 may be fabricated according to an optimal contact angle (e.g.
• processing time e.g. treatment time within a hydrogen peroxide (H 2 0 2 ) bath (see FIG. 6)
• processing time e.g. treatment time within a hydrogen peroxide (H 2 0 2 ) bath (see FIG. 6)
• H 2 0 2 hydrogen peroxide
• FIG. 9A a surface that minimizes thrombus deposition
• Micropattern pore size was also studied with respect to neointimal thickness and abluminal SMC migration. Pilot studies were performed to examine the effects of MTFN perforation size (i.e. permeability) on SMC migration and neointimal growth in vivo. Three types of MTFN sheets were used for this study. Each sheet had diamond-shaped apertures with dimensions of 7.5 x 10 ⁇ (sheet 90 of FIG. 8A), 10 x 20 ⁇ , and 45 x 60 ⁇ (sheet 94 of FIG. 8B). MTFN covered stents were then placed in the iliac arteries of swine and harvested after 30 days.
• FIG. 11 shows a representative image of a vessel wall 100 treated with an MTFN stent cover 90 having 7.5 ⁇ xlO ⁇ perforations (FIG. 8A).
• the neointima 102 is thin, well-organized, and does not extend into the vessel lumen 108 beyond the level of the stent struts 28.
• FIG. 12 shows the contralateral iliac artery 104 of the same animal treated with the stent cover 94 of FIG. 8B having 45 ⁇ x 60 ⁇ perforations (at the same magnification.
• the neointima 106 is thick, disorganized, and has increased numbers of inflammatory cells.
• FIG. 13 shows a graph of neointimal area (NIA— defined as the area between the MTFN stent cover and open vessel lumen 108) for various fenestration sizes, ranging from 7.5 X 10 micron fenestrations to 45 X 60 microns fenestrations.
• FIG. 13 shows an increase in NIA with increasing MTFN fenestration size. Note that the NIA (6.0 ⁇ 0.7mm 2 ) for the 7.5 ⁇ xlO ⁇ device is substantially smaller than the NIA for an ePTFE covered stent (not illustrated), which showed an NIA of 11.9 ⁇ 4.3mm 2 after 3 months of implantation in a sheep. On the far right of FIG. 13, NIA measurements are included for two non-micropatterned films with
• FIG. 14A through 14C show the wall of an artery treated with a 45 ⁇ x 60 ⁇ device at low magnification, medium
• magnification and high magnification, respectively.
• the fenestrations can be seen as small breaks in the MTFN stent cover.
• robust smooth muscle cell migration is observed (marked by the black arrows, most notably in FIG. 14B and FIG. 14C). These areas of cell migration appear as "mini-volcanoes," and significant SMC migration from the abluminal side of the MTFN stent covers is observed.
• the longitudinal and transverse dimensions for the fenestrations are ideally less than 10 ⁇ , and preferably between 5 ⁇ and 10 ⁇ . More generally, these dimensions should be less than 25 microns, and even more generally should be less than or equal to a dimension that inhibits smooth muscle migration.
• an MTFN covered stent designed with a "critical dimension" for its fenestrations e.g.
• HAECs Human Aortic Endothelial Cells
• FIG. 15A shows HAECs grown on unpatterned TFN. Their rounded "cobblestone" morphology is typical of ECs grown under normal culture conditions.
• FIGS. 15B scale bar 100 ⁇
• 15C scale bar 50 ⁇
• the lower-left inset shows the pore geometry used.
• the cells adopt an elongated morphology that follows the MTFN geometric designs, indicating that micropattern geometry regulates endothelial morphology (e.g. elongate and/or faceted, straight-edged geometry being preferred).
• an appropriately patterned MTFN stent 20 of the present invention may serve as a scaffold to encourage an atheroprotective EC morphology in ways not possible with ePTFE-based stents.
• the MTFN-based stents of the present invention address two main problems associated with ePTFE covered stents: 1. Patency independent of treated lesion length, and 2. late-term graft thrombosis.
• Patency independent of treated lesion length and 2. late-term graft thrombosis.
• ePTFE's thickness causes a size mismatch with the vessel wall that leads to restenosis, and that the relatively impermeable ePTFE barrier prevents communication between the luminal neointima and abluminal vessel wall. This causes a failure of ePTFE grafts to endothelialize and creates a chronically exposed thrombogenic surface that predisposes patients to late-term thrombosis.
• the MTFN-based stent of the present invention overcomes these limitations in at least three ways.
• the ultra-low profile of the MTFN stent 20 of the present invention eliminates edge-effect stenosis and persistent flow separation zones by allowing for proximal and distal cell migration.
• the MTFN stent 20 of the present invention has a porosity which can be controlled such that abluminal SMC migration is prevented, but still allows for intercellular communication between neointima and vessel wall throughout the length of the stent.
• the MTFN stent 20 of the present invention has surface characteristics and fenestration geometry that can be optimized to encourage growth of a non-thrombogenic, non-immunogenic endothelial layer on the stent's luminal surface that is in direct communication with the underlying vessel wall to maintain long-term patency.

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• 2014
  • 2014-02-25 JP JP2015559281A patent/JP6462592B2/ja not_active Expired - Fee Related
  • 2014-02-25 EP EP14753541.3A patent/EP2958526A4/en not_active Withdrawn
  • 2014-02-25 WO PCT/US2014/018410 patent/WO2014131037A1/en active Application Filing
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