WO2000010623A1 - Dispositif implantable destine a favoriser la reparation d'une lumiere corporelle - Google Patents

Dispositif implantable destine a favoriser la reparation d'une lumiere corporelle Download PDF

Info

Publication number
WO2000010623A1
WO2000010623A1 PCT/US1999/019412 US9919412W WO0010623A1 WO 2000010623 A1 WO2000010623 A1 WO 2000010623A1 US 9919412 W US9919412 W US 9919412W WO 0010623 A1 WO0010623 A1 WO 0010623A1
Authority
WO
WIPO (PCT)
Prior art keywords
stent
cells
temperature
stent according
surface features
Prior art date
Application number
PCT/US1999/019412
Other languages
English (en)
Inventor
Robert A. Van Tassel
Robert S. Schwartz
David R. Holmes
Original Assignee
Tricardia, L.L.C.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tricardia, L.L.C. filed Critical Tricardia, L.L.C.
Publication of WO2000010623A1 publication Critical patent/WO2000010623A1/fr

Links

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
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0002—Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network
    • A61B5/0031—Implanted circuitry
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/02—Detecting, measuring or recording pulse, heart rate, blood pressure or blood flow; Combined pulse/heart-rate/blood pressure determination; Evaluating a cardiovascular condition not otherwise provided for, e.g. using combinations of techniques provided for in this group with electrocardiography or electroauscultation; Heart catheters for measuring blood pressure
    • A61B5/026—Measuring blood flow
    • A61B5/0275—Measuring blood flow using tracers, e.g. dye dilution
    • A61B5/028—Measuring blood flow using tracers, e.g. dye dilution by thermo-dilution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
    • A61B5/6847—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
    • A61B5/6862—Stents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
    • A61B5/6867—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive specially adapted to be attached or implanted in a specific body part
    • A61B5/6876—Blood vessel
    • 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
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • 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
    • 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

Definitions

  • This invention relates generally to an implantable medical device; and more particularly to an implantable stent.
  • Endothelial cells initiate metabolic processes, like the secretion of prostacylin and endothelium-derived relaxing factor (EDRF), which actively discourage platelet deposition and thrombus formation in vessel walls.
  • EDRF endothelium-derived relaxing factor
  • damaged arterial surfaces within the vascular system are highly susceptible to thrombus formation.
  • Abnormal platelet deposition, resulting in thrombosis is more likely to occur in vessels in which endothelial, medial and adventitial damage has occurred.
  • systemic drugs have been used to prevent coagulation and to inhibit platelet aggregation, a need exists for a means by which a damaged vessel can be treated directly to prevent thrombus formation and subsequent intimal smooth muscle cell proliferation.
  • stenotic arteries are often treated with balloon angioplasty, which involves the mechanical dilation of a vessel with an inflatable catheter.
  • balloon angioplasty involves the mechanical dilation of a vessel with an inflatable catheter.
  • the effectiveness of this procedure is limited in some patients because the treatment itself damages the vessel, thereby inducing proliferation of smooth muscle cells and reocclusion or restenosis of the vessel. It has been estimated that approximately 30 to 40 percent of patients treated by balloon angioplasty and/or stents may experience restenosis within one year of the procedure.
  • the stent itself reduces restenosis in a mechanical way by providing a larger lumen. For example, some stents gradually enlarge over time.
  • many stents are implanted in a contracted form mounted on a partially expanded balloon of a balloon catheter and then expanded in situ to contact the lumen wall.
  • U. S. Patent No. 5,059,211 discloses an expandable stent for supporting the interior wall of a coronary artery wherein the stent body is made of a porous bioabsorbable material.
  • U. S. Patent No. 5,662,960 discloses a friction-reducing coating of commingled hydrogel suitable for application to polymeric plastic, rubber or metallic substrates that can be applied to the surface of a stent.
  • agents that affect cell proliferation have been tested as pharmacological treatments for stenosis and restenosis in an attempt to slow or inhibit proliferation of smooth muscle cells.
  • These compositions have included heparin, coumarin, aspirin, fish oils, calcium antagonists, steroids, prostacyclin, ultraviolet irradiation, and others.
  • Such agents may be systemically applied or may be delivered on a more local basis using a drug delivery catheter or a drug eluting stent.
  • biodegradable polymer matrices containing a pharmaceutical may be implanted at a treatment site. As the polymer degrades, a medicament is released directly at the treatment site.
  • U.S. Patent No. 5,342,348 to Kaplan and U.S. Patent No. 5,419,760 to Norciso are exemplary of this technology.
  • U.S. Patent 5,766,710 discloses a stent formed of composite biodegradable polymers of different melting temperatures.
  • Porous stents formed from porous polymers or sintered metal particles or fibers have also been used for release of therapeutic drugs within a damaged vessel, as disclosed in U. S. Patent No. 5,843,172.
  • tissue surrounding a porous stent tends to infiltrate the pores.
  • pores that promote tissue ingrowth are considered to be counte ⁇ roductive because the growth of neointima can occlude the artery, or other body lumen, into which the stent is being placed.
  • Another approach to controlling the healing of a damaged artery or vein is to induce apoptosis in neointimal cells to reduce the size of a stenotic lesion.
  • U.S. Patent No. 5,776,905 to Gibbons et al. which is inco ⁇ orated herein by reference in its entirety, describes induction of apoptosis by administering anti-sense oligonucleotides that counteract the anti-apoptotic gene, bcl-x, which is expressed at high levels by neointimal cells.
  • anti-sense oligonucleotides are intended to block expression of the anti-apoptotic gene bcl-x so that the neointimal cells are induced to undergo programmed cell death.
  • nitric oxide is produced by an inducible enzyme, nitric oxide synthase, which belongs to a family of proteins beneficial to arterial homeostasis.
  • nitric oxide synthase which belongs to a family of proteins beneficial to arterial homeostasis.
  • the effect of nitric oxide in the regulation of apoptosis is complex. A pro-apoptotic effect seems to be linked to pathophysiological conditions wherein high amounts of NO are produced by the inducible nitric oxide synthase.
  • U.S. Patent 5,766,584 to Edelman et al. describes a method for inhibiting vascular smooth muscle cell proliferation following injury to the endothelial cell lining by creating a matrix containing endothelial cells and surgically wrapping the matrix about the tunica adventitia.
  • the matrix, and especially the endothelial cells attached to the matrix secrete products that diffuse into surrounding tissue, but do not migrate to the endothelial cell lining of the injured blood vessel.
  • a number of blood flow measurements may be needed, over time, to effectively monitor the patient's condition.
  • One known method of monitoring the flow of blood in a vessel involves the percutaneous application of an instrument to measure the flow. Such methods are termed "invasive" because the body must be pierced to obtain the blood flow measurement.
  • invasive techniques to measure blood flow have a disadvantage in that the measurement must be taken under controlled conditions. For example, it is difficult, if not impossible, to monitor blood flow during periods of increased exercise.
  • the present invention is based upon the discovery that neointimal proliferation can be promoted and turned to healing effect if the infiltrating cells can be forced to assume an organized growth pattern or by subjecting the cells to increased stress, such as temperature or fluid shear stress.
  • increased stress such as temperature or fluid shear stress.
  • stent(s) comprising a tubular stent body and having surface features sized and/or arranged to promote an organized growth pattern of infiltrating cells.
  • a film of cells covering at least the interior surface of the stent body may encourage ingrowth of infiltrating cells.
  • the organized growth pattern develops into an organized cellular structure within the stent body to aid in repair of a damaged body lumen.
  • the surface features are selected to promote angiogenesis when the stent is implanted intravascularly.
  • the surface features for promoting organized cell growth can comprise a plurality of depressions in the surface of at least a portion of the stent body, preferably arranged in a regular pattern on at least the interior surface of the stent body, such as a waffle weave.
  • the surface features comprise a plurality of pleats, ridges, channels or pores in the stent body wherein at least some of the pores run between the interior and exterior sides of the stent body (i.e., penetrate the stent body) and are sized to promote the organized cell growth.
  • the invention stent body is formed from a biocompatible polymer or a biocompatible metal with the surface features stamped or molded into the surface.
  • the invention stent body can be formed of a porous biocompatible material, such as a porous matrix of sintered metal fibers or a polymer wherein the pores are sized to promote the organization of ingrowing cells therein.
  • the invention stent is diametrically expandable for implant mounted upon such a device as a balloon catheter.
  • stents having a surface feature that creates or enhances a condition of turbulence in a fluid flowing through the tubular stent body such that ingrowing cells are subjected to increased fluid shear stress by action of the turbulence, and or the surface features create stagnant flow through the stent body sufficient to cause clotting of blood, thereby promoting angiogenesis and/or neovascularization within the stent body when the stent is implanted intravascularly.
  • the stent body is covered by a biocompatible substance that expands or thickens in an aqueous environment to assume a three-dimensional form that promotes turbulence within the stent body.
  • the liquid-expandable substance can be applied to the stent body in a pattern, for example, a pattern of dots, lines or curvilinear markings.
  • the biocompatible substance is a biocompatible hydrogel, or a mixture thereof.
  • Biocompatible hydrogels useful in manufacture of the invention stents are those that provide an inte ⁇ enetrating polymer network (LPN) structure, which upon expansion in an aqueous environment, is characterized by the presence of interconnecting pores.
  • LPN inte ⁇ enetrating polymer network
  • the stent body is itself formed of a fibrous mesh, there is communication between cells external to the stent (i.e., in the vessel or lumen wall) via the holes or pores in the stent body and those growing within the interconnecting pores of the hydrogel layer.
  • Presently preferred hydrogels for use in fabrication of the invention stents are biodegradable hydrogels consisting of hydrophobic biodegradable polymers, (e.g., polylactide) and hydrophilic natural polymers (e.g., dextran) with an inte ⁇ enetrating polymer network structure.
  • the stent body is designed to promote infiltration and population of the stent by living cells, when the stent is cultured in a cell-rich medium or when the stent is implanted into a blood vessel or other tubular body lumen in a living subject, such as a mammal. Further the surface features in the stent body are selected to cause the living cells that infiltrate and populate the stent to undergo cell growth in a specific pattern determined by the placing and dimensions of the surface features of the stent body.
  • One example of such pre-determined cell growth pattern is angiogenesis and/or neovascularization.
  • the invention stent optionally further comprises a transcutaneously energized heating mechanism attached to the stent body.
  • the heating mechanism which can be energized remotely (i.e., transcutaneously), is adapted to controllably heat cells within and surrounding the stent in the lumen wall to a temperature sufficient to cause infiltrating cells, or cells seeded thereon prior to transplant, to increase production of one or more bioactive agents, such as one or more anti-proliferative, anti-restenotic, apoptotic, or angiogenesis-stimulating agents.
  • the heating mechanism includes from one to about six temperature sensors and is adapted to control the heating of the cells to an elevated temperature in the range of from 38° C to about 49°C.
  • a temperature of 49°C would cause damage. Therefore, those of skill in the art will be able to adjust the allowable maximum temperature to the body lumen being treated.
  • the stent Upon application of external energy to the implanted stent, its temperature can be elevated to promote the production of beneficial molecules, such as nitric oxide, to effect a cessation of neointimal hype ⁇ lasia within the cells in the lumen wall and/or cells growing within the stent.
  • beneficial molecules such as nitric oxide
  • the stent can be populated before implant with cells engineered to express a bioactive agent that promotes a healing bodily process, such as angiogenesis and/or neovascularization.
  • Suitable bioactive agents that can be obtained from such genetically engineered cells include several growth factors, e.g., platelet derived growth factor-A (PDGF-A), transforming growth factor (TGF), nuclear factor- ⁇ (NF- ⁇ ), an inducible redox-controlled transcription factor.
  • PDGF-A platelet derived growth factor-A
  • TGF transforming growth factor
  • NF- ⁇ nuclear factor- ⁇
  • an inducible redox-controlled transcription factor e.g., low levels of thermal therapy inhibited smooth muscle cell proliferation after balloon injury through suppression of growth factors PDGF-A and NF- ⁇ .
  • a heat sensitive promoter such as a heat shock protein promoter
  • the heating mechanism can be used to switch on or off the production of the bioactive agent upon application or withdrawal of external energy to the implanted stent.
  • the invention stent can be used in a number of different applications wherein it is desirable to chronically release a therapeutic substance from an implant, on demand, for example to cells within the wall of a damaged
  • the invention treatment method comprises promoting the ingrowth of living cells on a stent having surface features sized to promote ingrowth and/or orderly development of the cells, and implanting the stent into the tubular organ of the subject prior to or following the promoting of the ingrowth of the living cells so as to treat the tubular body organ.
  • the living cells can be donor or autologous cells.
  • the living cells can be provided by a donor or the cells can be autologous.
  • the invention treatment method is particularly useful for promoting or inhibiting angiogenesis within the stent body.
  • the invention stents are adapted for measuring the flow of a fluid through the stent body.
  • the invention stent comprises a tubular stent body and a transcutaneously energized heating mechanism attached to the stent body that includes at least two to about six temperature sensors attached at spaced locations along the length thereof, and a telemetering device for transcutaneously transmitting the output of the temperature sensors to an external monitor that records the output.
  • Methods are provided for using the output from the temperature sensors to obtain the flow of a fluid, such as blood, through the stent body.
  • an implantable stent that is adapted to promote angiogenesis within a blood vessel or other tubular lumen into which the stent is implanted.
  • Figure 1 is a greatly enlarged cross-sectional view through an artery showing a stent positioned therein, the stent including elements and/or circuitry for measuring and transmitting temperature information from the stent;
  • Figure 2 is a greatly enlarged cross-sectional view of a preferred material from which a stent like that shown in Figure 1 may be formed;
  • Figure 3 is a schematic block diagram of the system used with the stent of Figure 1;
  • Figure 4 is a bar chart graph showing the percentage increase in cell production of heat shock protein and inducible nitric oxide synthase resulting from the hyperthermia.
  • Figure 5 is a graph showing the results of experiments conducted using the invention heatable stent to measure the rate of flow of blood through the stent.
  • the temperatures shown are the average for four data points for three equidistant temperature sensors on the stent, with “distal stent” representing the sensor distal to the heating element and “proximal stent” representing the sensor proximal to the heating element.
  • Flow rate was measured with flow from the distal to the proximal sensor (Flow Distal) and from the proximal to the distal sensor (Flow Proximal).
  • stents comprising a tubular stent body having surface features adapted to promote an organized growth pattern of infiltrating cells, such as takes place during angiogenesis and/or neovascularization.
  • the surface features comprise a plurality of depressions in the surface of at least a portion of the stent body, for example the interior surface of the stent body. It is presently preferred that the surface depressions have an average volume per depression in the range from about 10 ⁇ m to about 100 ⁇ m.
  • the surface depressions are generally arranged in an orderly pattern, such as a waffle weave pattern than can be readily stamped into the material from which the stent body is fabricated.
  • the invention stent has surface features comprising pores in the stent body having an average diameter in the range from about 30 microns to about 65 microns.
  • the invention stent has a slightly greater inner diameter than that of the lumen into which it is placed such that a layer of ingrowing cells will cause the effective inner diameter to match the inner diameter of the vessel or lumen into which it is placed.
  • Cells growing in the stent e.g. in pores contained in the stent
  • the overall porosity of the invention stent is in the range from about 50% to about 85%, for example, at least about 70%.
  • an invention stent having such pores is implanted into a body lumen, for example intravascularly, the implanted stent will readily be infiltrated by cells from the surrounding cellular environment so as to create an organized cellular structure similar to that of the surrounding bodily environment.
  • the type of organized structure formed within the stent may be dictated by the biological environment surrounding the implanted stent (e.g. whether a blood vessel or a urethra).
  • the type of organized structure formed will correlate with the type of cells seeded into the stent or that infiltrate the stent from the implant site.
  • pores in the size range from about 30 microns to about 65 microns are particularly effective for promoting the growth and organization of infiltrating cells, such as cells of the vascular intima, into organized cellular structures, such as takes place during angiogenesis and neovascularization.
  • the invention stent has surface features selected to organize the infiltrating cells into a longitudinal growth pattern.
  • the surface features of the invention stent can comprise a plurality of longitudinal pleats, grooves, channels, and the like, in the stent body (i.e., running along the axis of the tubular stent body).
  • the pleats, grooves, or channels are preferably spaced and sized to create turbulence in flow of blood through the stent and/or to cause longitudinal alignment of cells that infiltrate the pleats, grooves, and/or channels.
  • the pleats, grooves, or channels generally have an average height or depth in the range from about 10 ⁇ m to about 100 ⁇ m and an average distance from center to center in the range from about 10 ⁇ m to about 100 ⁇ m.
  • the surface features can be selected to create turbulence in a fluid, such as blood, flowing through the tubular stent body.
  • a fluid such as blood
  • the turbulence created by the surface features is intended to apply increased fluid shear stress on infiltrating cells (as compared with that applied by a similarly composed stent, but lacking the surface features of the invention stent) when the stent is implanted in the vasculature of a living body.
  • the elevated shear may force cells to mature earlier, the increased shear force being a mechanical and fluid dynamic stimulus to maturation.
  • the fluid shear stress is created in the longitudinal direction relative to the stent.
  • the invention stent has a tapered inner diameter for restricting fluid flow in a nozzle like manner, thereby tending to control cell growth by exerting increased fluid shear on the ingrowing cells.
  • angiogenesis and neovascularization are enhanced when blood flow through an implanted stent is slowed down sufficiently to promote clot formation, as clot formation is an initial step in the process leading to formation of new vasculature. Therefore, the surface features on the interior surface of the invention stent body can efficaciously be selected to promote stagnation of blood flow through the stent.
  • smooth muscle cells migrate from sites distant to colonize a resorbing thrombus, using it as a bioabsorbable proliferation matrix in which to migrate and replicate. Typically, the thrombus is colonized at progressively deeper levels until the neointimal healing is complete R. S.
  • the surface features on the stent body can comprise an array of upstanding projections that promote or enhance shear turbulence in blood flow along at least a portion of the surface of the stent body (as compared with that applied by a similarly composed stent, but lacking the surface features of the invention stent).
  • the array covers at least the interior surface of the stent body .
  • the projections generally have an average height of from about 10 ⁇ m to about 100 ⁇ m.
  • the projections comprise an orderly array of hooks, such as is used in Velcro® fasteners, or stalks having a diameter to height ratio of from about 10:1 to about 100:1. Generally such stalks have a flow impeding feature, such as a bulbous tip.
  • the orderly array can have a uniform spacing of from about 10 ⁇ m to about 200 ⁇ m from center to center.
  • the surface features on the invention stent comprise a layer of a biocompatible substance that expands or thickens in an aqueous environment to assume a three-dimensional form, wherein the layer covers at least a portion of the surface of the stent body.
  • the biocompatible substance can be or comprise one or more hydrogels, such that the hydrogel layer expands as it absorbs water upon contact with an aqueous environment to create a porous three dimensional layer.
  • the three dimensional form can comprise an array of upstanding projections, such as described above.
  • the surfaces of the stent be relatively smooth (e.g., with the projections lying recumbent against the surface of the stent body or in an undeveloped state) until such time as the stent is implanted and/or comes into contact with an aqueous environment.
  • the projections can be formed from dots of a substance that expands upon contact with water, such as dots of hydrogel or calcium hydroxyapatite crystals upon at least the interior surface of the stent body that expand upon contact with an aqueous environment, thereby forming projections into the interior void of the stent body. Such projections aid in slowing the flow of fluid through the stent body.
  • the surface features on the invention stent comprise a pattern of hydrogel markings on at least a portion of the surface of the stent body, such as a pattern of dots, lines, curvilinear tracings, or a mixture thereof.
  • the markings are distributed over at least the interior surface of the stent body, but the pattern of markings can also cover the exterior surface of the stent body.
  • the stent body can be formed of any suitable substance, such as is known in the art, that can be adapted (e.g., molded, stamped, woven, etc.) to contain the surface features described herein.
  • the stent body can be formed from a biocompatible metal, such as stainless steel, tantalum, nitinol, elgiloy, and the like, and suitable combinations thereof.
  • Preferred metal stents are formed of a material comprising metallic fibers uniformly laid to form a three-dimensional non-woven matrix and sintered to form a labyrinth structure exhibiting high porosity, typically in a range from about 50 percent to about 85 percent, preferably at least about 70 percent.
  • the metal fibers typically have a diameter in the range from about 1 micron to 25 microns.
  • the average effective pore size is in the stent body such that cellular ingrowth into the pores and interstices is enhanced, for example having an average diameter in the range from about 30 microns to about 65 microns.
  • a material having these desired properties that can be used in manufacture of the invention stent is available from the Bekaeart Co ⁇ oration of Marietta, GA, and sold under the trademark, BEKLPOR® filter medium.
  • the stent body can be formed of a biocompatible non porous polymer or a polymer made porous by inco ⁇ orating dissolvable salt particles prior to curing thereof and then dissolving away the salt particles to leave voids and interstices therein.
  • the polymer may be biostable or bioabsorbable, such as a number of medical grade plastics, including but not limited to, high-density polyethylene, polypropylene, polyurethane, polysulfone, nylon and polytetra-fluoroethylene.
  • a porous polymer stent body can be made having pores with an average diameter in the range from about 30 microns to about 65 microns, by procedures known in the art.
  • polymer granules can be ground down to obtain small particles of about 100 microns in diameter, mixed with salt, and compressed into a compact form, for example using a jack, a plate and a die.
  • the compressed forms are then placed in a pressure vessel and subjected to a gas, such as carbon dioxide, at high pressure of about 800 pounds per square inch until the gas dissolves into the polymer, the pressure is released rapidly, and the polymer particles expand and fuse together, to yield a porous polymer.
  • a gas such as carbon dioxide
  • Autologous cells naturally invade the invention stent, particularly the surface features thereof, following placement in a body lumen of a host subject and spontaneously generate an organized cellular structure that varies depending upon the cellular makeup of the bodily lumen into which the stent is implanted.
  • endothelial or other suitable cells may be made to invade the stent in a cell culture lab to create a living stent prior to implant, using methods known in the art.
  • a living stent can be obtained according to the invention wherein the stent is populated with live cells selected from endothelial cells, smooth muscle cells, leukocytes, monocytes, epithelial cells, polymo ⁇ honuclear leukocytes, lymphocytes, basophils, fibroblasts, stem cells, epithelial cells, eosinophils, and the like, and combinations of any two or more thereof.
  • live stent such cells actually live within the surface features of the stent, such as the pores, grooves, channels, etc., and are not merely a surface coating, as may be the case when a metal wire braided stent is used, or other stent lacking suitable surface features as disclosed herein.
  • the stent may first be coated with a suitable component, such as a protein like fibronectin, elastin, mucopolysaccharide, or other suitable extracellular matrix protein.
  • a suitable component such as a protein like fibronectin, elastin, mucopolysaccharide, or other suitable extracellular matrix protein.
  • the thus-treated stent is placed in a cell culture dish and the selected living cells are allowed to form a coating on non-porous stents and to invade the interior of a porous stent material. Once the stent is populated with living cells, it is ready for implant.
  • a typical intravascular stent may have an outer diameter in a range of from about 2.0 mm to about 6.0 mm and a wall thickness in a range from about 0.1 mm to about 12 mm, for example about 0.1 mm to about 1.0 mm.
  • the particular size depends on the anatomy where the stent is to be implanted.
  • the invention stent is diametrically adjustable, being designed to be remotely introduced into a body cavity by the use of a catheter type of delivery system. Any of a variety of techniques or designs, as is known in the art, can be used for making the invention stent diametrically expandable. For example, such designs are disclosed for example in U.S. Patent No.
  • the stent body can be made of an expanded metal or plastic device having a fenestrated side wall to facilitate expansion thereof, as shown in Figure 1.
  • the stent may instead have a tubular configuration that is pleated longitudinally prior to implant so as to exhibit a reduced outside diameter to facilitate routing and placement thereof, but which may later be expanded to a diameter equal to or only slighter greater than the diameter of the blood vessel, body lumen, or tubular organ at the treatment site.
  • the stent may also have a rolled or braided construction known in the art which can be expanded from a lesser diameter to a larger diameter.
  • the diametrically expandable stent is designed to be implanted in a contracted form, for example, mounted on a partially expanded balloon of a balloon catheter and then expanded in situ to contact the lumen wall.
  • a ratio between the collapsed and expanded diameters of the invention stent can be employed, depending upon the body lumen into which the stent is to be placed, generally in the diametrically adjustable stent, the expanded diameter is at least about 1.5 times the size of the collapsed diameter.
  • the invention stent can be coated with a friction-reducing coating, for example of commingled hydrogel, to reduce friction during implant, as disclosed in U.S. Patent No. 5,662,960.
  • FIG. 1 there is illustrated a greatly enlarged cross-sectional view, through an arterial blood vessel 10.
  • a stenotic lesion 12 that has been subjected to balloon angioplasty for establishing greater patency to the artery.
  • the blood vessel has been damaged, and a stent 14 constructed of a material capable of supporting cellular growth thereon, has been implanted into the lumen of the blood vessel and expanded to abut the inner layer of the injured blood vessel.
  • Stent 14 is preferably a balloon expandable device made of expandable metal or braided wire, but also may be designed as a self-expanding structure. It may also be fabricated from a composition of metallic fibers, uniformly laid to form a three- dimensional, non- woven structure, such as is shown in Figure 2.
  • the invention stent may be used as part of a stent system which comprises, in addition to the invention stent, an energy source for transcutaneously transmitting heating energy to the stent to raise the temperature of the implanted stent to a temperature above body temperature.
  • the energy source is external to the subject and delivers electromagnetic energy to the stent in the form of radio frequency energy, microwave energy, a magnetic field, and the like.
  • the percutaneously delivered electromagnetic energy is transformed to heat energy in the stent body itself, for example through induction of Eddy currents or dielectric heating.
  • delivery of energy to the stent, and consequently heating of the stent is controlled by from one to about six heat sensors attached to the stent body that commumcate percutaneously with the energy source to regulate the heating of the stent to a safe level.
  • the energy source can transmit sufficient energy to the implanted stent to stimulate the live cells therein to increase production of one or more bioactive agents, such as are effective to modify vascular structure in the hemato logic system. For example, if the ingrowing cells produce heparin, a coating of heparin will be formed on the stent surface that modifies platelet function.
  • the energy source for transcutaneously transmitting heating energy to the invention stent can comprise a source of high frequency AC current, shown here as generator 15, for externally applying an alternating electromagnetic field that is transcutaneously transmitted from generator 15 to the implanted stent 14 so as to induce Eddy currents therein, thereby causing the temperature of the stent to rise above normal body temperature.
  • generator 15 a source of high frequency AC current
  • the stent is made of a suitable metal alloy exhibiting a Curie point at a desired maximum temperature of about 49 °C or less, no control need be maintained over the externally applied magnetic field because the heating of the stent will not increase above the point corresponding to the Curie point.
  • the source of transcutaneously applied heating energy can comprise a source of microwave energy, or another form of high frequency dielectric heating known in the art, for transcutaneoulsy generating heat in the polymer stent.
  • the invention stent used in the stent system as disclosed herein further comprises a thermostat/heat regulator for monitoring the temperature of the implanted stent and regulating the temperature therein to avoid over-heating of the stent and cells living therein to a temperature where cell necrosis occurs, as described above.
  • Figure 1 shows the thermostat/heat regulator as an electronic sensor and telemetering device comprising antenna coil 16, which is wrapped about the surface of the stent 14, the antenna coil being connected to a hybrid integrated circuit chip 18, which is also mounted on the surface of the stent.
  • the source of high frequency energy used in the invention stent system to transcutaneously transmit energy to the invention stent is a radio frequency generator
  • a portion of the RF energy used in heating the stent 14 is picked up by the antenna coil 16 and converted to a DC voltage for powering the electronics comprising the hybrid circuit.
  • a metal stent body may itself act as an antenna and transfer energy to a temperature sensor sufficient to activate the sensor and transmit temperature readings to a transcutaneous monitor, and the like.
  • Figure 3 is a schematic diagram of a representative hybrid circuit and it shows an AC/DC converter 19 for producing a DC voltage for powering the microprocessor 20.
  • a temperature sensor such as a thermistor bead 22, is applied to the microprocessor and more particularly to an on-chip A/D converter 24 to produce a binary signal train proportional to the difference between stent temperature and body temperature.
  • a program for controlling the conversion of the analog output from the temperature sensor 22 to a digital representation is stored in a ROM memory 26 in the hybrid circuit 18 and the data may be transmitted to an external monitor/controller 28 by means of a telemetry link 30 of conventional design known in the art.
  • the monitor/controller will then operate to increase or decrease the energy being transcutaneously delivered to the stent by the high frequency AC generator such that the stent temperature can be maintained at a predetermined set-point value previously programmed into the RAM memory 32 of the hybrid circuit 18.
  • the temperature sensor can be a passive heat sensor, such as a temperature sensitive crystal, affixed to the stent and when an interrogation frequency is applied, via an external power source, such as a generator, the crystal will resonate at a frequency that varies with temperature.
  • a passive heat sensor such as a temperature sensitive crystal
  • nitric oxide synthase the enzyme known to trigger production of nitric oxide in endothelial cells of the vasculature, among others, has been found to be a by-product of hyperthermia and NO has been shown to be shown to produce apoptosis inhibiting proliferation of smooth muscle cells.
  • the graph of Figure 4 illustrates the up-regulation in a heat shock protein, HSP70, and inducible nitric oxide synthase resulting from an increase in the cell temperature from 37 °C to 43 °C. Also shown is the corresponding increase in apoptosis in smooth muscle cells.
  • the invention treatment method comprises promoting the ingrowth of living cells in a stent having surface features sized and/or arranged to promote ingrowth of the cells, and implanting the stent into the tubular organ of the subject prior to or following the promoting of the ingrowth of the living cells so as to treat the tubular body organ.
  • the invention stent used in the treatment method holds the cells in a specific pattern or stimulates the growth of the cells into an organized growth pattern.
  • the organized growth pattern develops into an organized cellular structure within the stent body, such as takes place during angiogenesis and/or neovascularization.
  • the living cells can be either donor or autologous cells.
  • the stent of the present invention can be implanted using any surgical technique known in the art as is dictated by the particular tubular body organ to be treated. However, it is presently preferred to implant the invention living stent by placing the device in an unexpanded form over a deflated balloon on the distal end of an intravascular catheter. The catheter is routed through the vascular system until the stent is positioned adjacent to target tissue where the balloon is then inflated to expand the stent against the wall of the blood vessel. Once the stent is lodged in place, the balloon is again deflated and the placement catheter is withdrawn from the body.
  • the invention treatment method can be used to stimulate the growth and/or repair of numerous tubular body organs, including, but not limited to blood vessels, trachea, ureters, urethrea, the common bile duct, the bronchi, and the like. So long as the body lumen has not suffered a circumferential lesion that completely destroys or disrupts the integrity of the lumen, the invention stent can be used to repair most types of injuries in a tubular body lumen, including tears, splits, and the like.
  • the invention treatment method further comprises transcutaneously applying energy to the stent, thereby heating the stent to a temperature above normal body temperature sufficient to cause the living cells to express one or more bioactive agents.
  • the invention treatment method can be self-administered.
  • the subject can place the energy source on or next to the outer body surface proximal to the stent so as to place the stent in the energy field.
  • the stent comprises a thermostat/heat regulator as described herein, or as known in the art, the sensor in the implanted stent will regulate the energy field produced by the energy source as needed to modulate the temperature of the stent and surrounding tissue to the desired temperature range (i.e. above body temperature, but below the temperature at which necrosis will occur).
  • the treatment can comprise operating the energy source with the stent in the energy field for a single period of time, or at repeated short intervals, for example about 20 to 30 minutes per day.
  • the treatment can be continued in this manner for as long as desired, for example, over a period of weeks or even months.
  • the living cells ingrowing in the stent in the invention treatment method, which produce beneficial bioactive agents can be autologous cells of the subject into which the stent is implanted, cells seeded into the stent prior to implant that naturally produce the desired bioactive agent, or cells that are genetically modified to produce a desired bioactive agent.
  • Living cells that naturally produce one or more bioactive agents useful in practice of the invention methods include endothelial cells, smooth muscle cells, leukocytes, monocytes, polymo ⁇ honuclear leukocytes, lymphocytes, basophils, fibroblasts, stem cells, epithelial cells, eosinophils, and the like, and suitable combinations thereof. Such cells can be either donor or autologous cells.
  • the cells used in the invention treatment method can be engineered to express and release a bioactive agent in response to heating above body temperature such that the recombinant gene products are delivered to a site implanted with an invention stent.
  • a heat sensitive gene promoter can be operatively associated with a gene that encodes such a bioactive agent or a protein that regulates production of a bioactive agent to regulate expression of the gene product.
  • Heat sensitive gene promoters suitable for use in the invention method include the E. Coli and Drosophila heat shock promoters, and the like.
  • Heating can be made to either turn on, or turn off, the recombinant gene when the temperature is elevated, depending upon the selection of the transcription regulatory region, e.g., the promoter and other regulatory elements, as is known in the art.
  • the temperature elevation may be achieved, as indicated above, utilizing an external energy source to transcutaneously (i.e., non-invasively or potentially invasively) heat the stent material and proximal cells.
  • the recombinant promoter/gene combination DNA can be transfected into the cells of interest near the implant site, or alternatively, may be eluted from the stent or implant device to transfect, locally, proximal cells. Cells may also be externally transfected with the heat sensitive promoter and gene, and then implanted with the stent device, so that heating the device following implant will activate (or inhibit) the gene product directly. Heating can be done chronically over time, being available to the biologic site of interest as long as the recombinant cells survive at the implant site.
  • the cells can be obtained from a donor or from the host subject to be treated, modified as above, and then reintroduced into the subject to be treated.
  • the transplanted cells are "autologous" with respect to the subject, meaning that the donor and recipient of the cells are one and the same.
  • Stably transfected mammalian cells may be prepared by transfecting cells with an expression vector having a selectable marker gene (such as, for example, the gene for thymidine kinase, dihydrofolate reductase, neomycin resistance, and the like), and growing the transfected cells under conditions selective for cells expressing the marker gene.
  • a selectable marker gene such as, for example, the gene for thymidine kinase, dihydrofolate reductase, neomycin resistance, and the like
  • mammalian cells are transfected with a reporter gene (such as the E. coli ⁇ -galactosidase gene) to monitor transfection efficiency.
  • a reporter gene such as the E. coli ⁇ -galactosidase gene
  • Genes that encode useful bioactive agents that are not normally transported outside the cell can be used in the invention if such genes are “functionally appended” to a signal sequence that can "transport” the encoded product across the cell membrane.
  • a variety of such signal sequences are known and can be used by those skilled in the art without undue experimentation.
  • Gene transfer vectors contemplated for use herein are recombinant nucleic acid molecules that are used to transport nucleic acid into host cells for expression and/or replication thereof.
  • Expression vectors may be either circular or linear, and are capable of inco ⁇ orating a variety of nucleic acid constructs therein.
  • Expression vectors typically come in the form of a plasmid that, upon introduction into an appropriate host cell, results in expression of the inserted nucleic acid.
  • Suitable expression vectors for use herein are well known to those of skill in the art and include a recombinant DNA or RNA construct(s), such as plasmids, phage, recombinant virus or other vectors that, upon introduction into an appropriate host cell, result(s) in expression of the inserted DNA.
  • Appropriate expression vectors are well known to those of skill in the art and include those that are replicable in eukaryotic cells and/or prokaryotic cells and those that remain episomal or those which integrate into the host cell genome. Expression vectors typically further contain other functionally important nucleic acid sequences encoding antibiotic resistance proteins, and the like.
  • the amount of exogenous nucleic acid introduced into a host organism, cell or cellular system can be varied by those of skill in the art.
  • the amount of nucleic acid introduced can be increased by increasing the amount of plaque forming units (PFU) of the viral vector.
  • PFU plaque forming units
  • operatively associated with refers to the functional relationship of DNA with regulatory and effector sequences of nucleotides, such as promoters, enhancers, transcriptional and translational stop sites, and other signal sequences.
  • operative linkage of DNA to a promoter refers to the physical and functional relationship between the DNA and promoter such that the transcription of such DNA is initiated from the promoter by an RNA polymerase that specifically recognizes, binds to, and transcribes the DNA.
  • the transcription regulatory region may further comprise a binding site for ubiquitous transcription factor(s).
  • binding sites are preferably positioned between the promoter and the regulatory element.
  • Suitable ubiquitous transcription factors for use herein are well-known in the art and include, for example, Spl.
  • Exemplary eukaryotic expression vectors include eukaryotic constructs, such as the pSV-2 gpt system (Mulligan et al, (1979) Nature, 277:108-114); pBlueSkript®
  • Suitable means for introducing (transducing) expression vectors containing heterologous nucleic acid constructs into host cells to produce transduced recombinant cells are well-known in the art (see, for review, Friedmann, Science, 244:1275-1281. 1989; Mulhgan, Science, 260:926-932. 1993, each of which are inco ⁇ orated herein by reference in their entirety).
  • Exemplary methods of transduction include, e.g., infection employing viral vectors (see, e.g., U.S. Patent 4,405,712 and 4,650,764), calcium phosphate transfection (U.S.
  • transduced nucleic acid can optionally include sequences which allow for its extrachromosomal (i.e., episomal) maintenance, or the transduced nucleic acid can be donor nucleic acid that integrates into the genome of the host.
  • Bioactive agents suitable for delivery according to the invention methods include those which the mammalian body utilizes to stimulate angiogenesis, including those which regulate capillary formation in wounds and attract smooth muscle to coat and support the capillaries.
  • bioactive agents include vascular endothelial growth factor (VEGF), fibroblast growth factors (FGFs), particularly FGF-1, angiopoietin 1, thrombin, and the like.
  • bioactive agents suitable for delivery according to the invention methods include anti- proliferative, anti-restenotic or apoptotic agents, such as platelet-derived growth factor- A (PDGF-A), transforming growth factor beta(TGF- ⁇ ), nuclear factor- ⁇ ⁇ (NF- ⁇ ), an inducible redox-controlled transcription factor, and the like.
  • PDGF-A platelet-derived growth factor- A
  • TGF- ⁇ transforming growth factor beta
  • NF- ⁇ nuclear factor- ⁇ ⁇
  • an inducible redox-controlled transcription factor an inducible redox-controlled transcription factor
  • temperature-sensing stents for measuring the flow of a liquid, such as blood, through the stent.
  • the invention temperature sensitive stent is based upon the principle that a liquid (e.g., blood) flowing through stent is a cooling medium and that the amount of cooling of a stent that has been heated above body temperature is directly proportional to the flow rate of the liquid flowing through the stent.
  • the invention temperature-sensitive stent can be used to measure and monitor the flow of blood in the blood vessel in a non-invasive manner.
  • the invention temperature-sensitive stent comprises a tubular stent body having attached thereto a heating mechanism that includes one to about six temperature sensors, with the temperature sensors attached at discrete spaced locations along the length thereof, each adapted for sensing the temperature at the discrete location, and a telemetering device for transcutaneously conveying the temperature sensed by each sensor to a monitor.
  • the monitor can transform the message from the telemetering device to a visible display, or record the message in some other readable format.
  • the monitor generally is in communication with the energy source so that temperature information from the sensors is used to turn the energy source on and off to modulate and/or control the temperature of the invention stent.
  • the stent comprises from two to about six with the temperature sensors spaced out along the length of the stent body.
  • the stent may comprise three heat sensors equally spaced along the length of the stent body. It is preferred that the temperature sensors have sufficient sensitivity to detect a temperature difference as small as 0.1 °C from one end of the stent to the other end. When the temperature sensor is a thermocouple or thermopile, temperature differences as small as 0.1 °C can be detected.
  • the invention temperature-sensing stent may further comprise surface features in the stent body adapted to promote an organized growth pattern of infiltrating cells as described herein.
  • methods are provided for using the invention temperature-sensing stent to measure flow of a fluid through a body lumen into which the stent is implanted, for example blood flow through a blood vessel.
  • the invention method for measuring flow of a fluid comprises implanting an invention stent temperature-sensitive stent, as described herein, into a body lumen having a flow of fluid therethrough, energizing the implanted stent transcutaneously to raise the temperature thereof above body temperature, monitoring transcutaneously the output from one or more of the temperature sensors upon cessation of the energizing to determine the cooling rate at the sensors, and obtaining the flow rate of the fluid from the cooling rate at the one or more sensors.
  • the stent body is generally sufficiently to raise the temperature of the stent about 2 to 12 degrees Centigrade above body temperature.
  • Determination of the fluid flow rate from the temperature information e.g., the cooling rate of the fluid flowing through the stent
  • the temperature information e.g., the cooling rate of the fluid flowing through the stent
  • Such algorithms generally take into account such parameters as the heat capacity properties of the fluid, the interior cross-sectional area of the stent body, the length of the stent, the distance between the relevant temperature sensors, the difference between temperatures sensed at any two locations along the length of the stent, the difference between the temperature sensed at any discrete location and body temperature, the neointimal thickness/area, and the like.
  • Equation I can be used to obtain a fluid flow rate based on such parameters as follows:
  • T temperature
  • x distance of fluid flow
  • p 0 specific heat of fluid
  • P power in to heat the stent
  • Q flow rate
  • A cross-sectional area of the stent.
  • the concept of flow measurement by the temperature sensitive stent is based upon the principle that a liquid (e.g. blood) flowing through a stent is a cooling medium and that the amount of cooling of a stent that has been heated above body temperature is directly proportional to the flow rate of the liquid through the stent. This is expressed by Equation I above.
  • Equation I To validate the use of the heated stent as a measure of flow rate, experimental data was obtained through the bench testing as follows.
  • a GR2 type configuration stent was created using 38 AWG Nichrome resistance wire.
  • 30 AWG Type J thermocouples were attached to the stent in three locations described as distal (furthest away from stent heating leads), mid and proximal.
  • the stent was deployed in a simulated blood vessel made of silicone and submerged in a 37°C distilled water bath. The water bath temperature was held constant during the testing. While a constant voltage of 11 V was applied to the stent leads, 37°C distilled water was pumped via a peristaltic pump through the deployed stent/vessel assembly at flow rates of 10, 20, 30, 40, 50, 60, 70, 80 ml/min while temperature data was collected from each of the three thermocouples.
  • FIG. 1 is a graph showing the average temperature plotted against flow rate (ml/min) for each of the three thermocouples.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biomedical Technology (AREA)
  • Surgery (AREA)
  • Molecular Biology (AREA)
  • Medical Informatics (AREA)
  • Pathology (AREA)
  • Biophysics (AREA)
  • Physics & Mathematics (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Hematology (AREA)
  • Physiology (AREA)
  • Epidemiology (AREA)
  • Computer Networks & Wireless Communication (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Prostheses (AREA)
  • Materials For Medical Uses (AREA)

Abstract

L'invention concerne un extenseur implantable présentant des caractéristiques de surface qui favorisent un motif de croissance organisée de cellules infiltrantes lorsqu'elles sont implantées dans un organe tubulaire. Les caractéristiques de surface comprennent des creux, pores, saillies, plis, canaux ou sillons dans le corps de l'extenseur et sont conçues pour accroître le mouvement ou la stagnation dans l'écoulement d'un liquide, tel que le sang, à travers l'extenseur, et/ou de favoriser la croissance de cellules infiltrantes dans un motif organisé. Autre variante, l'extenseur, selon l'invention, peut être peuplé de cellules vivantes avant son implantation et peut être chauffé par une source de chaleur extérieure, induisant ainsi la production d'agents bioactifs thérapeutiques à partir de cellules en croissance. L'invention concerne également un extenseur pouvant être chauffé et implanté, conçu pour suivre l'écoulement du liquide à travers une lumière dans laquelle l'extenseur est implanté, par mesure de la vitesse de refroidissement dudit extenseur en réaction à l'écoulement du sang, une fois la source de chaleur enlevée.
PCT/US1999/019412 1998-08-25 1999-08-25 Dispositif implantable destine a favoriser la reparation d'une lumiere corporelle WO2000010623A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US13980498A 1998-08-25 1998-08-25
US09/139,804 1998-08-25

Publications (1)

Publication Number Publication Date
WO2000010623A1 true WO2000010623A1 (fr) 2000-03-02

Family

ID=22488365

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/019412 WO2000010623A1 (fr) 1998-08-25 1999-08-25 Dispositif implantable destine a favoriser la reparation d'une lumiere corporelle

Country Status (1)

Country Link
WO (1) WO2000010623A1 (fr)

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6254564B1 (en) 1998-09-10 2001-07-03 Percardia, Inc. Left ventricular conduit with blood vessel graft
EP1254673A1 (fr) * 2001-05-02 2002-11-06 InFlow Dynamics, Inc. Stent immunotolérant ayant une surface microstructurée
WO2003032867A1 (fr) * 2001-10-12 2003-04-24 Gyne Ideas Limited Biomateriau comportant des microelements
WO2001089420A3 (fr) * 2000-05-19 2003-08-21 Advanced Bio Prosthetic Surfac Procedes et dispositif de fabrication d'un extenseur intravasculaire
US7704275B2 (en) 2007-01-26 2010-04-27 Reva Medical, Inc. Circumferentially nested expandable device
US7722662B2 (en) 1998-02-17 2010-05-25 Reva Medical, Inc. Expandable stent with sliding and locking radial elements
US7763065B2 (en) 2004-07-21 2010-07-27 Reva Medical, Inc. Balloon expandable crush-recoverable stent device
US7914574B2 (en) 2005-08-02 2011-03-29 Reva Medical, Inc. Axially nested slide and lock expandable device
US7947071B2 (en) 2008-10-10 2011-05-24 Reva Medical, Inc. Expandable slide and lock stent
US7988721B2 (en) 2007-11-30 2011-08-02 Reva Medical, Inc. Axially-radially nested expandable device
US8133277B2 (en) 2004-10-21 2012-03-13 Bard Peripheral Vascular, Inc. Medical device for fluid flow and method of forming such device
US8277500B2 (en) 2004-12-17 2012-10-02 Reva Medical, Inc. Slide-and-lock stent
US8329021B2 (en) 2010-10-28 2012-12-11 Palmaz Scientific, Inc. Method for mass transfer of micro-patterns onto medical devices
US8523936B2 (en) 2010-04-10 2013-09-03 Reva Medical, Inc. Expandable slide and lock stent
US8632583B2 (en) 2011-05-09 2014-01-21 Palmaz Scientific, Inc. Implantable medical device having enhanced endothelial migration features and methods of making the same
US8728563B2 (en) 2011-05-03 2014-05-20 Palmaz Scientific, Inc. Endoluminal implantable surfaces, stents, and grafts and method of making same
US9149378B2 (en) 2005-08-02 2015-10-06 Reva Medical, Inc. Axially nested slide and lock expandable device
US9408732B2 (en) 2013-03-14 2016-08-09 Reva Medical, Inc. Reduced-profile slide and lock stent
CN105868577A (zh) * 2016-06-06 2016-08-17 任勇 基于颈动脉支架的血液流速监测装置及其方法
WO2020150525A1 (fr) * 2019-01-18 2020-07-23 Lawrence Livermore National Security, Llc Stent en matériau à mémoire de forme et procédé
US10993805B2 (en) 2008-02-26 2021-05-04 Jenavalve Technology, Inc. Stent for the positioning and anchoring of a valvular prosthesis in an implantation site in the heart of a patient
US11065138B2 (en) 2016-05-13 2021-07-20 Jenavalve Technology, Inc. Heart valve prosthesis delivery system and method for delivery of heart valve prosthesis with introducer sheath and loading system
CN113539516A (zh) * 2021-07-07 2021-10-22 深圳睿心智能医疗科技有限公司 治疗方案的应用后效果的获取方法及装置
US11185405B2 (en) 2013-08-30 2021-11-30 Jenavalve Technology, Inc. Radially collapsible frame for a prosthetic valve and method for manufacturing such a frame
US11197754B2 (en) 2017-01-27 2021-12-14 Jenavalve Technology, Inc. Heart valve mimicry
US11337800B2 (en) 2015-05-01 2022-05-24 Jenavalve Technology, Inc. Device and method with reduced pacemaker rate in heart valve replacement
US11357624B2 (en) 2007-04-13 2022-06-14 Jenavalve Technology, Inc. Medical device for treating a heart valve insufficiency
CN115414163A (zh) * 2022-11-04 2022-12-02 清华大学 血管支架、人体血管局部变形与血管局部动力学监测系统
US11517431B2 (en) 2005-01-20 2022-12-06 Jenavalve Technology, Inc. Catheter system for implantation of prosthetic heart valves
US11564794B2 (en) 2008-02-26 2023-01-31 Jenavalve Technology, Inc. Stent for the positioning and anchoring of a valvular prosthesis in an implantation site in the heart of a patient
US11589981B2 (en) 2010-05-25 2023-02-28 Jenavalve Technology, Inc. Prosthetic heart valve and transcatheter delivered endoprosthesis comprising a prosthetic heart valve and a stent

Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4047252A (en) * 1976-01-29 1977-09-13 Meadox Medicals, Inc. Double-velour synthetic vascular graft
US4869714A (en) * 1986-02-13 1989-09-26 California Institute Of Technology Luminal surface fabrication for cardiovascular prostheses
WO1990001969A1 (fr) * 1988-08-24 1990-03-08 Slepian Marvin J Etancheification a l'aide d'un polymere biodegradable de la surface interieure d'une lumiere d'un organe
US5059211A (en) 1987-06-25 1991-10-22 Duke University Absorbable vascular stent
US5078736A (en) * 1990-05-04 1992-01-07 Interventional Thermodynamics, Inc. Method and apparatus for maintaining patency in the body passages
US5342348A (en) 1992-12-04 1994-08-30 Kaplan Aaron V Method and device for treating and enlarging body lumens
US5380589A (en) * 1993-04-19 1995-01-10 Wisconsin Alumni Research Foundation Biotextured surfaces
WO1995001138A1 (fr) * 1993-07-02 1995-01-12 Materials Evolution And Development Usa, Inc. Systeme implantable s'appliquant a la regulation du developpement cellulaire
US5419760A (en) 1993-01-08 1995-05-30 Pdt Systems, Inc. Medicament dispensing stent for prevention of restenosis of a blood vessel
US5653745A (en) * 1991-02-28 1997-08-05 Medtronic, Inc. Prosthetic vascular graft with a pleated structure
US5662960A (en) 1995-02-01 1997-09-02 Schneider (Usa) Inc. Process for producing slippery, tenaciously adhering hydrogel coatings containing a polyurethane-urea polymer hydrogel commingled with a poly (n-vinylpyrrolidone) polymer hydrogel
US5685847A (en) * 1994-06-30 1997-11-11 Boston Scientific Corporation Stent and therapeutic delivery system
US5766710A (en) 1994-06-27 1998-06-16 Advanced Cardiovascular Systems, Inc. Biodegradable mesh and film stent
US5843172A (en) 1997-04-15 1998-12-01 Advanced Cardiovascular Systems, Inc. Porous medicated stent
WO1999023977A1 (fr) * 1997-11-07 1999-05-20 Expandable Grafts Partnership Stent intravasculaire et procede de fabrication
WO1999026530A1 (fr) * 1997-11-25 1999-06-03 Cimochowski George E Implant endoluminal a capacite de detection de parametres

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4047252A (en) * 1976-01-29 1977-09-13 Meadox Medicals, Inc. Double-velour synthetic vascular graft
US4869714A (en) * 1986-02-13 1989-09-26 California Institute Of Technology Luminal surface fabrication for cardiovascular prostheses
US5059211A (en) 1987-06-25 1991-10-22 Duke University Absorbable vascular stent
WO1990001969A1 (fr) * 1988-08-24 1990-03-08 Slepian Marvin J Etancheification a l'aide d'un polymere biodegradable de la surface interieure d'une lumiere d'un organe
US5078736A (en) * 1990-05-04 1992-01-07 Interventional Thermodynamics, Inc. Method and apparatus for maintaining patency in the body passages
US5653745A (en) * 1991-02-28 1997-08-05 Medtronic, Inc. Prosthetic vascular graft with a pleated structure
US5342348A (en) 1992-12-04 1994-08-30 Kaplan Aaron V Method and device for treating and enlarging body lumens
US5419760A (en) 1993-01-08 1995-05-30 Pdt Systems, Inc. Medicament dispensing stent for prevention of restenosis of a blood vessel
US5380589A (en) * 1993-04-19 1995-01-10 Wisconsin Alumni Research Foundation Biotextured surfaces
WO1995001138A1 (fr) * 1993-07-02 1995-01-12 Materials Evolution And Development Usa, Inc. Systeme implantable s'appliquant a la regulation du developpement cellulaire
US5766710A (en) 1994-06-27 1998-06-16 Advanced Cardiovascular Systems, Inc. Biodegradable mesh and film stent
US5685847A (en) * 1994-06-30 1997-11-11 Boston Scientific Corporation Stent and therapeutic delivery system
US5662960A (en) 1995-02-01 1997-09-02 Schneider (Usa) Inc. Process for producing slippery, tenaciously adhering hydrogel coatings containing a polyurethane-urea polymer hydrogel commingled with a poly (n-vinylpyrrolidone) polymer hydrogel
US5843172A (en) 1997-04-15 1998-12-01 Advanced Cardiovascular Systems, Inc. Porous medicated stent
WO1999023977A1 (fr) * 1997-11-07 1999-05-20 Expandable Grafts Partnership Stent intravasculaire et procede de fabrication
WO1999026530A1 (fr) * 1997-11-25 1999-06-03 Cimochowski George E Implant endoluminal a capacite de detection de parametres

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DICHEK D A ET AL: "Seeding of intravascular stents with genetically engineered endothelial cells [see comments].", CIRCULATION, (1989 NOV) 80 (5) 1347-53., XP000856923 *

Cited By (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7722662B2 (en) 1998-02-17 2010-05-25 Reva Medical, Inc. Expandable stent with sliding and locking radial elements
US6254564B1 (en) 1998-09-10 2001-07-03 Percardia, Inc. Left ventricular conduit with blood vessel graft
US10806614B2 (en) 2000-05-19 2020-10-20 Vactronix Scientific, Llc Method of making recessed features on inner surface of tubular structure by thermal ablation
WO2001089420A3 (fr) * 2000-05-19 2003-08-21 Advanced Bio Prosthetic Surfac Procedes et dispositif de fabrication d'un extenseur intravasculaire
US9788980B2 (en) 2000-05-19 2017-10-17 Vactronix Scientific, Inc. Method for making grooves on a luminal surface of an intravascular stent
US8920660B2 (en) 2000-05-19 2014-12-30 Advanced Bio Prosthetic Surfaces, Ltd., a wholly owned subsidiary of Palmaz Scientific Inc. Method for making grooves on a luminal surface of an intravascular stent
US8512579B2 (en) 2000-05-19 2013-08-20 Advanced Bio Prosthetic Surfaces, Ltd. Method for making grooves on a luminal surface of an intravascular stent
US10758383B2 (en) 2000-05-19 2020-09-01 Vactronix Scientific, Llc Method of making recessed features on inner surface of tubular structure by photolithography
US8037733B2 (en) 2000-05-19 2011-10-18 Advanced Bio Prosthetic Surfaces, Ltd. Methods and apparatus for manufacturing an intravascular stent
EP1254673A1 (fr) * 2001-05-02 2002-11-06 InFlow Dynamics, Inc. Stent immunotolérant ayant une surface microstructurée
EP1656961A1 (fr) * 2001-05-02 2006-05-17 InFlow Dynamics, Inc. Stent immunotolérant ayant une surface microstructurée
WO2003032867A1 (fr) * 2001-10-12 2003-04-24 Gyne Ideas Limited Biomateriau comportant des microelements
US8512394B2 (en) 2004-07-21 2013-08-20 Reva Medical Inc. Balloon expandable crush-recoverable stent device
US7763065B2 (en) 2004-07-21 2010-07-27 Reva Medical, Inc. Balloon expandable crush-recoverable stent device
US8133277B2 (en) 2004-10-21 2012-03-13 Bard Peripheral Vascular, Inc. Medical device for fluid flow and method of forming such device
US8277500B2 (en) 2004-12-17 2012-10-02 Reva Medical, Inc. Slide-and-lock stent
US8292944B2 (en) 2004-12-17 2012-10-23 Reva Medical, Inc. Slide-and-lock stent
US9173751B2 (en) 2004-12-17 2015-11-03 Reva Medical, Inc. Slide-and-lock stent
US11517431B2 (en) 2005-01-20 2022-12-06 Jenavalve Technology, Inc. Catheter system for implantation of prosthetic heart valves
US7914574B2 (en) 2005-08-02 2011-03-29 Reva Medical, Inc. Axially nested slide and lock expandable device
US8617235B2 (en) 2005-08-02 2013-12-31 Reva Medical, Inc. Axially nested slide and lock expandable device
US9149378B2 (en) 2005-08-02 2015-10-06 Reva Medical, Inc. Axially nested slide and lock expandable device
US8540762B2 (en) 2007-01-26 2013-09-24 Reva Medical, Inc. Circumferentially nested expandable device
US7704275B2 (en) 2007-01-26 2010-04-27 Reva Medical, Inc. Circumferentially nested expandable device
US11357624B2 (en) 2007-04-13 2022-06-14 Jenavalve Technology, Inc. Medical device for treating a heart valve insufficiency
US9314354B2 (en) 2007-11-30 2016-04-19 Reva Medical, Inc. Axially-radially nested expandable device
US8460363B2 (en) 2007-11-30 2013-06-11 Reva Medical, Inc. Axially-radially nested expandable device
US7988721B2 (en) 2007-11-30 2011-08-02 Reva Medical, Inc. Axially-radially nested expandable device
US11564794B2 (en) 2008-02-26 2023-01-31 Jenavalve Technology, Inc. Stent for the positioning and anchoring of a valvular prosthesis in an implantation site in the heart of a patient
US10993805B2 (en) 2008-02-26 2021-05-04 Jenavalve Technology, Inc. Stent for the positioning and anchoring of a valvular prosthesis in an implantation site in the heart of a patient
US11154398B2 (en) 2008-02-26 2021-10-26 JenaValve Technology. Inc. Stent for the positioning and anchoring of a valvular prosthesis in an implantation site in the heart of a patient
US8545547B2 (en) 2008-10-10 2013-10-01 Reva Medical Inc. Expandable slide and lock stent
US7947071B2 (en) 2008-10-10 2011-05-24 Reva Medical, Inc. Expandable slide and lock stent
US9066827B2 (en) 2008-10-10 2015-06-30 Reva Medical, Inc. Expandable slide and lock stent
US9452068B2 (en) 2010-04-10 2016-09-27 Reva Medical, Inc. Expandable slide and lock stent
US8523936B2 (en) 2010-04-10 2013-09-03 Reva Medical, Inc. Expandable slide and lock stent
US11589981B2 (en) 2010-05-25 2023-02-28 Jenavalve Technology, Inc. Prosthetic heart valve and transcatheter delivered endoprosthesis comprising a prosthetic heart valve and a stent
US9422633B2 (en) 2010-10-28 2016-08-23 Palmaz Scientific, Inc. Method for mass transfer of micro-patterns onto medical devices
US9987398B2 (en) 2010-10-28 2018-06-05 Vactronix Scientific, Llc Pattern transfer device for mass transfer of micro-patterns onto medical devices
US8329021B2 (en) 2010-10-28 2012-12-11 Palmaz Scientific, Inc. Method for mass transfer of micro-patterns onto medical devices
US10258719B2 (en) 2010-10-28 2019-04-16 Vactronix Scientific, Llc Pattern transfer device for mass transfer of micro-patterns onto medical devices
US10669645B2 (en) 2010-10-28 2020-06-02 Vactronix Scientific, Llc Pattern transfer device for mass transfer of micro-patterns onto medical devices
US8668818B2 (en) 2010-10-28 2014-03-11 Palmaz Scientific, Inc. Method for mass transfer of micro-patterns onto medical devices
US8728563B2 (en) 2011-05-03 2014-05-20 Palmaz Scientific, Inc. Endoluminal implantable surfaces, stents, and grafts and method of making same
US9439789B2 (en) 2011-05-09 2016-09-13 Palmaz Scientific, Inc. Implantable medical device having enhanced endothelial migration features and methods of making the same
US8632583B2 (en) 2011-05-09 2014-01-21 Palmaz Scientific, Inc. Implantable medical device having enhanced endothelial migration features and methods of making the same
US10786343B2 (en) 2011-05-09 2020-09-29 Vactronix Scientific, Llc Implantable medical device having enhanced endothelial migration features and methods of making the same
US10206772B2 (en) 2011-05-09 2019-02-19 Vactronix Scientific, Llc Implantable medical device having enhanced endothelial migration features and methods of making the same
US9408732B2 (en) 2013-03-14 2016-08-09 Reva Medical, Inc. Reduced-profile slide and lock stent
US11185405B2 (en) 2013-08-30 2021-11-30 Jenavalve Technology, Inc. Radially collapsible frame for a prosthetic valve and method for manufacturing such a frame
US11337800B2 (en) 2015-05-01 2022-05-24 Jenavalve Technology, Inc. Device and method with reduced pacemaker rate in heart valve replacement
US11065138B2 (en) 2016-05-13 2021-07-20 Jenavalve Technology, Inc. Heart valve prosthesis delivery system and method for delivery of heart valve prosthesis with introducer sheath and loading system
CN105868577A (zh) * 2016-06-06 2016-08-17 任勇 基于颈动脉支架的血液流速监测装置及其方法
US11197754B2 (en) 2017-01-27 2021-12-14 Jenavalve Technology, Inc. Heart valve mimicry
US11083604B2 (en) 2019-01-18 2021-08-10 Lawrence Livermore National Security, Llc Preventing stent failure using adaptive shear responsive endovascular implant
WO2020150525A1 (fr) * 2019-01-18 2020-07-23 Lawrence Livermore National Security, Llc Stent en matériau à mémoire de forme et procédé
US11918495B2 (en) 2019-01-18 2024-03-05 Lawrence Livermore National Security, Inc. Preventing stent failure using adaptive shear responsive endovascular implant
CN113539516A (zh) * 2021-07-07 2021-10-22 深圳睿心智能医疗科技有限公司 治疗方案的应用后效果的获取方法及装置
CN115414163B (zh) * 2022-11-04 2023-02-28 清华大学 血管支架、人体血管局部变形与血管局部动力学监测系统
CN115414163A (zh) * 2022-11-04 2022-12-02 清华大学 血管支架、人体血管局部变形与血管局部动力学监测系统

Similar Documents

Publication Publication Date Title
US7235096B1 (en) Implantable device for promoting repair of a body lumen
WO2000010623A1 (fr) Dispositif implantable destine a favoriser la reparation d'une lumiere corporelle
DE69906797T2 (de) Stent-transplantate mit bioaktiven beschichtungen
EP1711126B1 (fr) Dispositif d'administration de medicaments
US5342348A (en) Method and device for treating and enlarging body lumens
US8252044B1 (en) Device for in vivo delivery of bioactive agents and method of manufacture thereof
US7447550B2 (en) System method and apparatus for localized heating of tissue
US6340368B1 (en) Implantable device with radiopaque ends
EP1015017B1 (fr) Systeme implantable comportant des cellules a elution de medicament pour l'administration locale de medicament a la demande
CN101827567A (zh) 具有内部药物递送系统的医疗植入物
US20060204556A1 (en) Cell-loaded prostheses for regenerative intraluminal applications
EP2879751B1 (fr) Dispositifs de régulation de l'écoulement d'un vaisseau
US10092507B2 (en) Implantable cellular and biotherapeutic agent delivery canister
US20090149947A1 (en) Implantable device for drug delivery and improved visibility
US20100261662A1 (en) Utilization of mural thrombus for local drug delivery into vascular tissue
WO1994014485A1 (fr) Repartition de materiaux biologiques
Zhu et al. Design principles in biomaterials and scaffolds
JP4735111B2 (ja) 人工弁を有するステント
WO2006069349A9 (fr) Protheses chargees de cellules pour applications intraluminales regeneratives
KR102221074B1 (ko) 생분해성 고분자 및 니티놀을 포함하는 스텐트 및 이의 제조방법
WO2014036809A1 (fr) Dispositifs d'administration de médicament endoluminaux ayant des applications dans des vaisseaux sanguins
US20080188926A1 (en) Stem Cell Coated Stent
US11857670B2 (en) Implantable cellular and biotherapeutic agent delivery canister
US8303639B2 (en) Releasable polymer on drug elution stent and method
US11857672B2 (en) Implantable cellular and biotherapeutic agent delivery canister

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA JP

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
CFP Corrected version of a pamphlet front page

Free format text: REVISED ABSTRACT RECEIVED BY THE INTERNATIONAL BUREAU AFTER COMPLETION OF THE TECHNICAL PREPARATIONS FOR INTERNATIONAL PUBLICATION