WO1999061107A9 - Radioactive intraluminal endovascular prosthesis and method for the treatment of aneurysms - Google Patents
Radioactive intraluminal endovascular prosthesis and method for the treatment of aneurysmsInfo
- Publication number
- WO1999061107A9 WO1999061107A9 PCT/US1999/011321 US9911321W WO9961107A9 WO 1999061107 A9 WO1999061107 A9 WO 1999061107A9 US 9911321 W US9911321 W US 9911321W WO 9961107 A9 WO9961107 A9 WO 9961107A9
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- Prior art keywords
- endovascular
- aneurysm
- radiation
- radioactive
- selected region
- Prior art date
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
- A61N5/1001—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy using radiation sources introduced into or applied onto the body; brachytherapy
- A61N5/1002—Intraluminal radiation therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
- A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
- A61B17/12099—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder
- A61B17/12109—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder in a blood vessel
- A61B17/12113—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder in a blood vessel within an aneurysm
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
- A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
- A61B17/12099—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder
- A61B17/12109—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder in a blood vessel
- A61B17/12113—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder in a blood vessel within an aneurysm
- A61B17/12118—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder in a blood vessel within an aneurysm for positioning in conjunction with a stent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
- A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
- A61B17/12131—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device
- A61B17/1214—Coils or wires
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
- A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
- A61B17/12131—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device
- A61B17/12181—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device formed by fluidized, gelatinous or cellular remodelable materials, e.g. embolic liquids, foams or extracellular matrices
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
- A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
- A61B17/12131—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device
- A61B17/12181—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device formed by fluidized, gelatinous or cellular remodelable materials, e.g. embolic liquids, foams or extracellular matrices
- A61B17/12186—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device formed by fluidized, gelatinous or cellular remodelable materials, e.g. embolic liquids, foams or extracellular matrices liquid materials adapted to be injected
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
- A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
-
- 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
- A61F2/88—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure the wire-like elements formed as helical or spiral coils
-
- 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
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
- A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
- A61F2250/0067—Means for introducing or releasing pharmaceutical products into the body
Definitions
- the present invention relates, generally, to the treatment of vascular disorders and, more particularly, to the treatment of ancurysms with radioactive intraluminal endovascular prosthesis.
- bypass graft treatment of aneurysms has steadily improved, mortality rates continue to be relatively high in cases such as abdominal aortic aneurysms. These often asymptomatic aneurysms 15 of blood vessel 16, as shown in FIGURE 1, generally progressively enlarge in most patients over time, increasing the risk of rupture.
- Traditional bypass grafts arc then required which are extremely invasive and include all the risks of open surgeries such as paraplegia, renal insufficiency, and myocardial infarction.
- DACRON ® grafts endovascular stent grafts and covered stents (referred heretofore generally as " stent grafts" ), which have rapidly developed in an effort to expand stent technology, may be employed as a means of aneurysm treatment.
- stent grafts These hybrid devices combine graft material with a stent or stent-like device to provide an expandable, stent-like structure having an impervious luminal surface.
- a graft material is mounted to and positioned along an exterior circumferential surface and/or the interior circumferential surface of the prosthesis in a manner forming an endovascular, blood impervious lumen therethrough.
- a proximal end of the graft is preferably endovascularly positioned just upstream from the vascular disorder while a distal end thereof terminates at a position just downstream thereof.
- the vascular disorder becomes endovascularly excluded from the blood flow while the stent graft impervious lumen maintains vessel patency
- cell matrix formation and tissue healing may commence in the aneurysmal sac and on the luminal surface.
- the residual blood clotting and inflammatory response cause cellular proliferation and connective formation, forming a matrix that may seal the sac.
- the resulted wall which is a combination of prosthesis, connective tissue matrix, and arterial wall provides a conduit support of proper hemodynamic blood flow.
- thromboembolic processes will occur on the luminal surface of the graft/stent. Briefly, during this thrombotic phase, platelets and blood clots adhere to the surface to form a fibrin rich thrombus. Endothelial cells then appear, followed by intense cellular infiltration. Finally, during the proliferative phase, actin-positive cells colonize the residual thrombus, resorbing the thrombus.
- the primary problem associated with this technique is the time period required for endovascular sealing and repair of the aneurysmal sac. Tissue response to injuries of this nature are generally on the order of a few months to years. This is especially true for the luminal surface of the graft material where organized thrombus formation may be difficult to achieve. Such endothelial cell growth to line the lumen of the stent graft may require years of healing or may never be fully completed.
- aortoentenic fistula arises when the seal integrity between the vessel wall and the proximal end of the stent graft is compromised due to slow thrombus formation and incomplete tissue growth. Such upstream, proximal seal breaches cause blood infiltration through the incomplete anastomosis that may lead to abdominal blood loss. Stent grafts efficiency and effectiveness are substantially reduced since the luminal surface is not re-endothelialized, exposing the foreign surface to the risk of thrombosis and its complications.
- a method for promoting and increasing the rate of at least one of thrombus formation and proliferative cell growth of a selected region of cellular tissue.
- the method includes the step of endovascularly irradiating of the selected region endovascular radiation, having a dose range of about 1 Gy to about 600 Gy at a low dose rate of about 1 cGy/hr to about 320 cGy/hr, to promote thrombus proliferation followed by cellular proliferation of the affected selected region.
- the dose of endovascular radiation is about 1 Gy to about 25 Gy at the graft surface, and at a low dose rate of about 1 cGy/hr to about 15 cGy/h.
- the selected region is preferably the luminal blood contents such as platelets, clotting proteins, and fibrin, while the target cells may include circulatory stem cells and cells from the adjacent connective tissue.
- the present method includes the step of positioning a deformable endovascular device, adapted to endovascularly emit the radioactive field, proximate the aneurysm. This step is performed by implanting the deformable endovascular device adjacent the aneurysm of the blood vessel. To generate the radioactive field and before the positioning step, the present invention includes the step of embedding radioactive material in the deformable endovascular device.
- the embedding step further includes the step of: embedding a central portion of the endovascular prosthesis, sized to extend substantially adjacent the aneurysm when properly positioned, with a first radioactive activity generating the first named radiation acting upon the aneurysm; and embedding the end portions of the endovascular prosthesis, positioned on opposed sides of the central portion and extending beyond the upstream end and the downstream end of the aneurysm, with a second radioactive activity generating a second radiation having a dosage adapted to decrease thrombus formation and/or cell proliferation of the affected regions flanking the aneurysm.
- the method of the present invention includes the step of positioning an intra-luminal endovascular prosthesis in the vessel proximate the aneurysm; and deploying the endovascular prosthesis from a contracted condition to an expanded condition, wherein the endovascular prosthesis engages the interior walls of the blood vessel forming a void between the endovascular prosthesis and the aneurysm for receipt of the radioactive seeds therein and such that the radioactive seeds are substantially retained is the void by the endovascular prosthesis.
- radiosensitizers may be deposited within the void or the aneurysmal sac, or be inserted into the aneurysmal contents. These radiosensitizers will be made radioactive or activated through external beam radiation or endovascular irradiation.
- a proliferation device for increasing the rate of proliferative cell growth and/or induce thrombus formation of a selected region of cellular tissue.
- the proliferation device includes a deformable endovascular device adapted for secured positioning adjacent to the selected region of cellular tissue, and a radioactive source. This source cooperates with the deformable endovascular device in a manner endovascularly irradiating the selected region with endovascular radiation, having a dose range of about 1 Gy to about 600 Gy at a low dose rate of about 1 cGy/hr to about 320 cGy/hr, to increase thrombus formation and/or cell proliferation of the affected selected region.
- the radioactive source is provided by radioactive material embedded in the deformable endovascular device.
- the deformable endovascular device is provided by radioactive coils, endovascularly irradiating the radiation, sized and dimensioned for receipt in a pseudoaneurysm.
- the deformable endovascular device is provided by a tubular-shaped intraluminal endovascular prosthesis radially expandable from a contracted condition and an expanded condition. In the contracted condition, percutaneous delivery into the blood vessel is enabled, and an expanded condition, the deformable endovascular device radially contacts the interior walls of the blood vessel for implanting thereto.
- the described endovascular sources can be radiosensitizers or radioactive sources that are coated with biologic factors such as growth factors, adhesion molecules, and organic matrix
- the thrombus formation and/or cellular proliferation device further includes a tubular-shaped sheath device defining a lumen therethrough, and cooperating with the endovascular prosthesis to substantially prevent fluid communication between fluid flow through the lumen of the blood vessel and the aneurysm, while maintaining vessel patency.
- the prosthesis is sized and dimensioned to extend beyond an upstream end of the aneurysm and beyond a downstream end of the aneurysm each by at least about 1.0 mm when properly positioned in the vessel.
- FIGURE 1 is a fragmentary, side elevation view, in cross-section, of a typical fusiform aneurysm.
- FIGURE 2 is a fragmentary top perspective view, partially broken away, of an aneurysm incorporating a radioactive stent graft device constructed in accordance with the present invention.
- FIGURE 3 is a fragmentary, side elevation view, in cross-section, of the stent graft device of FIGURE 2 being percutaneously delivered in a contracted condition.
- FIGURES 4A and 4B is a sequence of side elevation views, in cross-section, of the stent graft device of FIGURE 3 being moved from the contracted condition to an expanded condition.
- FIGURE 5 is an enlarged 2-dimensional representation of a multi-cell, pre- deployed stent applicable for use with the present invention.
- FIGURE 6 is a 2-dimensional dose graphical representation for a Phosphorus 32 stent taken substantially along the plane of the line 6-6 in FIGURE 5.
- FIGURE 7 is an enlarged, fragmentary, side elevation view, in cross-section, of the expanded stent graft device of FIGURE 4B, and illustrating delivery of the endovascular radiation from the radioactive stent.
- FIGURE 8 is a fragmentary, side elevation view, in cross-section, of the stent graft device and repaired aneurysm of FIGURE 4B in a stable proliferative phase.
- FIGURE 9 is an enlarged, front elevation view, in cross-section, of the of the deployed stent graft device taken substantially along the plane of the line 9-9 in FIGURE 8.
- FIGURE 10 is a fragmentary, side elevation view, in cross-section, of an alternative embodiment stent graft device of FIGURE 4B having an extemal graft.
- FIGURE 11 is a fragmentary, side elevation view, in cross-section, of an alternative embodiment stent graft device of FIGURE 4B incorporating the deposition of radioactive seeds.
- FIGURES 12A and 12B is a sequence of side elevation views, in cross-section, of a pseudoaneurysm having a radioactive coil device of the present invention deployed therein.
- the method includes the step of endovascularly irradiation the selected region with radiation, having a dose range of endovascular radiation of about 1 Gy to about 600 Gy at a low dose rate of about 1 cGy/hr to about 320 cGy/hr, for increasing the rate of cell proliferation and/or induce thrombus formation of the affected selected region.
- An endovascular device is adapted for endovascular positioning in close proximity to the selected region 21 of cellular tissue 22.
- the endovascular device includes a radioactive material or source collectively delivering a radioactive field upon the selected region 21 of a dosage adapted to increase the rate of cell proliferation and/or induce thrombus formation in the affected selected region 21.
- a continuous irradiation enables a continuous promotion of thrombosis on the vascular surface to establish a matrix for cellular adhesion, while a constant low dose irradiation provides a continuous stimulation of cellular proliferation.
- selectively increasing cell proliferation and/or inducing thrombus formation has enormous medical device and biotechnological implications. Further, this approach is applicable to a wide range of cellular tissue, such as endothelial cells, myofibroblast cells, fibroblast cells, other fibroblast-type cells, inflammatory cells, smooth muscle cells of different phenotypes, spindle-type cells and other connective tissue.
- the rate of proliferative cell growth and/or thrombus formation may be selectively increased.
- the rate of proliferative cell growth secondary to thrombosis has been observed to increase by between about 100% and about 500% in a time frame of about 3 months as compared to a control non-radioactive implant.
- the radioactive dose is in the range of about 1 Gy to about 25 Gy at about 0.1 mm from the stent surface, and at a low dose rate of about 1 cGy/hr to about 15 cGy/hr.
- a radioactive material or source is preferably positioned in close proximity to the selected or target region of cellular tissue such that the proper dose of radioactivity can be applied thereto.
- This radioactive source is preferably provided by implantable structures which can be alloyed, embedded, or implanted with the proper radioactivity of radioisotopes so that the proper dose of endovascular radiation may be endovascularly emitted to the designated selected region.
- implantable structures include intraluminal endovascular prosthesis such as stents, stent grafts, or covered stents can be made radioactive to provide low dose radiation on the luminal surface in promoting fibrin deposition, cellular adhesion, and cellular proliferation on the selected region 21.
- implantable structures include emboli coils 25 (as shown in FIGURES 12A and 12B, and to be discussed in greater detail below) or the like, which may be irradiated or made radioactive to direct the radiation to target region 44.
- Still other implantable structures include radioactive seeds 43 and radiosensitizers (as shown in FIGURE 11, and also to be discussed in greater detail below) which may be deployed to target selected region 21 of the cellular tissue. Accordingly, the emission of the proper dose of endovascular radiation, as will be apparent below, requires consideration of factors such as the coil or structure density of the implant device, the proximity to the desired selected region, the dose rate, volume of the target tissue, specific type of isotopes, and the half-life of the particular type of radioisotope employed.
- the emission of the radioactive dose from the implantable structures will be omnidirectional in nature, and generally only affect the cellular tissues in close proximity to structure.
- the radioisotopes employed for the purpose of the present invention are preferably alpha, beta or low energy gamma emitters. Other considerations include the predetermined depth of penetration of the radiation to the target region, the vascular and device geometry, as well as the specific type of isotope, and the half-life of the radioisotope.
- Phosphorus 32 ( 32 P), for instance, is a pure beta-particle emitter while Paladium 103 ( 103 Pd) is an X-ray photon emitter.
- Each type of radiation moreover, generates different amount of energy which in turn affect the depth of penetration, as well as the amount of radiation absorbed by the targeted tissue.
- Gamma or X-ray photon as a wave typically penetrate further into the tissue, as compared to alpha particles with a mass which penetrate into the tissue the least.
- Beta particles typically penetrate into the tissue between the gamma particles and the alpha particle.
- the device will be used with a beta or low energy gamma emitter.
- the described properties of the isotopes must be employed to determined the desired amount of radiation which is to be irradiated from the device. For instance, in order to achieve an equivalent dose of about 1470 cGy at about 0.1 mm from the stent surface of a 15mm length stent, a 32 P irradiating stent requires a radioactivity of about 0.93 ⁇ Ci whereas a 103 Pd irradiating stent requires a radioactivity of about 160 ⁇ Ci.
- the desired half-life of the radioisotope particle which preferably ranges from about one (1) hour to less than about one (1) year.
- the half-life of the preferred optimum emitter may be about one (1) day to less than about twelve (12) weeks, and most preferably about two (2) weeks to less than about nine (9) weeks.
- the required energy level and predetermined half-life may be selected to optimize vascular repair.
- Radioisotopes such as Phosphorus 32 ( 32 P), Yttrium 90 ( 90 Y), Calcium 45 ( 45 Ca), Palladium 103 ( 103 Pd) and Iodine 125 ( 125 I), for example, have been found to be particularly beneficial.
- Phosphorus 32 is a pure ⁇ -particle emitter, and it typically has a maximum energy of 1.69 MeV, an average energy of 0.695 MeV, a half-life of 14.3 days and a maximum particle penetration of a about three (3) millimeters into cellular tissue.
- One preferred application for the present invention is for use in the field of endovascular aneurysm repair, and more specifically, for use in combination with stent graft or covered stent devices or the like.
- a blood vessel 22 is illustrated having a fusiform aneurysm 21 which is endovascularly excluded from the vessel lumen 26 by a radioactive intraluminal endovascular prosthesis 23 (e.g., a stent graft).
- This stent graft 23 is constructed to deliver a dose of endovascular radiation upon the selected region 21 (i.e., the arterial wall of the aneurysmal sac 27 that is formed between the stent graft and the wall of the blood vessel), while maintaining vessel patency.
- the aneurysmal sac 27 will be endovascularly excluded from fluid communication with the blood flow through the vessel lumen 26.
- the selected region targeted for irradiation preferably includes the arterial wall and adventitial tissues such as smooth muscle cells and fibroblats and the blood contents contained in the excluded aneurysmal sac such as platelets, clotting proteins, and fibrin.
- thrombus formation in the graft lumen 32 is difficult to achieve in a short time period since there is a lack of promotional factors such as natural thrombosis.
- Exposure of the interior surface of the graft lumen 32 to this low level radiation substantially induces thrombus formation (i.e., platelet adhesion and fibrin deposition) therealong which, in turn, commences cascade of endothelialization of the lumen.
- thrombus formation i.e., platelet adhesion and fibrin deposition
- the initial response is explosive activation, adhesion, aggregation and platelet deposition.
- fibrin-rich thrombus accumulates around the platelet site.
- the initial appearance of cellular infiltration occurs, followed by endothelial cells 24.
- the actin-positive cells colonize the residual thrombus, resorbing the thrombus. Smooth Muscle Cell migration and proliferation into the degenerated thrombus creates substantially increased neointimal volume.
- Exposure of the blood contents in the gap 27 to this dose of radiation has been determined to be beneficial in two respects.
- the rate of thrombotic formation in the luminal surface of the graft has been found to substantially increase which ultimately shortens the Thrombotic Phase.
- a dose of endovascular radiation of between about 1 Gy and about 50 Gy has been shown to induce thrombus formation along the interior surface in 28 days or by a rate increased by 4-20 times (See Experiment A).
- thrombosis which is the initial step towards endothelization of the lumen interior surface 29
- proliferative cellular healing can commence.
- One hypothesis for the inducement of thrombus formation is due to the inflammatory response which induces the platelets, erythrocytes, and fibrin to adhere to the luminal surface 29 at a faster rate.
- the increased proliferative cell growth shortens both the Recruitment Phase and the Proliferative Phase in both the endothelialization of the lumen interior surface, as well as the repair of the aneurysmal sac 27.
- increased biochemical molecules such as cytokines to the region occurs which increases the rate of vascular repair and further enhances the cascade of healing.
- the stent-graft delivery may be performed through conventional open surgery or endovascular cut-down techniques. More preferably, the stent- graft delivery is performed percutaneously using a guide wire (not shown) positioned through vessel 22 and conventional stent-graft delivery system 28.
- a balloon expandable radioisotope stent graft 23 is provided having a deformable, tubular stent 25 and a thin walled material graft 30 coaxially aligned and mounted onto balloon 31 at a distal portion of stent-graft delivery system 28.
- FIGURES 3 and 4A illustrate the balloon and mounted stent graft 23 in a contracted condition which enables percutaneous advancement of the distal portion of the catheter through the vessel to the treatment site.
- selective inflation of the balloon 31 radially expands the stent graft 23 from the contracted condition (FIGURE 4A) to the expanded condition (FIGURE 4B).
- Such exposure secures the stent against and into the intima of the vessel to prevent migration of the stent, and to promote anastomoses with the stent.
- Use of the radiation shields or the like may be employed to reduce unnecessary exposure to the radioactive field during percutaneous delivery.
- One such patented radiation shield for radioisotope stents is disclosed in U.S. Patent No. 5,605,530 to Fischell et al.
- the stent graft 23 is sized and dimensioned such that an upstream portion of the stent graft 23 is adapted for positioning just upstream of the aneurysm 21 , while a downstream portion thereof is adapted positioning just downstream of the vascular disorder (e.g., aneurysm 21) each by at least about 1.0 mm.
- these anchor regions of the stent which may be provided by hooks, sutures or shape memory alloys such as NiTi, typically contact the intimal surface of the vessel along a sufficient longitudinal dimension to anchor the stent in place.
- Another stent delivery approach for vascular disorders is delivery through conventional cut-down techniques. Briefly, in this more invasive surgical technique, an incision may be made at the aneurysmal site for direct insertion of the stent graft therein. Upon proper deployment and anchoring of the stent graft, the incised arterial wall is opposed and is sutured together to close the incision, enveloping the graft within the lumen.
- This seal is important to secure isolation of the aneurysmal sac 27 from the blood vessel lumen 26 which is desirable to be reproducible and to be performed as quickly as possible.
- the radioactivity endovascularly emitted from the stent surface directly upon the target endothelial cells of the intima at the proximal and distal end portions end 40, 41 of stent graft substantially increases anastomosed proliferative cell matrix growth thereof at these contact regions.
- the neointimal layer 34 i.e., the matrix formation with its cellular constituents
- the new endothelial layer 24 FIG. 9
- an arterial media 39 forms the connective tissue growth which eventually binds the vessel wall 26 against the exterior circumferential surface of the stent graft.
- the proper dose of endovascular radiation emitted from the stent 25 will induce thrombus formation on the interior surface 29 of the material graft 30 defining the lumen.
- a fibrin rich thrombus layer with trapped erythrocytes is deposited along the entire length of the lumen. This initiation of the localized thrombotic process functions as the initial building blocks for endothelialization of the stent graft lumen.
- endothelial cells subsequently appear, followed by intense cellular infiltration.
- actin-positive cells colonize the residual thrombus, resorbing the thrombus and forming a thin intima layer of endothelial cells lining the interior surface.
- this low dose endovascular radioactive stent graft has been shown to increase the rate of endothelialization about several times faster than conventional techniques.
- the interior surface 29 of the material graft 30 may include a biomaterial coating of biological growth factor to form a template in which cells may adhere.
- a biomaterial coating of biological growth factor to form a template in which cells may adhere.
- One such organic substance is preferably provided
- FIBRONECTIN ® or collagen or the like. Additionally, the use of the present invention device in combination with proteins (e.g., fibroblast growth factors), or gene thereapy (e.g., VEGF) can provide beneficial results.
- proteins e.g., fibroblast growth factors
- gene thereapy e.g., VEGF
- the endovascular prosthesis 23 may be provided by any conventional stent design capable of expansion and retention from a contracted condition to an expanded condition.
- a tubular slotted stainless steel Palmaz-Schatz stent from Johnson and Johnson Interventional Systems may be employed with the present invention.
- Another stent pattern, as shown in FIGURE 5 which is the subject of a stent design disclosed in U.S. Patent No. 5,697,971 to Fischell et al. and incorporated by reference herein in its entirety, may also be deployed with the present invention.
- the stent design is the denser the stent pattern or number of coils, the more uniform the dose of endovascular radiation.
- the stent activity is preferably between about 0.07 ⁇ Ci/mm to about 0.8 ⁇ Ci/mm to provide a dose of endovascular radiation in the range of about 1 Gy to about 600 Gy from about 0.1 mm of the stent surface where the selected region 21 is preferably about 1.0 mm to about 3.0 mm from the surface of the stent. More preferably, the stent activity is between about 0.13 ⁇ Ci/mm to about 0.2 ⁇ Ci/mm.
- FIGURE 6 represents a two- dimensional graph of the Dose to Tissue vs. Distance From the Surface of the Stent.
- the radioactive field becomes relatively more uniform as little as 0.5 mm from the stent surface which endovascularly irradiates a dose of about 10,000 cGy; and substantially more uniform from about 1-3 mm away from the stent surface.
- This graph represents measurements taken from stent design substantially similar to that of the '971 patent irradiated with phosphorus 32 ( 32 P) isotope with an activity of about 1.33 ⁇ Ci/mm with a 3 month total dose.
- the material graft 30 is provided by a relatively flexible material composition which enables expansion from the contracted condition to the expanded condition and is impervious to blood flow.
- materials may include DACRON ® , TEFLON ® , PET (Polyethylene Terephthalate), polyester or a biocompatible metallic mesh material.
- This material graft 30 is affixed to the stent 25 using conventional anchor means employed in the field to prevent migration thereof along the stent.
- the proximal edge 33 and the distal edge 35 of the material graft 30 preferably terminate at or at a position slightly less than the corresponding proximal and distal edge 36, 37 of the stent 25.
- This configuration prevents any overhang of the ends of the material graft into either of the openings of the stent to minimize any current or potential occlusion of the stent passageway. This is especially problematic should excess in-growth be experienced at the ends of the stent graft were formation of the seal is to occur.
- the radioactive stent 25 of the present invention will begin endovascularly irradiating or delivering radioisotopes to the materials contained in the sac in the proper dose of endovascular radiation (FIGURE 7).
- the thrombotic phase is accelerated by the radioactivity, as is the recruitment phase and the proliferative phase for endothelialization of the aneurysmal sac 27 for aneurysm repair (FIGURE 8).
- the stent graft may be configured to irradiate different levels of radiation longitudinally and/or circumferentially along the stent.
- full circumferential healing may not be necessary along the vessel wall.
- the endovascular irradiation from the stent may not need to be uniformly applied, as well.
- a stent graft having an uniform radioactivity longitudinally therealong will not emit a uniform dose rate of radiation near the proximal and distal ends there, as compared to the center of the stent graft, due to the distribution geometry. Accordingly, it may be desirable to selectively apply the desired amount of radioactivity along the geometry to either increase or inhibit cellular proliferation.
- the proximal and distal end portions of the stent which anchor the stent to the vessel may have different activities as compared to the growth inducing radioactivity of the central portion 38 of the stent (FIGURE 8).
- the proximal and distal end portions 40, 41 of the stent graft 23 which physically contact the endothelial cells of the intima may be embedded oi ⁇ irradiated with an activity which reduces proliferative cell growth.
- the reduction of cell growth should not be at a magnitude where sealing time and reproducibility are detrimentally affected, or where seal integrity formation at the end portions is compromised.
- Such secondary stent activities and resulting doses of endovascular radiation are disclosed in U.S. Patents Nos. 5,176,617 and 5,059,166 to Fischell et al., incorporated herein by reference.
- the secondary activities are positioned on opposed sides of the central portion 38 and extending beyond the upstream end and the downstream end of the aneurysm.
- Another approach to limit occlusive in-growth at the proximal and distal end portions of the stent graft would be to subsequently expose those portions to higher levels of radiation which decrease cell proliferation.
- the end portions may be irradiated with radioactive isotopes at levels sufficient to decrease or prevent further cell proliferation. It will be appreciated, however, that such radiation dosages should not be so high as to damage the target tissue at the proximal and distal end portions.
- Delivery of such radiation may be performed endovascularly through catheters or the like, or may be performed through more external techniques such as external beam irradiation.
- This technique may also be applied to smaller branch vessels which are to be anastomotized to the side of stent graft (not shown).
- the immediate area surrounding anastomosis site may be irradiated with the above mentioned higher level of radiation to decrease or prevent further cell proliferation.
- tubular material graft 30 may be positioned along the exterior surface of the stent 25, as shown in FIGURES 10 and 11.
- This covered stent also provides an impervious luminal surface 42 which prevents fluid communication between the stent-graft lumen 32 and the aneurysmal sac 27 so that thrombus formation and cell growth may be accelerated with the proper dose of radioactivity.
- radioactive seeds 43 maybe implanted into the excluded aneurysmal sac 27 in combination with either a stent graft or covered stent. This radioactive seeding may be employed alone with a non- radioactive stent 25, or together with a radioactive stent. As shown in FIGURE 11 , the cumulative affect of the radioactive seeds produce the preferred dose of radioactivity to increase the cell/thrombus proliferation. In the preferred form, these particles 43 may be provided by stainless steel or platinum seeds about
- the activity of the seeds can be determined to produce the cumulative dose of endovascular radiation to be delivered to the selected region 21.
- the density of the distribution of radioactive seeds is about 2 particles/cm 3
- the activity per seed is about 0.1 ⁇ Ci to about 0.5 ⁇ Ci.
- the radioactive seeds 43 may be deposited into the occluded aneurysmal sac 27 to induce thrombus formation and accelerate proliferative cell growth.
- the seeds are implanted through conventional injection techniques, through lumens of a (seed) delivery catheter or placement during open surgery.
- the graft may be embedded with a radiosensitizer capable of being activated by either an external or endovascular radiation source. Once activated, the radioactive stent would subsequently emit the proper dose of radiation to increase the rate cell proliferation and/or induce thrombosis.
- a radiosensitizer capable of being activated by either an external or endovascular radiation source.
- the radioactive stent would subsequently emit the proper dose of radiation to increase the rate cell proliferation and/or induce thrombosis.
- Another approach would be to deliver or seed the aneurysmal sac 27 with a radiosensitizer, similar to the radioactive seeds, and then activate the same to emit the proper dose of radiation.
- One such radiosensitizer for example, may include halogenated pyrimidines, while the activator may be provided by an X-ray, ultraviolet, and external electron beam source.
- a saccular or pseudoaneurysm 21 such as an intracranial aneurysm, is illustrated which is formed along an upper portion of vessel 22.
- a radioactive coil emboli 25 may be implanted and anchored in the aneurysmal sac 44 of the pseudoaneurysm 21 to induce intravascular thrombosis (FIGURE 12A).
- thrombus formation can be accelerated when the coils 25 deliver endovascular radiation of the proper radioactive dose to the aneurysmal sac 44 of the peusdoaneurysm 21.
- the rate of the recruitment phase and the proliferative phase are also increased by the radioactivity emanating from the coil.
- the pseudoaneurysm 21 will then be repaired once the cell growth fill in the aneurysmal sac 44 of the pseudoaneurysm 21.
- the activity of the coils depends upon the predetermined coil density when positioned in the aneurysmal sac 44 of the pseudoaneurysm.
- a higher coil density to increase thrombogenicityic will require a smaller activity to generate a uniform radioactive field in the desirable range of about 1 cGy to about 600 cGy.
- Still other embodiments may include a radioactive external beam device (not shown) which may be positioned on the outside of the vessel and disposed adjacent to the aneurysm sac or gap.
- This device may be used in combination with a radioactive or non-radioactive stent graft device to promote the rate of vascular repair of the vessel.
- the beam may be configured to focus the endovascular radiation toward the aneurysmal sac.
- the radioactive coil emboli may be employed in the aneurysmal sac in combination with a radioactive or non-radioactive stent graft (not shown). In this manner, the coil emboli will function in the same manner as the radioactive seeds.
- a radioactive catheter wire (not shown) may be advanced pcrcutancously through the vessel and into the aneurysm to promote and accelerate thrombosis and vascular repair. This temporary radioactive wire may then be removed upon completion of the proper dose of endovascular radiation.
- This configuration may also be applied in combination with radioactive or non- radioactive stents, stent grafts, covered stents, coil emboli or the seed embodiments above-mentioned.
- the radioactive stent, coil emboli or seed embodiments may apply any other cellular growth inducing materials which are utilized to promote cellular growth.
- the exterior stent surface or the exterior material graft surface, as well as the graft interior surface may be coated with a conventional tissue growth inducing biomaterial such as FIBRONECTIN ® , VEGF or the like.
- Other medical application upon which the present invention may apply include the rate of increase of cell growth proliferation of vascular dissections, wound healing, wound closures, atrial septal defects, atrial venus malformation, orthopedic implants to encourage osteoblast growth with the use of bone chip gel with radiation, and varicose veins, to encourage cell proliferation in obliteration of the lumen.
- the isotopes were Phosphorus 32 ( 32 P) and Yttrium 90 ( 90 Y).
- 32 P is a pure beta-emitting particles with a half-life of 14.3 days, an average energy of 0.60 MeV, and a maximum energy of 1.7 MeV.
- the 90 Y is also a pure beta-emitting particles with a half-life of 2.7 days, an average energy of 0.90 MeV, and a maximum energy of 2.3 MeV.
- These radioactive stents were implanted in the coronary arteries of forty Yucatan miniature pigs, and the vascular response was analyzed for three (3) months after the implantation.
- the corresponding initial maximum dose-rate at 0.10 mm from the stent surface ranged from 1 cGy/hr to 120 cGy/hr.
- the radioisotope was radiochemically coated onto the stent surface to yield an activity level of 1.0, 2.0, 4.0, 8.0, 16.0, and 32.0 ⁇ Ci.
- the total 3 month dose ranged from 3 Gy to 280 Gy at 0.10 mm from the stents surface, and the corresponding initial maximum dose-rate ranged from 5 cGy/hr to 320 cGy/hr.
- control sample stents in this study were the non-radioactive BXTM-stents of 15mm in length and were fabricated in a manner similar to the radioactive stents except for ion implantation of 32 P or radiochemical process. All these stents were pre- mounted on PAS balloon catheters (Fischell IsoStentTM with delivery system, Johnson & Johnson Delivery System).
- the stent radioactivity was determined as follows: In the 32 P stents, the activity level of each stent was determined by comparison to standard 32 P sources of known activity using liquid scintillation counting methods. After ion implantation, the stents were placed in a sealed cylindrical acrylic resin radiation shield and gamma-ray sterilized in a conventional manner. The stents were then implanted when the radiation level had decreased to the desired activity.
- heparin 150 U/kg was administered intra-arterial to achieve an activated clotting time greater than 300 seconds (Hemochron, International Technidync, Edison, NJ).
- the 15 mm stents were implanted using the guiding catheter as a reference in order to obtain a 1: 1.2-1.3 stent to artery ratio (i.e., 20%-30% oversizing) as compared with the baseline vessel diameter.
- Stents were manually crimped onto non-compliant 3.0 or 3.5 mm diameter 10 mm length angioplasty balloons (SCIMED, Maple Grove, MN).
- Placement of the stent was completed with two balloon inflation at 12 or 14 ATM for 30 seconds.
- Angiography was completed after stent implant to confirm patency of the stent and side-branches as well as to assess for migration or intra-luminal filling defects.
- the animals were allowed to recover and returned to care facilities where they received a normal diet and aspirin 81 mg daily.
- the animals were returned for coronary angiography and euthanasia 3 months after the stent implantation.
- the animals were euthanized with a lethal dose of barbiturate.
- the hearts were harvested and the coronary arteries were perfusion-fixed with 10% neutral buffered formalin at 60-80 mmHg for 30 minutes via the aortic stump.
- Non-contrast postmortem radiography was completed on each stented vessel prior to sectioning in order to assess stent expansion and structural integrity.
- the fixed hearts were X-rayed and the stented coronary artery segments were carefully dissected from the epicardial surface of the heart. Control sections of the adjoining non-stented artery were taken from the proximal and the distal ends.
- the stented arteries were then processed in graded series of alcohol and xylene and embedded in methyl mefhacrylate.
- the plastic embedded stents are then cut with a rotatory diamond edged blade into 6.0-8.0 mm blocks from the proximal, mid, and distal segments of the stent and then sectioned with a stainless steel carbide knife into 4-5 ⁇ m sections.
- Arterial sections proximal and distal to the stent were processed in paraffin and sectioned as above. All histologic section were stained with hcmatoxylin-cosin and Movat pentachromc stains. All three sections were examined by light microscopy and used for morphometric measurements. The paraffin embedded sections were similarly cut and stained in a routine manner and examined for any abnormalities.
- the mean injury score, neointimal area and percent area stenosis were determined. Data are expressed as the mean ⁇ the Standard Deviation (SD). Lesion morphology and injury score were compared for the control and radioactive stents using ANOVA with a post hoc analysis for multiple comparisons. The stent activity, neointimal, and medial cell density were analyzed with a polynomial regression model to derive a slope, intercept and correlation coefficient to determine relations. Significance was established with a p value SD. Lesion morphology and injury score were compared for the control and radioactive stents using ANOVA with a post hoc analysis for multiple comparisons.
- the stent activity, neointimal, and medial cell density were analyzed with a polynomial regression model to derive a slope, intercept and correlation coefficient to determine relations. Significance was established with a p value ⁇ 0.05. All statistics were calculated using Starview 4.5 (Abacus, Berkeley, CA).
- Procedural and postoperative One animal died due to balloon rupture during implantation of a control stent resulting in severe coronary spasm and refractory ventricular arrhythmias. Ventricular tachycardia and fibrillation occurred in one additional animal which required DC cardioversion to restore a normal sinus rhythm. All animals had a normal postoperative recoveiy and resumed a normal pig chow diet (Purina) the following morning after stent implant. There were no cases of wound infection, incomplete healing or dehiscence. Daily observation of the animals indicated nomial behavior and dietary intake. All animals had a stable or mild increase in body weight during the study (baseline 29.2+5. lkg versus 31.2 + 5.5 kg at following-up, p ⁇ 0.001).
- Blood samples were obtained for complete blood counts in all animals prior to and at 28 days after stent placement.
- Angiography was completed at 3 months after stent placement. Two animals did not have angiographic study because of the procedural or post operative complications previously described. In the 33 animals with 28 day angiographic follow-up, sixty-six of 66 stents (100%) were patent with normal angiographic coronary flow. There were no cases of stent migration or side-branch occlusion. Quantitative analysis of the coronary angiograms was note completed for this study.
- Necropsy The gross appearance of the mediastinum, pericardium and myocardium was normal in all animals.
- the pericardial fluid was clear and straw colored in all cases. There were no cases with bloody or purulent pericardial fluid.
- the epicardial surface of the heart and stented arterial segments when visible were normal in all cases.
- the radioactive groups for P 32 and Y 90 showed a luminal surface with a complete re-endothelialization.
- the neointima of the radioactive groups had a substantially higher neointimal area and thickness compared to the non- radioactive stents, consisting of smooth muscle proliferation and matrix formation.
- a few inflammatory cells were found on the luminal surface as well as the neointima.
- the adventitial showed occasional fibrosis.
- the 90 Y groups revealed a more complete re-endothelialization and healing. This may due to the shorter half-life of 90 Y, which is 2.7 days as compared to 14.3 days.
- vascular response parameters were determined: percent luminal reduction, percent adventitial change, presence of thrombus, percent internal elastic lamina disruption, percent external elastic lamina disruption, percent medial disruption, and percent of inflammation.
- the radioactive stents showed a re-endothelialized lumen.
- the neo-intima showed a dose dependence increase of cellular proliferation and cell matrix formation.
- the presence of trapped erythrocytes and fibrin material within the neointima indicates that radiation induces thrombosis on the luminal surface.
- the histopathologic results showed an increase of 100% to 500% of cellular proliferation, which indicates that the radiation promotes cellular growth.
- the 0.1 and 0.5 ⁇ Ci of the 32 P groups showed a lesser neointimal thickness and a lower precent restenosis as compared to the control group, the results suggested a faster and a more complete re-endothelialization of the luminal surface. It is believed that the lower amount of irradiation on the surface may stimulate and activate the proliferation of the endothelial cells.
- the dose for inducing localized thrombosis and cellular proliferation is lGy to 600 Gy for 32 P and 3Gy to 280 Gy for 90 Y.
- the total dose that will result in cellular proliferation range from 1 Gy to 600 Gy, regardless of the isotopes used. This is the case because the principle of radiobiology has shown a given cellular tissue will yield the same or similar results if given the same dose of radiation regardless of the isotope (i.e beta-emitting or gamma-emitting isotopes) or the method of delivery (i.e endovascular or external beam radiation, single dose or fractionation).
- the corresponding dose rate for inducing cellular proliferation also follows the same principle; that is, the initial dose rate of 1 cGy/hr to 320 cGy/hr will promote cellular proliferation regardless of the isotopes used or the methods of irradiation.
- the amount of activity on the stent the total activity to achieve the desired cellular proliferation (in ⁇ Ci) will vary, depending on the isotope used and volume of target tissue. For example, to achieve a total dose of 1470 cGy on the surface of the stent, the 32 P stent will require to have an activity of 0.93 ⁇ Ci, and the l03 Pd stent will require an activity of 160 ⁇ Ci.
- radiation can be used to induce cellular proliferation in the intima, media, and adventitia of the artery.
- Both the single dose of radiation and the fractionation of the total dose promote fibroblastic proliferation.
- the beta-emitting stents with the stated dose and dose rate showed a pronounced neointimal response and little adventitial cellular proliferation.
- the external beam irradiation showed cellular proliferation from adventitia to intima.
Abstract
Description
Claims
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AU40941/99A AU4094199A (en) | 1998-05-26 | 1999-05-21 | Radioactive intraluminal endovascular prosthesis and method for the treatment ofaneurysms |
EP99924441A EP1082163A1 (en) | 1998-05-26 | 1999-05-21 | Radioactive intraluminal endovascular prosthesis and method for the treatment of aneurysms |
CA002333019A CA2333019A1 (en) | 1998-05-26 | 1999-05-21 | Radioactive intraluminal endovascular prosthesis and method for the treatment of aneurysms |
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US09/084,675 US6296603B1 (en) | 1998-05-26 | 1998-05-26 | Radioactive intraluminal endovascular prosthesis and method for the treatment of aneurysms |
US09/084,675 | 1998-05-26 |
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EP (1) | EP1082163A1 (en) |
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- 1999-05-21 CA CA002333019A patent/CA2333019A1/en not_active Abandoned
- 1999-05-21 EP EP99924441A patent/EP1082163A1/en not_active Withdrawn
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WO1999061107A1 (en) | 1999-12-02 |
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AU4094199A (en) | 1999-12-13 |
US6296603B1 (en) | 2001-10-02 |
US6554758B2 (en) | 2003-04-29 |
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