US 20080097591 A1
An improvement in drug-eluting stents, and method of their making are disclosed. The surface of a metal stent is roughened to have a surface roughness of at least about 20 μin (0.5 μm) and a surface roughness range of between about 300-700 μin (7.5-17.5 μm). The roughened stent surface is covered with a polymer-free coating of a limus drug, to a coating thickness greater than the range of surface roughness of the roughened stent surface.
1. In a method for reducing the rate of occurrence and/or extent of restenosis or thrombosis resulting from vascular injury in a subject, relative to that observed by placing at the site of injury, a bare-metal expandable stent formed of interconnected metal filaments, by the step of coating the outer surface of the stent filaments with a polymer carrier containing a limus drug, an improvement which maintains or further reduces the rate of occurrence and/or extent of restenosis or thrombosis relative to that achieved with a polymer-coated, limus-eluting stent, but without the presence of a polymer carrier, comprising
roughening outer surface regions of the stent filaments to a surface roughness of at least about 20 μin (0.5 μm), and a surface roughness range of between about 300-700 μin (7.5-17.5 μm), and
coating the roughened regions of the stent filaments with a polymer-free coating of the limus drug, to a coating thickness greater than the range of surface roughness of the roughened stent surface.
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12. In a method for administering an anti-restenosis drug from an expandable stent formed of inter connected metal filaments, by coating the outer surface of the stent with a polymer-free limus drug coating, an improvement which reduces the occurrence and/or extent of restenosis or thrombosis, comprising roughening outer surface regions of the stent filaments which are coated by the limus drug, to a surface roughness of at least about 20 μin (0.5 μm), and a surface roughness range of between about 300-700 μin (7.5-17.5 μm).
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16. An expandable stent for use in reducing the rate of occurrence and/or extent of restenosis or thrombosis, without the inflammatory response produced by a stent having a limus-drug-eluting polymer coating, when the stent is placed at a site of vascular injury, comprising
an expandable stent body formed of interconnected metal filaments,
formed on outer surface regions of the stent filaments a roughened surface characterized by a surface roughness of at least about 20 μin (0.5 μm), and a surface roughness range of between about 300-700 μin (7.5-17.5 μm), and
carried on the roughened regions of the stent filaments, a polymer-free coating of the limus drug having a coating thickness greater than the range of surface roughness of the roughened stent surface.
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This application claims the benefit of priority to U.S. Provisional Application No. 60/853,077, filed Oct. 20, 2006, and U.S. patent application Ser. No. 11/690,768, filed Mar. 27, 2007, both of which are incorporated herein by reference in their entirety.
The present application relates to an endovascular stent at least partly including a textured or abraded surface, and a method of making and using the stent.
Complications such as restenosis are a recurring problem in patients who have received artherosclerosis therapy in the form of medical procedures such as percutaneous translumenal coronary angioplasty (PTCA). Restenosis is commonly treated by a procedure known as stenting, where a medical device is surgically implanted in the affected artery to prevent it from occluding post procedure.
A stent is typically cylindrical in shape and is usually made from a biocompatible metal, such as cobalt chromium or surgical steel. Most stents are collapsible and are delivered to the occluded artery via a translumenal catheter. The stent is affixed to the catheter and can be either self expanding or expanded by inflation of a balloon inside the stent that is then removed with the catheter once the stent is in place.
Complications that can arise from stent therapy include restenosis and thrombosis. In an effort to overcome these complications, stents may contain a layer or coating of an anti-restenosis drug that is released in a controlled fashion at the stent-implantation site. Typically, the drug is contained in a permanent or bioerodable polymer carrier, as disclosed, for example, in U.S. Pat. No. 5,716,981 issued to Hunter entitled “Anti-angiogenic Compositions and Methods of Use.” Examples of typical therapies that are proposed to be delivered in this manner are antiproliferatives, anticoagulants, anti-inflammatory agents and immunosuppressive agents, although there are many other chemical and biological agents also mentioned in the patent literature. It has been suggested that the polymer carrier with drug may be covered by a porous biodegradable layer that serves to regulate controlled release of the drug into the body, as disclosed for example, in U.S. Pat. Nos. 6,774,278 and 6,730,064.
More recently, stents in which an anti-restenosis drug is carried in channels, grooves or pores for release in “polymer-free” i.e. pure-drug form have been proposed. Alternatively, stents having roughened surface intended to anchor a drug layer on the surface of the stent, for release in pure-drug form have been proposed, for example, in U.S. Pat. Nos. 6,805,898 and 6,918,927. None of these patents show or suggest that with particular classes of anti-restenosis compounds, it is possible to enhance the anti-restenosis activity of the compounds by selection of surface roughness features within certain ranges on the stent surface.
In light of the complications associated with stent therapy, it would be desirable to develop a stent having at least one roughened or textured surface for increased surface area, which can be manufactured in such a way as to maximize structural integrity, drug loading capacity, and ability to deliver drug to the vessel wall in a therapeutically enhanced way, as evidenced by a reduced risk of rate of occurrence or extent of restenosis following stent placement at the site of vascular injury.
The invention includes, in one embodiment, an improvement in a method for reducing the rate of occurrence and/or extent of restenosis or thrombosis resulting from vascular injury in a subject, relative to that observed by placing at the site of injury, a smooth-surfaced expandable stent formed of interconnected metal filaments, by coating the outer surface of the stent filaments with a polymer carrier containing a limus drug. The improvement, which is intended to maintain or further reduce the rate of occurrence and/or extent of restenosis or thrombosis, relative to that achieved with a polymer-coated, limus-eluting stent, but without the presence of a polymer carrier, includes the steps of:
(a) roughening outer surface regions of the stent filaments to a surface roughness of at least about 20 μin (0.5 μm), and a surface roughness range (maximum peak-to-valley) of between about 300-700 μin (7.5-17.5 μm), and
(b) coating the roughened regions of the stent filaments with a polymer-free coating of the limus drug, to a coating thickness greater than the surface roughness range of the roughened stent surface, that is, to a thickness that covers the roughened surface.
The stent filaments may be roughened to have a surface roughness of between about 20-40 μin (0.5 to 1 μm), and/or a surface roughness range of between about 300-500 μin (7.5-12.5 μm).
The surface roughening may be carried out by abrading the outer surface regions of the stent filaments with a pressurized stream of abrasive particles, by forming a hydrocarbon-film mask over outer surface regions of the stent filaments, selectively removing stent material exposed by the mask, and removing the mask, by laser etching the outer surface regions of the stent filaments, or by peening the outer surface regions of the filaments to imprint a pattern thereon.
The drug coating may be applied as a viscous solution of the drug onto the outer surfaces of the stent filament, with drying to form a solid drug coating on the stent filaments. The coating may be applied to a final amount of limus drug on the stent between 25 to 240 ug/cm stent length, and to a final coating thickness between 5 and 15 μm. One preferred class of limus drugs are the 42-0-alkoxyalkyl limus compounds, as exemplified by the 42-O-ethoxyethyl compound referred to herein as Biolimus A9.
In another aspect, the invention includes an improvement in a method for administering an anti-restenosis drug from an expandable stent formed of interconnected metal filaments, by coating the outer surface of the stent with a polymer-free limus drug coating. The improvement, which is intended to reduce the rate of occurrence and/or extent of restenosis or thrombosis achieved with the polymer-free limus drug coating, comprises roughening the outer surface regions of the stent filaments which are coated by the limus drug, to a surface roughness of at least about 20 μin (0.5 μm), and a surface roughness range of between about 300-700 μin (7.5-17.5 μm).
Also disclosed is an expandable stent for use in reducing the rate of occurrence and/or extent of restenosis or thrombosis resulting when the stent is placed at a site of vascular injury. The stent includes an expandable stent body formed of interconnected metal filaments, and formed on outer surface regions of the stent filaments, a roughened surface characterized by a surface roughness of at least about 20 μin (0.5 μm), and a surface roughness range of between about 300-700 μin (7.5-17.5 μm), and carried on the roughened regions of the stent filaments, a polymer-free coating of the limus drug having a coating thickness greater than the range of surface roughness of the roughened stent surface.
These and other aspects and embodiments of the present invention will become better apparent in view of the detailed description in conjunction with the accompanying drawings.
Unless indicated otherwise, the terms below have the following meanings herein.
“Surface roughness” or “roughness average” or “Ra” is the arithmetic average of absolute values of the measured profile height deviations taken within the sampling length or area measured from the graphical centerline or centerplane (the mean line or plane). It is measured typically by a non-contact surface optical profilometer, as discussed below, but may also be measured by a contact profilometer or by estimating peak and valley heights from a surface micrograph.
“Surface roughness range” or “Rt” is the maximum peak-to-valley distance, calculated as the sum of the maximum peak and maximum valley measurements of roughness with respect to a centerline or centerplane. It is typically measured by non-contact surface optical profilometer, but can also be measured by the other methods noted above.
“Limus drug” refers to a macrocyclic triene immunosuppressive compound having the general structure shown, for example, in U.S. Pat. Nos. 4,650,803, 5,288,711, 5,516,781, 5,665,772 and 6,153,252, in PCT Publication No. WO 97/35575, in U.S. Pat. No. 6,273,913B1, and in U.S. Patent Application Nos. 60/176,086, 2000/021217A1, and 2001/002935A1.
“42-O-alkoxyalkyl limus drug” refers to the 42-O alkoxyalkyl derivative of rapamycin described in U.S. patent application 20050101624, published May 12, 2005, which is incorporated herein in its entirety. As exemplary “42-O-alkoxyalkyl limus drug” is “42-O-ethoxyethyl rapamycin, also referred to herein as Biolimus A9.
“Polymer-free coating” means a coating whose structure and cohesiveness are provided by the drug itself, with or without the presence of one or more binding agents, rather than by a polymer matrix in which the drug is embedded, i.e., a polymer carrier.
In the embodiment shown, the stent body is formed of a series of tubular members called struts 3 connected to each other by filaments called linkers 4. Each strut 3 has an expandable zig-zag, sawtooth, helical ribbon coil or sinusoidal wave structure, and the connections to each linker 4 serve to increase overall stent flexibility. The contracted-state diameter of the stent is between approximately 0.5 mm-2.0 mm, preferably 0.71 to 1.65 mm, and a length of between 5-100 mm. The expanded stent diameter is at least twice and up to 8-9 times that of the stent in its contracted state, for example, a stent with a contracted diameter of between 0.7 to 1.5 mm may expand radially to a selected expanded state of between 2.0-8.0 mm or more. Stents having this general stent-body architecture of linked, expandable tubular members are known, for example, as described in PCT Publication No. WO 99/07308, which is commonly owned with the present application and expressly incorporated by reference herein.
Preferably, the stent structure is made of a biocompatible material, such as stainless steel. Further examples of biocompatible materials that are typically used for the stent structure are, cobalt chromium, nickel, magnesium, tantalum, titanium, nitinol, gold, platinum, inconel, iridium, silver, tungsten, or another biocompatible metal, or alloys of any of these; carbon or carbon fiber; cellulose acetate, cellulose nitrate, silicone, polyethylene teraphthalate, polyurethane, polyamide, polyester, polyorthoester, polyanhydride, polyether sulfone, polycarbonate, polypropylene, high molecular weight polyethylene, polytetrafluoroethylene, or another biocompatible polymeric material, or mixtures or copolymers of these; poly-L-lactic acid, poly-DL-lactic acid, polyglycolic acid or copolymers thereof, a polyanhydride, polycaprolactone, polyhydroxybutyrate valerate or another biodegradable polymer, or mixtures or copolymers of these; a protein, an extracellular matrix component, collagen, fibrin or another biologic agent; or a suitable mixture of any of these. An example of a typical stent is described in U.S. Pat. No. 6,730,064. The dimensions of each stent will vary depending on the body lumen in which they are to be delivered. For example, a stent may have a diameter ranging from approximately 0.5 mm to approximately 25.0 mm and a length that ranges from approximately 4 mm to approximately 100 mm or longer. An example of stent measurements is described in co-owned U.S. Pat. No. 6,939,376, which is commonly owned and expressly incorporated by reference herein.
As seen in
In one embodiment, the method includes use of a mask to prevent at least a portion of the stent from being abraded. Preferably, the mask is a hydrocarbon film, such as PARAFILM®, however, it will be appreciated that any suitable barrier to abrasion is suitable for use in these methods. Accordingly, in a preferred embodiment, at least the lumenal surface of the stent is not abraded. In one embodiment, a sheet of the mask approximately 5 mm by 60 mm is rolled around the diameter of a mandrel such as a 1.4 mm glass capillary tube. The stent is positioned onto the mandrel and hand-crimped into the hydrocarbon mask. A stereo microscope set between 10× and 40× may be used to ensure that the portion of the stent that is not to be abraded is covered by the mask. In a preferred embodiment, at least 80% of the stent wall thickness on all surfaces is masked by the hydrocarbon film layer.
In one embodiment, the stent surface 5 is then treated by utilizing microblasting systems, such as the MICRO BLASTER® and PROCENTER® by Comco, Inc. or an equivalent. In one embodiment, 25 μm of an abrasive, such as aluminum oxide, is used to roughen the stent surface 5. The pressure is adjusted to 40 psi±5 psi, and a spray nozzle is positioned approximately 2.5 cm to 5.0 cm from the stent surface 5, making multiple passes over the stent.
In another embodiment, the mask is removed by any appropriate means such as via ultrasonic cleaning. Typically the ultrasonic cleaner is filled with deionized water which is heated to 45° C. A sample vial of HPLC grade chloroform is heated to between 50-60° C. on a hotplate. A glass capillary tube mandrel with a treated stent is incubated in a vial of 40° C. and 50° C. HPLC grade chloroform for 5-10 minutes. The vial containing the chloroform and mandrel is then sonicated in 45° C. deionized water for two minutes.
Due to the roughening of the stent surface 5, different elements are expressed on the metal surface, which can increase the susceptibility to corrosion. As a result, the treated stent is generally passivated according to ASTM standards and cleaned in a series of solvents such as Chloroform, Acetone and/or Isopropyl Alcohol. In one embodiment, after the mask is removed and the treated stent is sonicated, it is removed from the vial of chloroform. A sample vial is rinsed with Acetone and then refilled with Acetone. The treated stent is placed in the vial and sonicated in the ultrasonic cleaner for two minutes. The vial is rinsed with isopropyl alcohol and then refilled with isopropyl alcohol. The stent is sonicated in the ultrasonic cleaner for two more minutes. The treated stent is then passivated in a 60° C.±3° C. 20% by volume Nitric Acid bath for 30 minutes. The stent is then rinsed 10 times with copious amounts of deionized water. The stent is then placed in 600 mL of a solvent such as isopropyl alcohol and sonicated in the ultrasonic cleaner for 5 minutes and allowed to air dry.
In another embodiment, the surface of the stent is uniformly abraded in a controlled manner via shot peening. Roughening of a stent surface 5 is accomplished using metal particles called shot that range in size from approximately 1 to 5 microns and is made from an atomic element having at least a weight of 43 g/mol. For example, the shot may be in the form of particulate tantalum, particulate tungsten, particulate platinum, particulate iridium, particulate gold, particulate bismuth, particulate barium, particulate zirconium and alloys thereof. Examples of suitable alloys include a platinum/nickel alloy and a platinum/iridium alloy.
In another embodiment, a stent surface 5 can be treated to create mechanical injectors that range in size from about 3 to about 10 microns.
In another embodiment, a stent surface 5 can be laser etched to create regular or irregular patterns of asperities/mechanical injectors of about 5 to about 25 microns.
In another embodiment, the stent surface can be treated to have a different roughness factor on the ablumenal surface than the lumen surface. For example the whole surface may be treated via any of the above disclosed methods. Then a subsequent masking of the lumen surface is performed so that a second surface treatment can be directed to the ablumenal surface. The subsequent treatment would typically utilize the more aggressive texturing process. The differing surfaces thus obtained can be used to impart differing useful properties to the inside (i.e. lumenal) vs. outside (ablumenal) surfaces of the stent. In one embodiment, the lumenal surface roughness is optimized to improve cell ingrowth and adhesion for example as described in (US Patent Application No. 2005/0211680), and the ablumenal surface roughness may be optimized to provide drug transfer from the ablumenal surface of the stent to the surrounding tissues as described herein.
The stent surface 5 may be treated by placing desired amount of shot over a predetermined portion of the stent surface 5 and in the desired pattern. Pressure is applied to the particles using plates or rollers to make indentations in the stent surface 5. Roughness can also be achieved by jet blasting the particles at the stent surface 5 at a velocity sufficient to make indentations. An example of shot peening a metal surface is described in U.S. Pat. No. 6,911,100.
In a further embodiment, this uniform, controlled surface roughness can also be achieved similar to above by employing a laser rather than the use of shot. A series of electric discharges are applied to the desired portion of the outer or inner stent surface 5. The electric discharges contact the surface with sufficient energy to vaporize the material on the surface of the stent, creating pits, sometimes called voids, the combined effect of which is a rough surface having increased surface area. An example of this process is described in U.S. Pat. No. 6,913,617.
In another embodiment, the surface of the stent is uniformly treated by compression. The stent is affixed to a mandrel, which is inserted into a die that is equipped with preformed raised portions that form indentations in the desired amount, shape, size and pattern on the stent surface 5. The indentations may be made in a number of ways such as welding them onto the stent surface 5 or sandblasting. The die is then closed around the stent forming indentations of the desired depth and covering the desired surface area. The stent is treated over its entire surface, or a portion of the surface, depending on the manufacture of the die. An example of this process is described in U.S. Pat. No. 7,055,237.
In another embodiment, a stent surface 5 is treated with a pneumatic press or hydraulic press. Pneumatic presses are well known in the art as described in U.S. Pat. No. 4,079,617. Hydraulic presses are also well-known in the art as described in U.S. Pat. No. 7,033,155. As seen in
In another embodiment, the entire length of the tubing used to create stents, for example tubing that is 2.5 meters in length, is treated prior to laser cutting it into a plurality of desired stent lengths. The stent is horizontally or vertically attached to one or more mandrels 1 and abraded using one of the methods disclosed in this application. In terms of the abrading techniques, the stent is treated randomly, uniformly or in a desired pattern. Further, the length and sides of the stent is treated lengthwise, vertically or spirally. Moreover, the stent surface 5 is treated either by moving it over a stationary roughening mechanism, or in the alternative, the entire stent tube length is stationary and the roughening mechanism may be moved over the length of the tube in one of the manners disclosed, for example horizontally, vertically, spirally.
Potentiodynamic corrosion testing was performed on the treated stent to confirm the desirability of the passivation step and its effectiveness. The data shows that the treated, passivated stent breakdown potential is well within ASTM specified voltage levels standards. Therefore, after the roughening process and passivation, the treated stent does not exhibit a greater likelihood of corrosion when compared to the untreated control stent, and the roughening process does not increase the potential for restenosis and thrombosis. After passivation, the biocompatibility of the microstructured metal surface was observe d to be equivalent to that observed with stents having smooth electropolished surfaces.
The approximate thickness of an untreated stent wall is generally around 0.05 mm. As seen in
Example 2 provides surface roughness Ra and roughness factor Rt measurements for 4 stents prepared as above by surface abrasion with a pressurized particle blast. As seen, the surface roughness values were all at least 20 μin (0.5 μm) and are typically between about 20-40 μin. (0.5 μm-1.0 μm), and a roughness range between 300-700 μinch (7.5 to 17.5 μm), and typically between 300 and 500 0.5 μinch (7.5 and 12.5 μmm). In accordance with one aspect of the invention, these roughness values, and particularly the roughness range values, have been found optimal for achieving optimal anti-restenosis results in subjects.
Without wishing to be limited to a particular theory as to this effect, it appears that the surface asperities or projections in the 300-700 μinch peak to valley range are optimal for “injecting” drug in the drug coating into the surrounding vessel. Thus, for example, as the projections are exposed, either by drug dissolution from the coating or by fractures in the coating during stent placement, the projections, by impacting or penetrating the local vessel area, may facilitate entry of the drug into the vessel. The result is that the defined roughness range of the stent surface, combined with the polymer-free drug coating, maintains or further reduces the rate of occurrence and/or extent of restenosis or thrombosis seen with a polymer-coated, limus-eluting stent, but without the presence of a polymer carrier, and further reduces the rate of occurrence and/or extent of restenosis or thrombosis seen with a polymer-free coating on a less-roughened surface, i.e. having a lower surface roughness range. Further, studies conducted in support of the present invention indicate that a stent having surface-roughness features with peak-to-height values in the range 800-1,000 μinch (20-25 μm or more) may be less effective in reducing restenosis.
Thus, in one aspect, the invention is directed to improving the effectiveness, in terms of reduced incidence and/or extent of restenosis in treating a vascular injury with a drug-eluting stent, e.g., a limus-eluting stent. The improvement includes the steps of roughening at least the ablumenal surface portions of the stent to a surface roughness of at least about 20 μin (0.5 μm), and a surface roughness range of between about 300-700 μin (7.5-17.5 μm), and coating the roughened regions of the stent filaments with a polymer-free coating of the limus drug, to a coating thickness greater than the range of surface roughness of the roughened stent surface, that is, to a coating thickness that forms a substantially unbroken drug coating.
Preferably, an API (i.e. active pharmaceutical ingredient) such as the antiproliferative Biolimus A9® is applied at least to the ablumenal portion of the stent. The API may be applied to the stent surface by any appropriate means including by spraying the treated surface of the stent with a solution of the API. The API solution may also be applied by dipping the entire stent into the desired API or by applying it directly to the stent surface 5 manually. Biolimus A9® has an amorphous to semi-crystalline structure that does not crack or fracture like some other crystalline limus compounds. Therefore, the properties of Biolimus A9® permit adhesion to the stent's roughened treated surface in the unexpanded state and the expanded state.
Preferably, the API material is applied to the ablumenal portion of the stent via autopipetting as described in co-owned U.S. Pat. No. 6,939,376. A solution ranging in a concentration of approximately 100 mg/ml to approximately 200 mg/ml is made by dissolving the desired API in an appropriate solvent, such as ethyl acetate or acetonitrile. The solution is placed in a reservoir with a pump designed to deliver the solution at a predetermined rate. The pump is controlled by a microcontroller, such as the 4-Axis Dispensing Robot Model available from I&J Fisnar Inc. A solution delivery tube for delivery of the solvent mixture to the stent surface 5 is attached to the bottom of the reservoir. The reservoir and delivery tube are mounted to a moveable support that moves the solvent delivery tube continuously or in small steps, for example, 0.2 mm per step along the longitudinal axis.
An uncoated stent is gripped by a rotating chuck contacting the inner surface of the stent at least at one end. Axial rotation of the stent is accomplished by rotating the stent continuously, or in small degree steps, such as 0.5 degree per step. Alternatively, the delivery tube is held at a fixed position and, in addition to the rotation movement, the stent is moved along its longitudinal direction to accomplish the coating process.
Prior to use, the solution delivery tubes are drawn and shaped under a Bunsen burner to form a small tapered opening at the tip of the tube to facilitate precise application of the drug/solvent mixture, which can then be applied over the length and sides of the stent as needed with the formed tip of the tube. It is within the scope of the invention to use more than one of the fluid dispensing tube types working in concert to form the coating, or alternately to use more than one moveable solution reservoir equipped with different tips, or containing different viscosity solutions or different chemical makeup of the multiple solutions in the same process to form the coating.
In another embodiment, a non-porous layer of parylene, parylene derivative, or another biocompatible polymer is applied to the treated stent surface, and the desired API is applied or layered onto that. Optionally, an additional layer of slightly non-porous polymer is applied directly over the API, which aids in controlled release over time. According to the present invention, the stent comprises at least one layer of an API posited on its surface, and the other surfaces will either contain no API or one or more different APIs. In this manner, one or more APIs may be delivered to the blood stream from the lumenal surface of the stent, while different treatments for different conditions are delivered on the vascular injury site outside surface of the stent.
In another embodiment the stent is capable of being coated with an API molecule without the need of a polymer. As seen in
The stent may be included in an assembly consisting of a stent body surrounding a deflated balloon affixed to the distal portion of a catheter which is used to implant the stent at the vascular injury site. The stent is introduced into the cardiovascular system of a patient via the brachial or femoral artery using the catheter. The catheter assembly is advanced through the coronary vasculature until the deflated balloon and stent combination is positioned across the vascular injury site or site of vascular disease or site of vascular narrowing. The balloon is then inflated to a predetermined size to expand the stent to a diameter large enough to be in continuous contact with the lumen. The balloon is then deflated to a smaller profile to allow the catheter to be withdrawn from the patient's vasculature, leaving the stent in place. An example of a typical stent implantation procedure is described in U.S. Pat. No. 6,913,617.
This section describes vascular treatment methods in accordance with the invention, and the performance characteristics of stents constructed in accordance with the invention.
The methods of the invention are designed to minimize the risk and/or extent of restenosis in a patient who has received localized vascular injury, or who is at risk of vascular occlusion due to the presence of advanced atherosclerotic disease. Typically the vascular injury is produced during an angiographic procedure to open a partially occluded vessel, such as a coronary or peripheral vascular artery. Alternately, the stent may be introduced into a site of vascular narrowing, and expanded using the balloon to directly open up the narrowed portion of the vessel (i.e. the vascular injury disease site). In the first mentioned angiographic procedure, a balloon catheter is first placed at the occlusion site, and a distal-end balloon is inflated and deflated one or more times to force the occluded vessel open. This vessel expansion, particularly involving surface trauma at the vessel wall where plaque may be dislodged, often produces enough localized injury that the vessel responds over time by cell proliferation and reocclusion in the vicinity of the implanted stent. Not surprisingly, the occurrence or severity of restenosis is often related to the extent of vessel stretching involved in the angioplasty procedure. Particularly where overstretching is 10% or more, restenosis occurs with high frequency and often with substantial severity, i.e., vascular occlusion. In the second mentioned alternative procedure of direct stent placement without prior angioplasty (i.e. “direct stenting”) there is nevertheless still vascular injury induced by the expansion of the stent and balloon at the vascular injury disease site which results in restenosis and cellular proliferation at the site of the stent implantation, very similar in severity to that seen from the first mentioned procedure.
The present invention is intended to be used without limitations to any particular method of treating and injuring the vascular site, and can be used with either of the techniques described above, or with alternative techniques for vascular disease and injury as is known. In practicing the present invention, the stent is placed in its contracted state typically at the distal end of a catheter, either within the catheter lumen, or in a contracted state on a distal end balloon. The distal catheter end is then guided to the injury site, or to the site of potential occlusion, and released from the catheter, e.g., by pulling back a sheath covering the stent to release the stent into the site, if the stent is self-expanding, or by expanding the stent on a balloon by balloon inflation, until the stent contacts the vessel walls, in effect, implanting the stent into the tissue wall at the site.
Once deployed at the site, the drug coated stent begins to release active compound (API) into the cells lining the vascular site, to inhibit cellular proliferation and/or for other therapeutic benefits such as reduction of inflammation, limitation of thrombosis formation, reduction in cell apoptosis, etc.
Trials in a porcine restenosis animal model as generally described by Schwartz et al. (“Restenosis After Balloon Angioplasty—A Practical Proliferative Model in Porcine Coronary Arteries”, Circulation 82:(6) 2190-2200, December 1990.) Studies have been conducted in the Porcine model which demonstrate the ability of the stent of this invention to limit the extent of restenosis, and the other advantages of the stent over currently proposed and tested stents. The studies are summarized in Example 3.
Briefly, the studies compare the extent of restenosis at 28 days in an animal model following stent implantation, in bare metal stents, polymer-coated stents, and textured stents.
Further trials demonstrate the ability of the stents described herein to limit the extent of restenosis over an extended period of at least three months. The studies are summarized in Example 4.
Briefly, the studies compare the extent of restenosis at 3 months following stent implantation with bare metal stents (BMS) and polymer free drug eluting (pfDES) stents. Histomorphometry data shown in Table 4 shows the pfDES greatly reduced levels of restenosis as compared to the BMS.
The following examples illustrate various aspects of the making and using the stent invention herein. They are not intended to limit the scope of the invention.
In vitro drug release was conducted with Biomatrix® II stents coated with a polymer containing the antiproliferative drug Biolimus A9® and with stents containing an ablumenal microstructure including Biolimus A9® in a PBS pH 7.4/Tween medium at 37° C. Sampling was periodically conducted and the total amount of Biolimus A9® was measured by HPLC.
The outer surface of a Bioflex II 6 crown stent was treated with an abrasive to create a selectively micro-structured outer surface of the stent for drug loading capacity, called Bio-Freedom Stent (FS). The therapeutic agent can be coated directly on the selectively microstructured surface of the stent.
The roughness factor of the FS was characterized using a commercially available Veeco Metrology Group (Tucson, Ariz.) WYKO NT-2000 system, which is a non-contact optical profiler. VSI (vertical scanning interferometer) mode with Vision 32 software, removing cylinder and tilt terms so that the stent surface appears flat. A low pass filter is used which removes the effects of high spatial frequency roughness, smoothing over features that are smaller than a nine pixel window. The results are given in the table below for four different stents whose surface roughness is produced by sand blasting, where Ra is the mean surface roughness, and Rt is the range in surface roughness, as defined above.
Textured stents from Example 2 with and without Biolimus A9® were implanted in out-bred juvenile swine. A balloon catheter was used to place the stent according to the standard porcine overstretch model with 10-20% overstretch. The juvenile swine target vessels were predilated by known angioplasty techniques prior to stent placement.
After 28 days, the animals were euthanized according to approved protocols, the heart and surrounding tissue was removed from the animals.
A microscope containing a digital camera was used to generate high resolution images of the vessel cross-sections which had been mounted to slides with the results shown in
The stent and artery were dissected, and micro-tomed by a histologist. The samples were stained for various growth signals, cell proliferation, and other cellular debris. Histomorphometric measurements were made of:
The artery area in mm2 (
The following table shows the results of the treatment effect at 28 days follow-up. The data in the tables below under column heading “Lumen Area mm2” report the results of morphometric analysis of stents and vessels removed from the pigs at 28 days follow-up (f/u):
A. Stent Implantation
Polymer Free BioMatrix Stents sandblasted as in Example 2 with 225 μg Biolimus A9® or a bare BioFlex II stent was implanted in a Crossbred Farm Pig Model according to Table 3.
CV Path Institute, Inc. received hearts from 5 pigs. Non-overlapping stenting was performed in 5 pigs, and stents were explanted for light microscopic analysis at three months. Animal 1 died before scheduled follow up at three months for reasons not associated with stent implant procedure at 2 months. The left circumflex coronary artery (LCX) of animal #3 was not stented in this animal because the LCX, which was of an unsuitable size.
B. Materials and Methods Light Microscopy
For light microscopy, the stented vessel segments were embedded in methylmethacrylate plastic and sections from the proximal, middle, and distal stent were cut, mounted on charged slides, and stained with hematoxylin & eosin and Elastic Van Gieson (EVG). The non-stented proximal and distal sections of the artery were embedded in paraffin, sectioned at four to five microns, and stained with hematoxylin and eosin and EVG. All sections were examined by light microscopy for the presence of inflammation, thrombus, neointimal formation and vessel wall injury. Morphometric Analysis Morphometric software (IP Lab for Macintosh, Scanalytics, Rockville, Md.) was calibrated using NIST traceable microscope stage micrometers of 2.0 mm linear and 2.0 mm diameter circle with all objectives. Klarmann Rulings, Inc., (Manchester, N.H.) certified all micrometer graduations. Areas of measurement included the EEL (external elastic lamina), IEL (internal elastic lamina) and lumen. The neointimal thickness was measured at and between stent struts and averaged for each animal. By subtracting IEL from EEL, the medial area was determined. Percent stenosis was derived from the formula [1−(lumen area/stent area)]×lOO. Vessel injury score was determined using the Schwartz method (Schwartz R S et al., J Am Coll Cardiol 1992; 19:267-274). Inflammation, fibrin, and injury scores were generated for each section based on a graded analysis of 0=no inflammation/fibrin/injury to value 3=marked Inflammation/fibrin/injury. An inflammation score of 4 was given to sections with 2 or more granulomatous reactions present. Endothelial coverage was semi-quantified and expressed as the percentage of the lumen circumference.
C. Statistical Analysis
The morphometric continuous data were expressed as mean ±SD. Statistical analysis of the normally distributed parameters was performed using a Student's t-test. The Wilcoxon test was used in the analysis for non-normally distributed parameters or discrete values. Normality of distribution was tested with the Wilk-Shapiro test. A p value of <0.05 was considered statistically significant.
D. Radiographic Findings
All stents appeared widely and evenly expanded without evidences of fracture or bent.
E. Light Microscopy Observations
1. Polymer Free DES
All stents were widely expanded and patent without any evidence of thrombus at 3 months after implantation. Neointimal formation was mild with a mean neointimal thickness of 0.16 mm and composed by loosely packed smooth muscle cells and proteoglycan-rich matrix. Vessel injury was mild. Mild fibrin deposition localized around the struts was observed. Although granulomatous response was seen in the LCX of animal #5, inflammation was minimal overall in the other vessels. Giant cells were occasionally observed and documented. Endothelialization was complete without lumenal inflammatory cells and/or platelets adhesion. Notably, a dense calcification was seen in neointima at the proximal section in LCX of animal #2 which contained a bare metal stent.
2. Bare Metal Stents
All stents were widely expanded and patent without any evidence of thrombus at 3 months after implantation. Neointimal formation was mild with a mean neointimal thickness of 0.21 mm and composed of tightly packed smooth muscle cell. Medial rupture was observed in the Left Anterior Descending coronary artery (LAD) of animal #2. This vessel showed severe inflammation mainly around the struts probably due to the injury created by the implant procedure. However, except for this animal, vessel injury and inflammation was mild overall. Fibrin deposition and malapposition were not seen in any stents. Endothelialization was completed without presence of lumenal inflammatory cells and/or platelets adhesion.
The results of this animal study demonstrated a significant increase in Lumen Area (i.e. reduction in restenosis) at 3 months after stent implant in a porcine model for the Polymer Free drug eluting stent (Freedom DES) as compared to bare metal control stent implants (BMS).
The description of the invention is merely exemplary in nature and thus, variations that do not depart from the gist of the invention are intended to be within the scope of the invention. Such variations are not to be regarded as a departure from the spirit and scope of the invention.