Patent Application
20080249599
This invention relates generally to biomedical devices that are used for treating vascular conditions. More specifically, the invention relates to a therapeutic agent eluting stent having one or more therapeutic agent eluting portion localized in low strain regions of the stent.
Stents are generally cylindrical-shaped devices that are radially expandable to hold open a segment of a vessel or other anatomical lumen after implantation into the body lumen.
Various types of stents are in use, including expandable and self-expanding stents. Expandable stents generally are conveyed to the area to be treated on balloon catheters or other expandable devices. For insertion into the body, the stent is positioned in a compressed configuration on the delivery device. For example, the stent may be crimped onto a balloon that is folded or otherwise wrapped about the distal portion of a catheter body that is part of the delivery device. After the stent is positioned across the lesion, it is expanded by the delivery device, causing the diameter of the stent to expand. For a self-expanding stent, commonly a sheath is retracted, allowing the stent to expand.
Stents are used in conjunction with balloon catheters in a variety of medical therapeutic applications, including intravascular angioplasty. For example, a balloon catheter device is inflated during percutaneous transluminal coronary angioplasty (PTCA) to dilate a stenotic blood vessel. The stenosis may be the result of a lesion such as a plaque or thrombus. When inflated, the pressurized balloon exerts a compressive force on the lesion, thereby increasing the inner diameter of the affected vessel. The increased interior vessel diameter facilitates improved blood flow. Soon after the procedure, however, a significant proportion of treated vessels restenose.
To reduce restenosis, stents, constructed of metals or polymers, are implanted within the vessel to maintain lumen size. The stent is sufficiently longitudinally flexible so that it can be transported through the cardiovascular system. In addition, the stent requires sufficient radial strength to enable it to act as a scaffold and support the lumen wall in a circular, open configuration. Configurations of stents include a helical coil, and a cylindrical sleeve defined by a mesh, which may be supported by a stent framework of struts or a series of rings fastened together by linear connecter portions.
Stent insertion may cause undesirable reactions such as inflammation resulting from a foreign body reaction, infection, thrombosis, and proliferation of cell growth that occludes the blood vessel. Stents capable of delivering one or more therapeutic agents have been used to treat the damaged vessel and reduce the incidence of deleterious conditions including thrombosis and and restenosis.
Polymer coatings applied to the surface of the stents have been used to deliver drugs or other therapeutic agents at the placement site of the stent. The coating is sometimes damaged during expansion of the stent at the delivery site, causing the coating to chip off the stent and release flakes of the polymer coating, which reduces the effective dose of the drug at the treatment site, and under some circumstances, may result in emboli in the microvasculature.
Recently, stents have been introduced that have a porous surface, usually consisting of indentations in the surface of the stent. The indentations can be filled with a formulation containing drugs or other therapeutic agents that will leach from the stent after it is deployed, without a polymer coating covering the external surface of the stent. One drawback of stents comprising porous materials, however, is that the structure of the stent is weakened compared to a stent structure of solid metal or polymer. Consequently, a porous stent may crack or break during expansion at the treatment site as a result of the strain placed on certain regions of the stent.
Strain is a measure of the displacement that can be applied to a material before the material breaks or tears. Strain is measured as the ratio of the change in length of the material to the original length of the material.
Clearly, the strain applied to the various regions of the stent framework during delivery and deployment of the stent is a parameter that must be considered in stent design.
For delivery, vascular stents are frequently mounted on a delivery catheter in a compressed configuration as shown in
Regardless of stent configuration, experience has shown that chipping of a coating during delivery of a stent occurs in high strain areas of the stent due to the movement of the stent framework and the strain placed on the stent within these areas. In addition, the stent is most likely to crack or break in the high strain areas as the material comprising the stent framework is not strong and flexible enough to withstand the strain placed on these areas during expansion and contraction of the stent.
It would be desirable, to provide an implantable drug eluting stent that retains the lateral flexibility needed for delivery and deployment and the radial strength to support the vessel wall, but also exhibits minimal chipping and flaking of the drug/polymer coating, or cracking of the stent body in the case of porous stents, when the stent is stressed during delivery and deployment. Such a stent would overcome many of the limitations and disadvantages inherent in the devices described above.
One aspect of the present invention provides a system for treating abnormalities of the cardiovascular system comprising a catheter and a therapeutic agent-carrying stent disposed on the catheter. The stent includes a stent framework having plurality of therapeutic agent-carrying regions and non therapeutic agent-carrying regions. The therapeutic agent-carrying regions are disposed within regions of the stent that are subjected to low strain when the stent is expanded or contracted, and the non therapeutic agent-carrying regions are disposed within regions of the stent framework that are subjected to high strain when the stent is expanded or contracted.
Another aspect of the invention provides an expandable stent comprising a stent framework having a plurality of regions subjected to high strain during expansion or contraction of the stent and a plurality of regions subjected to low strain during expansion or contraction. Further, the stent has therapeutic agent-carrying regions localized within the low strain regions and non therapeutic agent-carrying regions localized within the high strain regions.
Another aspect of the invention provides a method for manufacturing a therapeutic agent-carrying stent having high and low strain regions during expansion and contraction of the stent. First, the stent framework is formed. Next, a formulation containing one or more therapeutic agents is disposed on the low strain regions of the stent framework, without contacting the high strain areas of the stent framework with the formulation.
The present invention is illustrated by the accompanying drawings of various embodiments and the detailed description given below. The drawings should not be taken to limit the invention to the specific embodiments, but are for explanation and understanding. The detailed description and drawings are merely illustrative of the invention rather than limiting, the scope of the invention being defined by the appended claims and equivalents thereof. The drawings are not to scale. The foregoing aspects and other attendant advantages of the present invention will become more readily appreciated by the detailed description taken in conjunction with the accompanying drawings.
Throughout this specification, like numbers refer to like structures.
Referring to the figures,
In one embodiment of the invention, the stent framework, such as stent frameworks 400 and 500, comprises one or more of a variety of biocompatible metals including stainless steel, titanium, gold, nickel/titanium alloys, such as nitinol, platinum, and platinum-tungsten alloys. These metallic materials are sufficiently flexible to allow the stent framework to be compressed and expanded, but also provide sufficient radial strength to maintain the stent in the expanded configuration, and apply adequate force to the vessel wall to hold the stent in place and maintain vessel patency.
In another embodiment of the invention, the stent framework comprises one or more biocompatible polymeric or metallic materials. Polymeric stents may be biodegradable, biostable, or comprise a mixture of polymeric materials that are both biostable and biodegradable. Biodegradable polymers appropriate for the stents of the invention include polylactic acid, polyglycolic acid, and their copolymers, caproic acid, polyethylene glycol, polyanhydrides, polyacetates, polycaprolactones, poly(orthoesters), polyamides, polyurethanes and other suitable polymers. Biostable polymers appropriate for the stents of the invention include polyethylene, polypropylene, polymethyl methacrylate, polyesters, polyamides, polyurethanes, polytetrafluoroethylene (PTFE), polyvinyl alcohol, and other suitable polymers. These polymers may be used alone or in various combinations to give the stent unique properties such as controlled rates of degradation, or to form biostable stents with a biodegradable or bioerodable coating that may reduce inflammation, control tissue ingrowth, and additionally, release one or more therapeutic agents. Alternatively, either a metallic or polymeric stent may be coated with a porous metal or metal oxide coating.
In one embodiment of the invention, therapeutic agent carrying regions 406 or 506 are treated to improve adherence of one of more therapeutic agents, as indicated in Block 604. Such treatment includes etching or pitting the surface of regions 406 or 506, or applying a primer polymeric coating or other appropriate methods. In other embodiments, the surface is chemically etched. Any such process is applied only to therapeutic agent carrying regions 406 or 506, and not to high strain regions 408 or 504.
Next, as indicated in Block 606, a formulation containing one or more therapeutic agents is applied to therapeutic agent-carrying regions 406 or 506 of stent framework 400 or 500 while preventing the formulation from contacting high strain regions 408 or 504 (Block 608). The therapeutic agent containing formulation may be applied to regions 406 or 506 by spraying or dipping stent framework 400 or 500 while shielding high strain regions 408 or 504 if needed. The framework is masked in one embodiment. Alternatively, an ink jet sprayer, in one embodiment, selectively applies the formulation to the stent framework.
Finally, the manufacture of the stent is completed by drying or curing the therapeutic agent formulation and adding a mesh over the exterior surface of stent framework 400 or 500, or any other procedure required by the design of the stent. The completed stent may then be compressed and mounted on a catheter, expanded at the delivery site, and otherwise handled as needed with minimal chipping, flaking, and loss of the therapeutic agent.
In one embodiment of the invention, a stent framework such as either stent framework 400 or 500 is formed from one or more metallic or polymeric materials. Next, the therapeutic agent-carrying region (406 or 506) of stent framework 400 or 500 is treated to improve adherence of one or more therapeutic agents. In one embodiment of the invention, cavities are created in the surface of the stent framework by processes such as abrasion, chemical etching, chemical dealloying, thermal dealloying, laser drilling, ion beam irradiation or any other appropriate method. The high strain regions of the stent framework, for example crown portions 404 of stent framework 400 or ring portions 504 of stent framework 500, are left unaltered. This is accomplished by directing the process only at the low strain regions of the stent framework, and if needed, additionally shielding the high strain regions. The cavities formed in the therapeutic agent carrying region are then filled with a formulation appropriate for the therapeutic agent(s) to be delivered. In one embodiment, the cavities are pores. In another embodiment, the cavities are nanopores with a diameter of less than about 500 nanometers.
In another embodiment of the invention, cavities are formed in low strain regions 402 and 502 as described above. However, in this embodiment, a gradient of decreasing density of cavities is formed in the regions of stent framework 400 or 500 approaching high strain regions 408 or 504. This design allows maximal therapeutic agent-carrying regions, while providing sufficient strength through the transition areas to prevent stent framework 400 or 500 from cracking or breaking.
In yet another embodiment, at least one region of a metallic wire is treated to increase porosity, interspersed with untreated regions. A stent framework such as stent framework 400 is then formed so that the treated regions become therapeutic agent-carrying regions 406 and untreated regions become high strain regions 408.
In one embodiment of the invention, various therapeutic agents, such as anticoagulants, antiinflammatories, fibrinolytics, antiproliferatives, antibiotics, therapeutic proteins or peptides, recombinant DNA products, or other bioactive agents, diagnostic agents, radioactive isotopes, or radiopaque substances are applied to the therapeutic agent-carrying region of the stent. The formulation containing the therapeutic agent may additionally contain excipients including solvents or other solubilizers, stabilizers, suspending agents, antioxidants, and preservatives, as needed to deliver an effective dose of the therapeutic agent to the treatment site. In some embodiments of the invention, the formulation is applied as a liquid to the therapeutic agent-carrying region of the stent framework so that the porous structures are filled with the formulation. The formulation is then dried to remove the solvent using air, vacuum, or heat, and any other effective means of causing the formulation to adhere to the stent framework.
In another embodiment of the invention one or more therapeutic agents are deposited on therapeutic agent-carrying region 406 or 506 of stent framework 400 or 500 in a coating applied to the external surface of stent framework 400 or 500. In another embodiment, the therapeutic agent(s) are deposited on the surface of therapeutic agent-carrying region 406 or 506 of stent framework 400 or 500, and then a polymeric or non-polymeric coating is applied over the therapeutic agents. In some embodiments the coating includes one or more polymers that optimize the delivery and availability of the therapeutic agent.
In one embodiment of the invention, the coating material is deposited on the surface of low strain regions 402 or 502 of stent framework 400 or 500 by rotating stent framework 400 or 500 and spraying the coating material from a nozzle that selectively directs the spray at low strain regions 406 or 506 of stent framework 400 or 500 while leaving high strain regions 408 or 504 unaffected. In some embodiments, the coating is then dried using air, vacuum, or heat, or is cured using ultraviolet light causing the coating to adhere to the surface of low strain region 402 or 502 of stent framework 400 or 500. In one embodiment, the nozzle is a portion of an ink jet printing device.
In still other embodiments of the invention, high strain regions 408 or 504 of stent framework 400 or 500 are shielded while the formulation containing the therapeutic agent is applied to low strain regions 402 or 502. For example, high strain regions 408 or 504 of stent framework 400 or 500 may be covered with a physical barrier while the therapeutic agent-containing formulation is applied to low strain regions 402 or 502 of stent framework 400 or 500. In another embodiment, high strain regions 408 or 504 may be coated with a polymer solution or oil before the therapeutic agent formulation is applied to stent framework 400 or 500 by dipping or spraying so that the formulation will not adhere to high strain regions 408 or 504.
While the invention has been described with reference to particular embodiments, it will be understood by one skilled in the art that variations and modifications may be made in form and detail without departing from the spirit and scope of the invention.
