|Publication number||US20060271169 A1|
|Application number||US 11/432,281|
|Publication date||Nov 30, 2006|
|Filing date||May 11, 2006|
|Priority date||Nov 13, 2002|
|Also published as||CA2503625A1, CN1725988A, DE60322581D1, EP1572032A2, EP1572032A4, EP1572032B1, US7294409, US20040148015, WO2004043292A2, WO2004043292A3|
|Publication number||11432281, 432281, US 2006/0271169 A1, US 2006/271169 A1, US 20060271169 A1, US 20060271169A1, US 2006271169 A1, US 2006271169A1, US-A1-20060271169, US-A1-2006271169, US2006/0271169A1, US2006/271169A1, US20060271169 A1, US20060271169A1, US2006271169 A1, US2006271169A1|
|Inventors||Whye-Kei Lye, Kareen Looi, Michael Reed|
|Original Assignee||Whye-Kei Lye, Kareen Looi, Reed Michael L|
|Export Citation||BiBTeX, EndNote, RefMan|
|Referenced by (12), Classifications (22), Legal Events (2)|
|External Links: USPTO, USPTO Assignment, Espacenet|
The present application is a continuation of U.S. application Ser. No. 10/713,244 filed on Nov. 13, 2003, which claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 60/426,106 filed on Nov. 13, 2002, the disclosures of which are incorporated by reference herein in their entirety.
The present invention relates generally to medical devices and methods for making same. More specifically, the invention relates to implantable medical devices having at least one porous layer, and methods for making such devices.
Implantable medical devices are increasingly being used to deliver one or more therapeutic agents to a site within a body. Such agents may provide their own benefits to treatment and/or may enhance the efficacy of the implantable device. For example, much research has been conducted into the use of drug eluting stents for use in percutaneous transluminal coronary angioplasty (PTCA) procedures. Although some implantable devices are simply coated with one or more therapeutic agents, other devices include means for containing, attaching or otherwise holding therapeutic agents to provide the agents at a treatment location over a longer duration, in a controlled-release manner, or the like.
Porous materials, for example, are commonly used in medical implants as matrices for the retention of therapeutic agents. Materials that have been used for this purpose include ceramics such as hydroxyapatites and porous alumina, as well as sintered metal powders. Polymeric materials such as poly(ethylene glycol)/poly(L-lactic acid) (PLGA) have also been used for this purpose. These materials are typically applied as coatings to the medical implant, raising issues regarding coating adhesion, mechanical properties, and material biocompatibility. Further, application of these coatings introduces additional complexity to the fabrication process, increasing overall production costs.
Therefore, it would be advantageous to have improved implantable medical devices with porous layers and methods for fabricating those devices. Such methods would ideally produce a more adherent and mechanically robust porous layer while simplifying device manufacture. Methods would also ideally provide porous layers having desired pore sizes and densities. At least some of these objectives will be met by the present invention.
Methods of the present invention provide means for fabricating an implantable medical device having at least one porous layer. In one aspect, a method of fabricating an implantable medical device having a porous layer for releasably containing at least one therapeutic agent includes providing an implantable medical device comprising at least one alloy and removing at least one component of the alloy to form the porous layer. In some embodiments, the component is removed to form the porous layer as a biocompatible material, such as gold. In some embodiments, the medical device comprises a tubular stent device having an outer surface and an inner surface. For example, the stent device may comprise a coronary artery stent for use in a percutaneous transluminal coronary angioplasty (PTCA) procedure. In some of these embodiments, the alloy is disposed along the outer surface of the stent device.
Optionally, providing the implantable medical device may also include depositing the alloy on at least one surface of the medical device. In various embodiments, the alloy may be disposed along an outer surface of the implantable medical device, such that the dissolving step forms the porous layer on the outer surface of the device. In some embodiments, the alloy includes one or more metals, such as but not limited to gold, silver, nitinol, steel, chromium, iron, nickel, copper, aluminum, titanium, tantalum, cobalt, tungsten, palladium, vanadium, platinum and/or niobium. In other embodiments, the alloy comprises at least one metal and at least one non-metal. Optionally, before the dissolving step at least one substance may be embedded within the alloy. For example, a salt or an oxide particle may be embedded in the alloy to enhance pore formation upon dissolution.
Dissolving one or more components of the alloy may involve exposing the alloy to a dissolving substance. For example, a stainless steel alloy may be exposed to sodium hydroxide in one embodiment. Typically, one or more of the most electrochemically active components of the alloy are dissolved. After the dissolving step, additional processing may be performed. For example, the device may be coated after the dissolving step with titanium, gold and/or platinum. Some embodiments further include introducing at least one therapeutic agent into the porous layer. For example, the therapeutic agent may be introduced by liquid immersion, vacuum dessication, high pressure infusion or vapor loading in various embodiments. The therapeutic agent may be any suitable agent or combination of agents, such as but not limited to anti-restenotic agent(s) or anti-inflammatory agent(s), such as Rapamycin, Sirolimus, Taxol, Prednisone, and/or the like. In other embodiments, live cells may be encapsulated by the porous layer, thereby allowing transport of selected molecules, such as oxygen, glucose, or insulin, to and from the cells, while shielding the cells from the immune system of the patient. Some embodiments may optionally include multiple porous layers having various porosities and atomic compositions.
In another aspect, a method for treating a blood vessel using an implantable medical device having a porous layer for releasably containing at least one therapeutic agent includes: providing at least one implantable stent having a porous layer for releasably containing at least one therapeutic agent; and placing the stent within the blood vessel at a desired location, wherein the stent releases the at least one therapeutic agent from the porous layer after placement. For example, in one embodiment the desired location may comprise an area of stenosis in the blood vessel, and the at least one therapeutic agent may inhibit re-stenosis of the blood vessel. Again, the therapeutic agent in some embodiments may be one or more anti-restenosis agents, anti-inflammatory agents, or a combination of both. In one embodiment, the blood vessel may be a coronary artery. In such embodiments, the placing step may involve placing the stent so as to contact the porous layer with at least one of a stenotic plaque in the blood vessel and an inner wall of the blood vessel.
In still another aspect, an implantable medical device has at least one porous layer comprising at least one remaining alloy component and interstitial spaces, wherein the interstitial spaces comprise at least one removed alloy component space of an alloy, the alloy comprising the at least one remaining alloy component and the at least one removed alloy component. In some embodiments, the porous layer comprises a matrix. Also in some embodiments, the implantable medical device comprises an implantable stent device having an outer surface and an inner surface, and the porous layer is disposed along the outer surface. For example, the stent device may comprise a coronary artery stent for use in a percutaneous transluminal coronary angioplasty procedure. As described above, the alloy may comprise one or more metals selected from the group consisting of gold, silver, nitinol, steel, chromium, iron, nickel, copper, aluminum, titanium, tantalum, cobalt, tungsten, palladium, vanadium, platinum and/or niobium. For example, the alloy may comprise stainless steel and the porous layer may comprise iron and nickel.
In some embodiments, the component (or components) that is dissolved comprises a most electrochemically active component of the alloy. Generally, the device further includes at least one therapeutic agent disposed within the at least one porous layer. Any such agent or combination of agents is contemplated. Finally, the device may include a titanium or platinum coating over an outer surface of the device.
Methods of the present invention provide means for fabricating an implantable medical device having at least one porous layer. Generally, the methods involve providing an implantable medical device containing an alloy and removing at least one component of the alloy to form the porous layer. In some embodiments, an alloy may first be deposited on an implantable device and one or more components of the alloy may then be removed to form the porous layer. Such methods are often referred to as “dealloying.” For a general description of dealloying methods, reference may be made to “Evolution of nanoporosity in dealloying,” Jonah Erlebacher et al., Nature 410, pp. 450-453, March 2001, the entire contents of which are hereby incorporated by reference. Dealloying a layer of an implantable device provides a porous layer, which may then be infused with one or more therapeutic agents for providing delivery of an agent into a patient via the device. Use of dealloying methods will typically provide more adherent and mechanically robust porous layers on medical implantables than are currently available, while also simplifying device manufacture.
Although the following description often focuses on the example of implantable stent devices for use in PTCA procedures, any suitable implantable medical device may be fabricated with methods of the invention. Other devices may include, but are not limited to, other stents, stent-grafts, implantable leads, infusion pumps, vascular access devices such as implantable ports, orthopedic implants, implantable electrodes, and the like. Similarly, devices fabricated via methods of the present invention may be used to deliver any suitable therapy or combination of therapies in a patient care context, veterinary context, research setting or the like. Therapeutic agents may include, for example, drugs, genes, anti-restenosis agents, anti-thrombogenic agents, antibiotic agents, anti-clotting agents, anti-inflammatory agents, cancer therapy agents and/or the like. Thus, the following description of specific embodiments is provided for exemplary purposes only and should not be interpreted to limit the scope of the invention as set forth in the appended claims.
Referring now to
As mentioned above, any medical device may be fabricated with one or more porous layers 12 according to embodiments of the present invention. Where the device is an implantable stent device 10, any suitable type, size and configuration of stent device may be fabricated with one or more porous layers 12. In one embodiment, stent device 10 comprises an expandable stent for implantation in a coronary artery during a PTCA procedure. Such a stent device 10 may be fabricated from any suitable material or combination of materials. In one embodiment, stent device 10 comprises a stainless steel non-porous layer 14 arid an iron and nickel porous layer 12. In some embodiments, porous layer 12 may be formed of a biocompatible material, such as gold. In other embodiments, porous layer 12 may be formed from a cobalt-chromium alloy such as L605. Any other suitable material or combination of materials is contemplated. Furthermore, stent device 10 may include a layer or coating comprising a biocompatible material such as titanium, gold or platinum, which may provide biocompatibility, corrosion resistance or both.
With reference now to
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In another embodiment, multiple therapeutic agents may be introduced into a porous matrix composed of a plurality of porous layer 23. As described previously, the plurality of porous layers may vary in atomic composition, as well as in pore size and density. Compositional variations may allow for preferential binding to occur between the therapeutic agent and the coating, changing the elution kinetics of the agent. Pore size and density will also affect the transport kinetics of therapeutics from and across each layer. The use of a plurality of porous layers may thus allow for controlling elution kinetics of multiple therapeutic agents. In a further embodiment, live cells may be encapsulated within lumen 26 of device 20. In one such embodiment, the entire device may be made porous (such that the internal lumen and the exterior of the device are separated by a porous layer). Live cells (such a pancreatic islet cells) can be encapsulated within the internal lumen, and the porosity of the layer adjusted to allow transport of selected molecules (such as oxygen, glucose; as well as therapeutic cellular products, such as insulin, interferon), while preventing access of antibodies and other immune system agents that may otherwise attack or compromise the encapsulated cells. In some embodiments, a protective layer or coating may be formed or added to medical device 20, such as a titanium, gold or platinum layer or coating. If there is a concern that porous layer 23 may not be biocompatible, a passivation layer may be deposited into porous layer 23 to enhance biocompatibility. For instance, a very thin layer of gold may be electroplated into the dealloyed porous layer 23. Electroless deposition may also be used to achieve the same effect. Depending on the composition of porous layer 23, the porous coating may also be passivated chemically or in a reactive ion plasma.
Although the present invention has been described in full, in relation to various exemplary embodiments, various additional embodiments and alterations to the described embodiments are contemplated within the scope of the invention. Thus, no part of the foregoing description should be interpreted to limit the scope of the invention as set forth in the following claims.
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|U.S. Classification||623/1.39, 623/23.5, 427/2.21, 623/1.42, 148/713|
|International Classification||A61L31/08, A61F, A61L31/16, A61L31/14, A61F2/86, A61F2/28|
|Cooperative Classification||Y10T428/12458, Y10S623/901, A61L31/16, A61L31/082, A61F2/86, A61L2300/41, A61L2300/416, A61L31/146|
|European Classification||A61L31/14H, A61L31/08B, A61L31/16|
|Nov 10, 2006||AS||Assignment|
Owner name: UNIVERSITY OF VIRGINIA PATENT FOUNDATION, VIRGINIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:UNIVERSITY OF VIRGINIA;REEL/FRAME:018506/0268
Effective date: 20061109
Owner name: UNIVERSITY OF VIRGINIA, VIRGINIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:LYE, WHYE-KEI;REED, MICHAEL L.;REEL/FRAME:018506/0216;SIGNING DATES FROM 20060824 TO 20060927
|Nov 18, 2008||AS||Assignment|
Owner name: MEDTRONIC VASCULAR, INC.,CALIFORNIA
Free format text: MERGER;ASSIGNOR:SETAGON, INC.;REEL/FRAME:021852/0703
Effective date: 20071002