CROSS REFERENCE TO RELATED APPLICATION
This is a divisional application of U.S. patent application Ser. No. 10/262,150, which was filed on Sep. 30, 2002.
This invention relates to implantable medical devices, such as stents. More particularly, this invention relates to a stent having drug delivery capabilities.
Percutaneous transluminal coronary angioplasty (PTCA) is a procedure for treating heart disease. A catheter assembly having a balloon portion is introduced into the cardiovascular system of a patient via the brachial or femoral artery. The catheter assembly is advanced through the coronary vasculature until the balloon portion is positioned across the occlusive lesion. Once in position across the lesion, the balloon is inflated to a predetermined size to radially compress against the atherosclerotic plaque of the lesion to remodel the lumen wall. The balloon is then deflated to a smaller profile to allow the catheter to be withdrawn from the patient's vasculature.
A problem associated with the procedure includes formation of intimal flaps or torn arterial linings that can collapse and occlude the conduit after the balloon is deflated. Moreover, thrombosis and restenosis of the artery can develop over several months after the procedure, which can require another angioplasty procedure or a surgical bypass operation. To reduce the partial or total occlusion of the artery by the collapse of arterial lining and to reduce the chance of the development of thrombosis and restenosis, an intraluminal prosthesis, an example of which includes an expandable stent, is implanted in the lumen to maintain the vascular patency. Stents are scaffolding structures, usually cylindrical or tubular in shape, functioning to physically hold open, and if desired, to expand the wall of the passageway. Typically stents are capable of being compressed for insertion through small cavities via small catheters, and then expanded to a larger diameter once at the desired location.
To treat the damaged vasculature tissue and further fight against thrombosis and restenosis, there is a need to administer therapeutic substances to the treatment site. For example, anticoagulants, antiplatelets and cytostatic agents are commonly used to prevent thrombosis of the coronary lumen, to inhibit development of restenosis, and to reduce post-angioplasty proliferation of the vascular tissue. To provide an efficacious concentration to the treated site, systemic administration of medication can produce adverse or toxic side effects for the patient. Local delivery is a highly suitable method of treatment in that smaller levels of medication, as compared to systemic dosages, are concentrated at a specific site. Local delivery produces fewer side effects and achieves more effective results.
One commonly applied technique for the local delivery of the drugs is through the use of medicated stents. One method of medicating stents involves the use of a polymeric carrier coated onto the body of the stent. A polymer dissolved in a solvent and a drug added thereto can be applied to the stent. Once the solvent evaporates, a coating of the polymer containing the drug remains on the stent. The embodiments of the present invention provide various stent structures for containing a coating, such as a polymeric coating, for the local delivery of a drug.
In accordance with one embodiment, a stent is disclosed comprising a strut having a first segment, a second segment and a third segment located between the first and second segments, wherein the transverse cross sectional area of the third segment is less than the transverse cross sectional area of the first segment and the second segment; and a coating disposed on the third segment of the strut, wherein the first and second segments of the strut are free of any coating. In one embodiment, the coating is disposed all the way around the third segment of the strut. The outer surface of the coating should not extend beyond the outer surface of the first or second segment of the strut. The coating can be made from a polymeric material containing a therapeutic substance. In accordance with one embodiment, the strut includes a linear segment extending into a curved segment, wherein the first, second and third segments define a part of the linear segment of the strut. The curved segment can include a notch or can be smaller in thickness or width than the first or second segment of the strut.
In accordance with another embodiment of the invention, a radially expandable stent is provided comprising a strut, at least a segment of the strut having a circumference smaller than the circumference of a remaining portion of the strut; and a coating supported by the segment of the strut having the smaller circumference. The strut can include four sides, wherein the width of the segment of the strut having the smaller circumference is less than the width of the remaining portion of the strut. Alternatively, the thickness of the segment of the strut having the smaller circumference is less than the thickness of the remaining portion of the strut. The coating can, for example, surround the segment of the strut having the reduced circumference. The remaining portion of the strut having the larger circumference can be free from any coating.
In accordance with another embodiment of the invention, a method of manufacturing a drug eluting stent is provided, comprising depositing a coating on a first segment of a strut of the stent, the stent including a second segment and a third segment, wherein the first segment is positioned between the second segment and the third segment, the first segment having a smaller transverse cross sectional area than the transverse cross sectional area of the second or third segment.
BRIEF DESCRIPTION OF THE DRAWINGS
In accordance with another embodiment of the invention, a method of manufacturing a drug eluting stent is provided, comprising depositing a coating on a stent, the stent including a strut having a first segment, a second segment, and a third segment located between the first and second segments, wherein the transverse cross sectional area of the third segment is less than the transverse cross sectional area of the first segment and the second segment; and removing the coating off of the first and second segments so that the coating remains on the third segment.
FIG. 1 illustrates an embodiment of a conventional stent;
FIG. 2 is an enlarged perspective view of the stent strut of encircled region 2 of FIG. 1;
FIGS. 2A and 2B are transverse cross sectional views along the line 2A-2A and 2B-2B, respectively, of FIG. 2; and
FIGS. 3, 4, 5, 6A, and 6B are perspective views of a stent strut according to other embodiments of the invention.
FIG. 1 illustrates one embodiment of a stent 10 that can be used with the practice of the present invention. Stent 10 can be generally cylindrical and radially self- or balloon-expandable. Stent 10 can be inserted and deployed in a patient with an appropriate delivery device such as a balloon dilatation catheter. Stent 10 can be made, for example, from a plurality of wave-like or serpentine-like struts 12 having curved segments and generally linear segments. Struts 12 are connected to the adjacent struts 12 via connecting elements 14. The embodiments of the present invention, however, should not be limited to the structure of FIG. 1. A variety of other scaffolding designs can also be used, such as “V” shaped struts or Struts having a “zigzag” formation.
Referring to FIG. 2, the linear section of strut 12 includes a segment, referred to by reference number 16, wherein any transverse cross sectional portion of segment 16 has a smaller cross sectional surface area than the remaining segment of strut 12. FIG. 2A illustrates a transverse cross sectional view of strut 12 of FIG. 2 taken along the line 2A-2A. FIG. 2B illustrates a transverse cross sectional view of strut 12 of FIG. 2 taken along the line 2B-2B. As illustrated by FIGS. 2A and 2B, segment 16 has a reduced thickness and width, which provides for a smaller circumference, as compared to the remaining portions of strut 12.
FIGS. 2, 2A and 2B illustrate a four-sided strut 12 wherein segment 16 has a reduced width W as well as thickness T. Struts 12 need not be four-sided, however, and can have any suitable transverse cross sectional geometry, such as a three sided, oval or circular struts. The reduced circumferential size of segment 16 defines a recessed volume 18 in which a coating 20 can be deposited. Coating 20 can be a drug or a therapeutic composition or can contain the drug. Coating 20 can be made from any suitable biocompatible polymer, examples of which are disclosed below. As best illustrated by FIG. 2, the remaining segments of strut 12 can be free from any substances or coatings. Coating 20 can be disposed all the way around segment 16 as coating 20 can completely encapsulate the narrowed segment 16 of strut 12. Recessed volume 18 can be fully filled with the coating substance such that the outer surfaces of coating 20 are “flush” with their respective outer surfaces of strut 12. In other words, the outer dimensions of coating 20 can equal the outer dimensions of strut 12, thereby creating a smooth transition between the surfaces of coating 20 and the surfaces of strut 12, thus minimizing intravascular flow turbulence around stent 10.
In accordance with another embodiment of the invention, as illustrated in FIG. 3, strut 12 can have a variable thickness T, but a constant width W. As best illustrated by FIG. 3, width W of strut 12 is the same, but thickness T is reduced along segment 16 of strut 12. The reduced thickness T provides recessed volume 18 containing coating 20 on the outer surface or tissue-contacting surface of strut 12. Although not illustrated, a recessed volume 18 can also be provided in the inner or lumen surface of strut 12.
In accordance with another embodiment, as illustrated by FIG. 4, a variable width W for strut 12 can be provided, while maintaining the thickness T constant. As best illustrated by FIG. 4, thickness T of strut is the same, but width W is reduced along segment 16 of strut 12. FIG. 4 illustrates recessed volumes 18 on opposing sides of strut 12. However, as is the case with FIG. 3, recessed volume 18 can be about only one of the two sides of strut 12.
Transition zones leading into segment 16 can be gradual, with a slight slop, as illustrated by FIG. 2 or can be a relatively sharp drop-off, as illustrated by FIG. 3 or 4. The smallest transverse cross sectional area in segment 16 can be up to about 50% smaller than the transverse cross sectional area of the remaining portions of strut 12. One having ordinary skill in the art should be cautious of mechanical fatigue and failure that could be caused if the circumference of segment 16 is too small or if the transition zone is sloped too non-compliant. Exemplary dimensions and design of strut 12 depend, of course, on an variety of factors including the material from which strut 12 is made, the length of segment 16, and the application for which stent 10 will be used. Accordingly, there is a tradeoff between trying to maximize recess volume 18 for maximizing drug delivery capabilities and eliminating mechanical failure that can be caused by radial expansion and use of stent 10.
In accordance with yet another embodiment, as illustrated in FIG. 5, any number of suitable segments 16 having a reduced circumferential area can be included in strut 12. Having a multitude of segments 16 allows for the incorporation of more than one type of therapeutic substance in different areas of stent 10. Accordingly, a variety of cocktail combinations of drugs can be delivered via stent 10. The longitudinal span of each segment 16 depends on the number of segments 16 that are to be incorporated into strut 12 and the length of strut 12, among other factors.
In accordance with yet another embodiment of the invention, FIG. 6A illustrates strut 12 having a thinned section, in either thickness or width, in the curved portion (as designated by reference number 22) of strut 12. Alternatively, as illustrated in FIG. 6B notches 24 can be provided in curved portion 22 of strut 12. The thinned section and/or pivot notches 24 in curved portion 22 of strut 12 can produce a weakened bending region for stent 10. The weakened bending region can maximize bending along curved region 22 or at pivot notches 24 and minimize stress along the linear portion of strut 12. This is advantageous in preserving the structural integrity of coating 20 so as to prevent or reduce fragmentation of coating during the radial expansion of stent 10.
Struts 12 can be made from a metallic material or an alloy such as, but not limited to, cobalt chromium alloy (ELGILOY), stainless steel (316L), “MP35N,” “MP20N,” ELASTINITE (nitinol), tantalum, nickel-titanium alloy, platinum-iridium alloy, gold, magnesium, or combinations thereof “MP35N” and “MP20N” are trade names for alloys of cobalt, nickel, chromium and molybdenum available from Standard Press Steel Co., Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum. Struts 12 can also be made fiom bioabsorbable or biostable polymers.
The drug, therapeutic substance or active agent, terms which are used interchangeably, in the coating 20 can inhibit the activity of vascular smooth muscle cells. More specifically, the active agent can be aimed at inhibiting abnormal or inappropriate migration and/or proliferation of smooth muscle cells for the inhibition of restenosis. The active agent can also include any substance capable of exerting a therapeutic or prophylactic effect for a diseased condition. For example, the agent can be for enhancing wound healing in a vascular site or improving the structural and elastic properties of the vascular site. Examples of agents include antiproliferative substances such as actinomycin D, or derivatives and analogs thereof (manufactured by Sigma-Aldrich, Inc., Milwaukee, Wis.; or COSMEGEN available from Merck & Co., Inc., Whitehorse Station, N.J.). Synonyms of actinomycin D include dactinomycin, actinomycin IV, actinomycin Il, actinomycin Xl, and actinomycin Cl. The active agent can also fall under the genus of antineoplastic, anti-inflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, antiallergic and antioxidant substances. Examples of such antineoplastics and/or antimitotics include paclitaxel (e.g., TAXOLŽ by Bristol-Myers Squibb Co., Stamford, Conn.), docetaxel (e.g., TaxotereŽ, from Aventis S.A., Frankfurt, Germany), methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g., AdriamycinŽ from Pharmacia & Upjohn, Peapack, N.J.), and mitomycin (e.g., MutamycinŽ from Bristol-Myers Squibb Co.). Examples of such antiplatelets, anticoagulants, antifibrin, and antithrombins include sodium heparin, low molecular weight heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor antagonist antibody, recombinant hirudin, and thrombin inhibitors such as Angiomax ä (Biogen, Inc., Cambridge, Mass.). Examples of such cytostatic or antiproliferative agents include angiopeptin, angiotensin converting enzyme inhibitors such as captopril (e.g. CapotenŽ and CapozideŽ from Bristol-Myers Squibb Co.), cilazapril or lisinopril (e.g., PrinivilŽ and PrinzideŽ from Merck & Co., Inc.); calcium channel blockers (such as nifedipine), colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand name MevacorŽ from Merck & Co., Inc.), monoclonal antibodies (such as those specific for Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors, suramin, serotonin blockers, steroids, thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), and nitric oxide. An example of an antiallergic agent is permirolast potassium. Other therapeutic substances or agents which may be appropriate include alpha-interferon, genetically engineered epithelial cells, rapamycin and its derivatives and analogs, and dexamethasone.
Coating 20 can be made from any suitable biocompatible polymer, examples of which include ethylene vinyl alcohol copolymer (commonly known by the generic name EVOH or by the trade name EVAL); poly(hydroxyvalerate); poly(L-lactic acid); polycaprolactone; poly(lactide-co-glycolide); poly(hydroxybutyrate); poly(hydroxybutyrate-co-valerate); polydioxanone; polyorthoester; polyanhydride; poly(glycolic acid); poly(D,L-lactic acid); poly(glycolic acid-co-trimethylene carbonate); polyphosphoester; polyphosphoester urethane; poly(amino acids); cyanoacrylates; poly(trimethylene carbonate); poly(iminocarbonate); copoly(ether-esters) (e.g., PEO/PLA); polyalkylene oxalates; polyphosphazenes; biomolecules, such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic acid; polyurethanes; silicones; polyesters; polyolefins; polyisobutylene and ethylene-alphaolefin copolymers; acrylic polymers and copolymers; vinyl halide polymers and copolymers, such as polyvinyl chloride; polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene halides, such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile; polyvinyl ketones; polyvinyl aromatics, such as polystyrene; polyvinyl esters, such as polyvinyl acetate; copolymers of vinyl monomers with each other and olefins, such as ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetate copolymers; polyamides, such as Nylon 66 and polycaprolactam; alkyd resins; polycarbonates; polyoxymethylenes; polyinides; polyethers; epoxy resins; polyurethanes; rayon; rayon-triacetate; cellulose; cellulose acetate; cellulose butyrate; cellulose acetate butyrate; cellophane; cellulose nitrate; cellulose propionate; cellulose ethers; and carboxymethyl cellulose. Coating 20 can also be silicon foam, neoprene, santoprene, or closed cell foam.
Stent 10 can be constructed, for example, from a tube of a desired strut material. The tube can be mounted onto a mandrel and angular grooves can be cut into the outer surface of the tube by a lathe or a Swiss screw, for example KJR-16Swiss Screw Machine available from STAR CNC Automatic Lathe in Shizuoka, Japan. The shape of strut 12 can then be radially cut from the tube by a laser. The laser cutting can also produce the thinned curved section 22 or pivot notches 24 illustrated in FIGS. 6A and 6B. Struts 12 can be electropolished to reshape or round off sharp comers.
Stent 10 can then be mounted on a TeflonŽ or paralyne coated mandrel fixed to a two-dimensional actuator controlled by a computer numerical control (CNC) controller, for example a Model DR500available from Aerotek, Inc., Pittsburgh, Pa. The two-dimensional actuator can translate and rotate stent 10 about the longitudinal axis of stent 10. A fluid applicator device, for example a Model 1500XL available from EFD, Inc., East Providence, R.I., with a needle tip, can be fixed adjacent to the mounted stent 10 and ejection of a coating substance can be controlled by the CNC controller. The needle tip can have an outer diameter of about 0.02 mm (0.0008in.) to about 0.038 mm (0.0015 in.) and an inner diameter from about 0.005 mm (0.0002 in.) to about 0.02 mm (0.0009 in.). The CNC controller then causes ejection of coating 20 in a liquid state from the needle tip into recessed volume 18 and simultaneously moves stent 10 longitudinally to spread coating 20 evenly in recessed volume 18. Once recessed volume 18 of segment 16 is coated with a desired volume of coating 20, ejection of the coating substance ceases and stent 10 can be moved until the next uncoated recessed volume 18 is adjacent to the needle tip of the fluid applicator device. The process can repeat until all the recessed volumes 18 are coated. The needle tip should also be capable of being raised and lowered relative to stent 10 by the CNC controller particularly when coating small volumes necessitates direct contact between the needle tip and stent 10.
Alternatively, coating 20 can be deposited in recessed volumes 18 by crimping stent 10 onto a mandrel covered with a soft material (for examples, having a D hardness rating of about 20 to about 50, such as silicon foam, neoprene, santoprene, or a closed cell foam). In a relaxed state, the soft material can have, for example, a soft material thickness of at least the thickness of strut 12. The mandrel and stent 10 can then be dipped into the coating substance or the coating substance can be sprayed onto stent 10. The mandrel and stent 10 can then be pulled through an orifice with a clearance around strut 12 of less than about 0.003 mm (0.0001 in.), more narrowly less than about 0.001 mm (0.00005 in.). Stent 10 can also be pulled over a reamer to scrape off excess coating substance.
In accordance with another embodiment of the invention, masking techniques as is known to a person having ordinary skill in the art can be used to deposit coating 20 in recessed volumes 18 of segment 16.
While particular embodiments of the present invention have been shown and described, it will be obvious to those having ordinary skill in the art that changes and modifications can be made without departing from this invention. Therefore, the appended claims are to encompass within their scope all such changes and modifications as they fall within the true spirit and scope of the invention.