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Inventors: Chen Yung-Ming
, Ho Henjen
The Patent Description data below is from USPTO Patent Application 20130035753 , Multiple scaffold design and coating thereof
Stents act as scaffoldings, functioning to physically hold open and, if desired, to expand the wall of the passageway of a target vessel. Stents are often used in the treatment of atherosclerotic stenosis and/or restenosis in blood vessels. “Stenosis” refers to a narrowing or constriction of the diameter of a bodily passage or orifice. Typically, stents are capable of being compressed, so that they can be inserted through small cavities via catheters, and then expanded to a larger diameter once they reach their target vessel. Mechanical intervention via stents has reduced the rate of restenosis; restenosis, however, is still a significant clinical problem. “Restenosis” refers to the reoccurrence of stenosis in a blood vessel or heart valve after it has been treated (as by balloon angioplasty or valvuloplasty) with apparent success. Accordingly, stents have been modified to perform not only as a mechanical scaffolding, but also to provide biological therapy.
Biological therapy can be achieved by medicating a stent, typically referred to as a drug delivery stent. Drug delivery stents provide for the local administration of a therapeutic substance at the diseased site. In contrast, systemic administration of a therapeutic substance may cause adverse or toxic side effects for the patient because large doses are needed in order for the therapeutic substance to have an efficacious effect at the diseased site. Thus, local delivery is a preferred method of treatment in that smaller total levels of medication are administered in comparison to systemic dosages, but are concentrated at a specific site. Local delivery therefore produces fewer side effects and achieves more favorable results.
Stents may be made of biostable materials that remain at an implant site permanently. However, the clinical need for a stent at an implant site may be temporary. Once treatment is complete, which may include structural tissue support and/or drug delivery, it may be desirable for the stent to be removed or disappear from the treatment location. One way of having a stent disappear may be by fabricating a stent in whole or in part from materials that erode or disintegrate through exposure to conditions within the body. Stents fabricated from bioresorbable, biodegradable, bioabsorbable, and/or bioerodable materials such as bioresorbable polymers can be designed to completely erode only after the clinical need for them has ended.
A typical method for medicating an implantable device includes, for example, applying a composition containing a polymer, a solvent, and a therapeutic substance to the implantable device using conventional techniques, such as spray-coating or dip-coating. The method further includes removing the solvent, leaving on the implantable device surface a coating of the polymer with the therapeutic substance impregnated in the polymer.
In a typical spray-coating method, a stent is mounted on a mandrel of a spray-coating device. Generally, the stent will rest on, or contact components of, a mandrel (or the mandrel itself) which supports the stent and allows it to rotate during a spray-coating process. The contact between the portions of the mandrel and stent, however, inevitably cause coating defects. These defects can include cob-webbing, tearing, bridging, clumping and/or lack of coating on portions of the stent. The embodiments of the present invention are intended to address coating defect issues caused by conventional mandrel designs.
Another issue with conventional stent coating operations is one of efficiency and cost. Stent coating is typically performed one stent or scaffold at a time. For each stent coated, the coating equipment must be set up. In addition, each stent or scaffold must be loaded prior to coating and unloaded after coating. Thus, machine utilization is limited by coating only one stent for machine set-up, loading, and unloading processes.
Various embodiments of the present invention include a medical device comprising: a structure comprising a plurality of stent bodies arranged end to end, wherein adjacent stent bodies of the structure are connected by a severable connecting portion disposed between the adjacent stent bodies, wherein at least one of the stent bodies at an end of the structure comprises a severable end portion at the end of the structure.
Further embodiments of the present invention include a method of coating a plurality of stents comprising: providing a structure comprising a plurality of stent bodies arranged end to end, wherein adjacent stent bodies along the structure are connected by a severable connecting portion disposed between the adjacent stent bodies; and depositing a coating on the plurality of stent bodies; and severing the severable connecting portions to disconnect the plurality of stent bodies.
The implantable medical device used in conjunction with the present invention may be any implantable medical device, examples of which include self-expandable stents, balloon-expandable stents, micro-depot or micro-channel stents, stent-grafts and grafts. Examples of stents include neurological, coronary, peripheral and urological stents. In some embodiments, the underlying structure of the implantable medical device can be virtually any design.
A stent such as stent may be fabricated from a polymeric tube or a sheet by rolling and bonding the sheet to form the tube. A tube or sheet can be formed by extrusion or injection molding. A stent pattern, such as the one pictured in , can be formed in a tube or sheet with a technique such as laser cutting or chemical etching. The stent can then be crimped on to a balloon or catheter for delivery into a bodily lumen.
An implantable medical device of the present invention can be made partially or completely from a biodegradable, bioresorbable, bioabsorbable, or biostable polymer. A polymer for use in fabricating an implantable medical device can be biostable, bioresorbable, bioabsorbable, biodegradable or bioerodable. Biostable refers to polymers that are not biodegradable. The terms biodegradable, bioresorbable, bioabsorbable, and bioerodable are used interchangeably and refer to polymers that are capable of being completely degraded and/or eroded into different degrees of molecular levels when exposed to bodily fluids such as blood and can be gradually resorbed, absorbed, and/or eliminated by the body. The processes of breaking down and absorption of the polymer can be caused by, for example, hydrolysis and metabolic processes.
A stent made from a bioresorbable polymer is intended to remain in the body for a duration of time until its intended function of, for example, maintaining vascular patency and/or drug delivery is accomplished. After the process of degradation, erosion, absorption, and/or resorption has been completed, no portion of the biodegradable stent, or a biodegradable portion of the stent will remain. In some embodiments, very negligible traces or residue may be left behind.
A therapeutic coating may be formed over a stent by applying a composition containing a polymer, a solvent, and a therapeutic substance to the stent using techniques, such as spray-coating or dip-coating. The solvent is then removed leaving a coating on the stent surface including the polymer with the therapeutic substance impregnated in the polymer.
In the spray-coating method described previously, there are contact areas between the stent and the stent holding device . Depending on the stent and its holding device, contact areas are the source of the coating defects, in the form of cob-webbing, tearing, bridging, clumping and/or lack of coating on portions of the stent.
Embodiments of the present invention solve both of the problems of the conventional coating methods by eliminating the contact defects and allowing coating of more than one stent during a coating process. The embodiments of the present invention include coating a multiple stent structure, which including a plurality of stent bodies arranged end to end in which adjacent stent bodies are connected by a severable support element disposed between the adjacent stent bodies. “End-to-end” is defined generally as with the end of one object in arranged lengthwise, such as along a cylindrical axis in the case of tubular objects, with the end of another object. “Adjacent stent bodies” refer to stent bodies in an end to end arrangement in the structure that are connected by a connecting portion and which have no intervening stent bodies between them. In further embodiments, the ends of stent bodies at one or both ends of the structure may also include severable portions or support elements.
In certain embodiments, the multiple stent structure is disposed over a stent support system. A coating is deposited on the multiple stent structure that is disposed over the stent support system. As described below, the multiple stent structure can include one or more of the severable portions or support elements that can engage the stent support system to allow deposition of coating material on the structure and . After the coating is formed over the structure and after an optional drying step, the severable portions are severed or removed to disconnect the plurality of stent bodies from one another to provide a plurality of disconnected coated stent bodies.
In some embodiments, a finished coating can be formed directly over the multiple stent structure composed of the plurality of stent bodies without unloading the stent structure from the support system. Therefore, the embodiments described allow coating multiple stent bodies without loading and unloading the stent bodies for each stent body. The plurality of stent bodies are coated in one coating operation. A coating operation refers to forming a coating over the stent structure which involves loading and unloading the stent structure on a support system. A stent body refers to a longitudinal section of a repeating pattern of struts, as described above, that is intended to be implanted into a patient and that does not include the severable support elements or the other stent bodies.
Severable portion also includes at least one “gate”, flange or bar (terms which are used interchangeably unless otherwise used specifically). Gate connects tube to distal end B of stent , specifically, to crest of distal ring of stent . Gate connects tube to proximal end A of stent , specifically, to crest of proximal ring of stent .
As indicated above, the ends of stent bodies at one or both ends of the multiple stent structure may also include severable support portions or elements. Referring to , a proximal end and a distal end of multiple stent structure include severable portions and , respectively. depicts a close-up view of proximal end of multiple stent structure . Severable portion includes an end tube and at least one gate that connects tube to proximal end A of stent , specifically, to crest of proximal ring of stent . In , severable portion likewise includes end tube and gate connects tube to distal end B of stent . Tubes and have a width W.
As an alternative to a tube or band at the ends of the multiple stent structure and for connecting adjacent stent bodies, the severable portion may have at least one tab. depicts a strut and strut that are a portions of adjacent stents in a multiple stent structure. Struts and are at two different circumferential positions of the multiple stent structure. Line A-A corresponds to the cylindrical axis of the multiple stent structure. Strut is connected to a tab by a gate . Strut of the adjacent stent is connected to a tab by a gate . The tabs have a width W.
In some embodiments, the stent bodies and one or more of the connecting tubes or tabs between adjacent stent bodies and end tubes at the proximal and distal ends of the structure can be monolithic. That is, when the stent pattern is originally cut or etched from a flat sheet or from a tube, the tubes or tabs of the pattern remain attached to the stent pattern by the at least one gate. Stent patterns can be formed by a variety of methods, including but not limited to, laser cutting and etching, such as chemical etching. Other stent pattern formation techniques may be utilized and are known by those skilled in the art.
In some embodiments, the end tubes or connecting tubes may be attached to the stent by a secondary process, such as, for example, by biocompatible glue or solder. In the process in which the stent pattern is cut into a flat sheet (as opposed to directly on a tube), the attaching may be done either after the cutting or after the cut pattern is rolled into a tube forming a stent thereof. In some embodiments, the severable portion can include, for example, a tab or tube attached to some portion of a stent body that is part of a multiple stent structure. Thus, illustrates an embodiment in which a tube is attached to the sidewall (not shown in this figure) of a ring adjacent to the tube by a gate. In another alternative embodiment, the tube or tab is attached to at least one ring that is not adjacent to the tab or ring by an attachment, for example attaching tube to a ring in . In any embodiment, the tubes or tabs can be attached monolithically or by secondary processes as explained above. Therefore, the at least one gate can be made from the same material as the stent body or made of different material. In some embodiments, the material for a gate, a tube, and a tab can be any of the polymeric and/or metallic materials disclosed below. For example, the gate can be made of the polymers from which the stent is made and/or coated.
The connecting and end portion(s) of the multiple stent structure, which may be at least one end tube or at least one tab, may function as the connecting support of the multiple stent structure to the spray-coating device (such as those illustrated in ) before, during or after the spray-coating process and optionally a drying stage. The connecting portions are severable via the at least one gate on both sides of the connecting portions. For example, gates that connect tube to stent body and gates that connect tube to stent body in are severed. Additionally, the end portions are severable via the at least one gate connecting the end portions to the proximal and distal ends of the multiple stent structure. For example, gates that connect tube to stent body are severed in . The gates can be very thin so that they can be easily removed after a spray-coating process. For example, the thickness (or width) of a gate can be between 0.0005″ and 0.0035″, typically 0.002″. In some embodiments, the gates can be perforated about a width segment thereof so as to facilitate breaking off of the gates from the stent bodies of the multiple stent structure. Such perforations can be positioned along any surface of the gate, such as adjacent to the sidewall such that no portion of the gate is left behind after the breaking thereof. In addition, the number of gates can number between one and ten, typically two. Because the weight of the stent is very low (between 1 mg and 50 mg), the number of gates should be minimized to reduce any rough areas caused by severing the connecting and end portion(s) at the at least one gate(s) after a spray-coating process.
In some embodiments, the multiple stent structure can be supported by a mandrel during the coating process. The mandrel may support the structure by engaging the one or more of the severable portion(s). The mandrel may be configured to engage or contact only the severable portion(s) and to make no contact with any of the stent bodies. Additionally, no other portion of the coating device may make contact with the stent bodies which eliminates defects arising from contact points.
In some embodiments, the mandrel may include an elongate member and one or more support portions along its length with a larger diameter than the elongate to provide more rigid support to avoid the deformation to the stent body during the coating process. For example, the diameter of the elongate member may be between 10 and 50% of the support portions. The support portions are adapted to support a multiple stent structure during coating. The elongate member has a diameter less than an inner diameter of a multiple stent structure so that there is no contact between the elongate member and a stent structure mounted on the mandrel. The one or more support portions have an outer diameter the same as the inner diameter of the multiple stent structure. The support portions may have an outer diameter slightly less than the inner diameter of the multiple stent structure, for example, up to 5% less. The support portions may be disks with a width less than or equal to a width of a tube or tab of the end portions or connecting portions. The disk width may be larger than these portions, but not wide enough to contact a stent body.
In some embodiments, a mandrel may provide support to some of the tubes of the between the end portions of the multiple stent structure. The mandrel in some embodiments may support the structure only at one or both severable end portions. For example, mandrel may have no disk B and supports structure with disks A and C only. In this and other embodiments, the width of the severable connecting portion (e.g., tube ) between adjacent stent bodies may be adjusted to provide more stiffness to the multiple stent structure during coating. For example, the tube may be 1 to 3 mm, 3 to 5 mm, 5 to 7 mm, or 7 to 10 mm.
In further embodiments, a multiple stent structure can be supported during a coating operation without the use of a mandrel. In such embodiments, the structure can be supported through engagement of one or both end tubes into a tailstock that is coupled to a support member of a coating device. illustrates one form of a method using the multiple stent structure described in with a modified version of the spray-coating device of . In some embodiments, end tube can be inserted into a circular opening of a tail stock (see ). The tail stock can be cylindrical and between 0.25 inches and 1.0 inch, preferably 0.5 inches in diameter. In addition, the tail stock can be metal, polymer or any combination thereof. The opening can function to secure the end tube when support member is rotating during a spray-coating process. Tail stock can thereafter be mounted onto the support member . Alternatively, tail stock can be mounted on support member , and end tube can thereafter be inserted into the tail stock . In some embodiments, end tube can be press-fitted directly onto support member . After positioning, multiple stent structure can then be coated by composition from nozzle (see ). In some applications, the stent movement and rotating device can move the multiple stent structure in a linear direction (arrow in ) to achieve uniform coating. In some applications, support member can rotate multiple stent structure (arrow ) to achieve a partial or uniform coating. In some applications, a combination of linear and rotational movements can be used to coat multiple stent structure . Other spray-coating techniques known by those skilled in the art can also be used.
After the spray-coating process (or optional drying process), end tube may be detached from the stent structure by mechanically breaking, chemically severing, a combination of mechanical/chemical processing, or laser cutting the at least one gate at the multiple stent structure or at some portion, or junction, along the at least one gate . Preferably, detachment is made adjacent to or at the surface of the stent with no portions or minimal portions of the gate left behind. In some embodiments, detachment can be accomplished by holding multiple stent structure and rotating the tube (or vice-versa) with sufficient torque. Additional polishing or touch up techniques at those break points can be implemented to remove any remaining portions of the gate or any roughness caused by the breaking of the at least one gate . For example, for polymer stent bodies or scaffolds (such as poly(L-lactide), the break points may be contacted briefly with solvent to smooth out the break points. Examples of solvents which can be used include, but are not limited to, chloroform, acetone, methyl ethyl ketone, or tetrahydrofuran. This smoothing technique is most beneficial if the gate is made from a polymer (e.g., bioabsorbable or biostable polymer disclosed below). Alternatively, a solvent for the polymer can be used to remove or etch away gate . The solvent, however, should not adversely affect the coating, the integrity of the multiple stent structure or any therapeutic agent contained on or within multiple stent structure .
Advantageously, the multiple stent structures of the present invention eliminate coating defects caused by contact points during coating and allow coating more than one stent body between loading and unloading steps in a coating operation. The structure can be supported by a mandrel by engaging tubes at the ends, and and tubes connecting adjacent stent bodies, e.g., , without any contact with stent bodies. The tubes are severable from the stent bodies and are not part of the stent final product to be implanted into a patient.
Also, in some embodiments, the multiple stent structures eliminate the need for a stent holding device, such as a mandrel, in the spray-coating process. That is, end tubes or tabs provide support to the stent when mounted on a spray-coating device, eliminating the need for support that would otherwise be provided by the mandrel. In this manner, coating defects caused by contact between stent bodies of the structure and the mandrel are thereby substantially or completely eliminated.
The multiple stent structures can be made of a metallic material or an alloy such as, but not limited to, stainless steel (316L or 300), “MP35N,” “MP2ON,” ELASTINITE (Nitinol), Egiloy, tantalum, tantalum alloy, cobalt-chromium alloy, nickel-titanium alloy, platinum, iridium, platinum-iridium alloy, gold, magnesium, or combinations thereof “MP35N” and “MP2ON” 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. “MP2ON” consists of 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum.
The multiple stent structures may also be made from and/or coated with a biostable polymer or a bioerodable, biodegradable, bioresorbable polymer or any combination thereof. Bioerodable, biodegradable or bioresorbable are intended to be used interchangeably unless otherwise indicated. Also, the stent inner diameter (“ID”) can range anywhere between two mm to four mm for coronary stents and five mm to twenty mm for peripheral stents. In some embodiments, a polymeric stent can include other materials, such as layers or deposits of metallic material which can be bioerodable.
Representative examples of polymers which may comprise a polymeric stent and/or a coating thereon are, but are not limited to, fluorinated polymers or copolymers such as poly(vinylidene fluoride), poly(vinylidene fluoride-co-hexafluoro propene), poly(tetrafluoroethylene), and expanded poly(tetrafluoroethylene); poly(sulfone); poly(N-vinyl pyrrolidone); poly(aminocarbonates); poly(iminocarbonates); poly(anhydride-co-imides), poly(hydroxyvalerate); poly(L-lactic acid); poly(L-lactide); poly(caprolactones); poly(L-lactide-co-glycolide); poly(L-lactide-co-glycolide); poly(hydroxybutyrates); poly(hydroxybutyrate-co-valerate); poly(dioxanones); poly(orthoesters); poly(anhydrides); poly(glycolic acid); poly(glycolide); poly(D,L-lactic acid); poly(D,L-lactide); poly(glycolic acid-co-trimethylene carbonate); poly(phosphoesters); poly(phosphoester urethane); poly(trimethylene carbonate); poly(iminocarbonate); poly(ethylene); and any derivatives, analogs, homologues, congeners, salts, copolymers and combinations thereof.
In some embodiments, the polymers include, but are not limited to, poly(propylene) co-poly(ether-esters) such as, for example, poly(dioxanone) and poly(ethylene oxide)/poly(lactic acid); poly(anhydrides), poly(alkylene oxalates); poly(phosphazenes); poly(urethanes); silicones; poly(esters); poly(olefins); copolymers of poly(isobutylene); copolymers of ethylene-alphaolefin; vinyl halide polymers and copolymers such as poly(vinyl chloride); poly(vinyl ethers) such as, for example, poly(vinyl methyl ether); poly(vinylidene halides) such as, for example, poly(vinylidene chloride); poly(acrylonitrile); poly(vinyl ketones); poly(vinyl aromatics) such as poly(styrene); poly(vinyl esters) such as poly(vinyl acetate); copolymers of vinyl monomers and olefins such as poly(ethylene-co-vinyl alcohol) (EVAL); copolymers of acrylonitrile-styrene, ABS resins, and copolymers of ethylene-vinyl acetate; and any derivatives, analogs, homologues, congeners, salts, copolymers and combinations thereof.
In some embodiments, the materials can also include, but are not limited to, poly(amides) such as Nylon 66 and poly(caprolactam); alkyd resins; poly(carbonates); poly(oxymethylenes); poly(imides); poly(ester amides); poly(ethers) including poly(alkylene glycols) such as, for example, poly(ethylene glycol) and poly(propylene glycol); epoxy resins; polyurethanes; rayon; rayon-triacetate; biomolecules such as, for example, fibrin, fibrinogen, starch, poly(amino acids); peptides, proteins, gelatin, chondroitin sulfate, dermatan sulfate (a copolymer of D-glucuronic acid or L-iduronic acid and N-acetyl-D-galactosamine), collagen, hyaluronic acid, and glycosaminoglycans; other polysaccharides such as, for example, poly(N-acetylglucosamine), chitin, chitosan, cellulose, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, cellophane, cellulose nitrate, cellulose propionate, cellulose ethers, and carboxymethylcellulose; and any derivatives, analogs, homologues, congeners, salts, copolymers and combinations thereof.
In some embodiments, the polymer can be a poly(ester amide), a poly(lactide) or a poly(lactide-co-glycolide) copolymer; and any derivatives, analogs, homologues, congeners, salts, copolymers and combinations thereof.
In some embodiments, the biodegradable polymers can include, but are not limited to, polymers having repeating units such as, for example, an α-hydroxycarboxylic acid, a cyclic diester of an α-hydroxycarboxylic acid, a dioxanone, a lactone, a cyclic carbonate, a cyclic oxalate, an epoxide, a glycol, an anhydride, a lactic acid, a glycolic acid, a lactide, a glycolide, an ethylene oxide, an ethylene glycol, and any derivatives, analogs, homologues, congeners, salts, copolymers and combinations thereof.
In some embodiments, the biodegradable polymers include, but are not limited to, polyesters, poly(ester amides); poly(hydroxyalkanoates) (PHA), amino acids; PEG and/or alcohol groups; polycaprolactones, poly(D-lactide), poly(L-lactide), poly(D,L-lactide), poly(mesolactide), poly(L-lactide-co-meso-lactide), poly(D-lactide-co-meso-lactide), poly(D,L-lactide-comeso-lactide), poly(D,L-lactide-co-PEG) block copolymers, poly(D,L-lactide-co-trimethylene carbonate), polyglycolides, poly(lactide-co-glycolide), polydioxanones, polyorthoesters, polyanhydrides, poly(glycolic acid-co-trimethylene carbonate), polyphosphoesters, polyphosphoester urethanes, poly(amino acids), polycyanoacrylates, poly(trimethylene carbonate), poly(imino carbonate), polycarbonates, polyurethanes, copoly(ether-esters) (e.g. PEO/PLA), polyalkylene oxalates, polyphosphazenes, PHA-PEG, and any derivatives, analogs, homologues, salts, copolymers and combinations thereof.
In other embodiments, the polymers can be poly(glycerol sebacate); tyrosine-derived polycarbonates containing desaminotyrosyl-tyrosine alkyl esters such as, for example, desamino-tyrosyl-tyrosine ethyl ester (poly(DTE carbonate)); and any derivatives, analogs, homologues, salts, copolymers and combinations thereof.
In some embodiments, the polymers are selected such that they specifically exclude any one or any combination of any of the polymers taught herein.
The multiple stent structure described herein may be coated with one or more therapeutic agents, including an anti-proliferative, anti-inflammatory or immune modulating, anti-migratory, anti-thrombotic or other pro-healing agent or a combination thereof. The anti-proliferative agent can be a natural proteineous agent such as a cytotoxin or a synthetic molecule or other substances such as actinomycin D, or derivatives and analogs thereof (manufactured by Sigma-Aldrich 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233; or COSMEGEN available from Merck) (synonyms of actinomycin D include dactinomycin, actinomycin IV, actinomycin I1, actinomycin X1,and actinomycin C1), all taxoids such as taxols, docetaxel, and paclitaxel, paclitaxel derivatives, all olimus drugs such as macrolide antibiotics, rapamycin, everolimus, structural derivatives and functional analogues of rapamycin, structural derivatives and functional analogues of everolimus, FKBP-12 mediated mTOR inhibitors, biolimus, perfenidone, prodrugs thereof, co-drugs thereof, and combinations thereof. Representative rapamycin derivatives include 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, or 40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin (ABT-578 manufactured by Abbott Laboratories, Abbott Park, Ill.), prodrugs thereof, co-drugs thereof, and combinations thereof.
The anti-inflammatory agent can be a steroidal anti-inflammatory agent, a nonsteroidal anti-inflammatory agent, or a combination thereof. In some embodiments, anti-inflammatory drugs include, but are not limited to, alclofenac, alclometasone dipropionate, algestone acetonide, alpha amylase, amcinafal, amcinafide, amfenac sodium, amiprilose hydrochloride, anakinra, anirolac, anitrazafen, apazone, balsalazide disodium, bendazac, benoxaprofen, benzydamine hydrochloride, bromelains, broperamole, budesonide, carprofen, cicloprofen, cintazone, cliprofen, clobetasol propionate, clobetasone butyrate, clopirac, cloticasone propionate, cormethasone acetate, cortodoxone, deflazacort, desonide, desoximetasone, dexamethasone dipropionate, diclofenac potassium, diclofenac sodium, diflorasone diacetate, diflumidone sodium, diflunisal, difluprednate, diftalone, dimethyl sulfoxide, drocinonide, endrysone, enlimomab, enolicam sodium, epirizole, etodolac, etofenamate, felbinac, fenamole, fenbufen, fenclofenac, fenclorac, fendosal, fenpipalone, fentiazac, flazalone, fluazacort, flufenamic acid, flumizole, flunisolide acetate, flunixin, flunixin meglumine, fluocortin butyl, fluorometholone acetate, fluquazone, flurbiprofen, fluretofen, fluticasone propionate, furaprofen, furobufen, halcinonide, halobetasol propionate, halopredone acetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol, ilonidap, indomethacin, indomethacin sodium, indoprofen, indoxole, intrazole, isoflupredone acetate, isoxepac, isoxicam, ketoprofen, lofemizole hydrochloride, lomoxicam, loteprednol etabonate, meclofenamate sodium, meclofenamic acid, meclorisone dibutyrate, mefenamic acid, mesalamine, meseclazone, methylprednisolone suleptanate, momiflumate, nabumetone, naproxen, naproxen sodium, naproxol, nimazone, olsalazine sodium, orgotein, orpanoxin, oxaprozin, oxyphenbutazone, paranyline hydrochloride, pentosan polysulfate sodium, phenbutazone sodium glycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicam olamine, pirprofen, prednazate, prifelone, prodolic acid, proquazone, proxazole, proxazole citrate, rimexolone, romazarit, salcolex, salnacedin, salsalate, sanguinarium chloride, seclazone, sermetacin, sudoxicam, sulindac, suprofen, talmetacin, talniflumate, talosalate, tebufelone, tenidap, tenidap sodium, tenoxicam, tesicam, tesimide, tetrydamine, tiopinac, tixocortol pivalate, tolmetin, tolmetin sodium, triclonide, triflumidate, zidometacin, zomepirac sodium, aspirin (acetylsalicylic acid), salicylic acid, corticosteroids, glucocorticoids, tacrolimus, pimecorlimus, prodrugs thereof, co-drugs thereof, and combinations thereof.
These agents can also have anti-proliferative and/or anti-inflammatory properties or can have other properties such as antineoplastic, antiplatelet, anti-coagulant, anti-fibrin, antithrombonic, antimitotic, antibiotic, antiallergic, antioxidant as well as cystostatic agents. Examples of suitable therapeutic and prophylactic agents include synthetic inorganic and organic compounds, proteins and peptides, polysaccharides and other sugars, lipids, and DNA and RNA nucleic acid sequences having therapeutic, prophylactic or diagnostic activities. Nucleic acid sequences include genes, antisense molecules which bind to complementary DNA to inhibit transcription, and ribozymes. Some other examples of other bioactive agents include antibodies, receptor ligands, enzymes, adhesion peptides, blood clotting factors, inhibitors or clot dissolving agents such as streptokinase and tissue plasminogen activator, antigens for immunization, hormones and growth factors, oligonucleotides such as antisense oligonucleotides and ribozymes and retroviral vectors for use in gene therapy. Examples of antineoplastics and/or antimitotics include methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g. Adriamycin® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g. Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). 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, thrombin inhibitors such as Angiomax ä (Biogen, Inc., Cambridge, Mass.), 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 Mevacor® from Merck & Co., Inc., Whitehouse Station, N.J.), 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), nitric oxide or nitric oxide donors, super oxide dismutases, super oxide dismutase mimetic, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), estradiol, anticancer agents, dietary supplements such as various vitamins, and a combination thereof. Examples of such cytostatic substance include angiopeptin, angiotensin converting enzyme inhibitors such as captopril (e.g. Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril (e.g. Prinivil® and Prinzide® from Merck & Co., Inc., Whitehouse Station, N.J.). An example of an antiallergic agent is permirolast potassium. Other therapeutic substances or agents which may be appropriate include alpha-interferon, and genetically engineered epithelial cells. The foregoing substances are listed by way of example and are not meant to be limiting. Other active agents which are currently available or that may be developed in the future are equally applicable. In some embodiments, any one of the stent bodies (e.g., , in ), gates (e.g., , in ), connecting tubes (e.g., in ), end tubes (e.g., , in ) or a tab (e.g., in ) can be made of the same material or different materials, such as any of the above-described materials.
From the foregoing detailed description, it will be evident that there are a number of changes, adaptations and modifications of the present invention which come within the province of those skilled in the art. The scope of the invention includes any combination of the elements from the different species or embodiments disclosed herein, as well as subassemblies, assemblies, and methods thereof. However, it is intended that all such variations not departing from the spirit of the invention be considered as within the scope thereof.