text:
|Publication number
|Publication type
|Application number
|Publication date
|Dec 15, 2009
|Filing date
|Dec 16, 2004
|Priority date
|Dec 16, 2004
|Fee status
|Also published as
|Publication number
|Stephen Dirk Pacetti, Jessica DesNoyer, Yung-Ming Chen, Lothar Kleiner, Syed F. A. Hossainy
|Original Assignee
|Advanced Cardiovascular Systems, Inc.
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (115), Non-Patent Citations (99), Referenced by (28), Classifications (8), Legal Events (4)
|External Links: USPTO, USPTO Assignment, Espacenet
1. Field of the Invention
The invention relates to drug delivery implantable medical devices, one example of which is a stent. More particularly, the invention relates to abluminal, multilayer coating constructs for drug-delivery stents.
2. Description of the Background
This invention relates to radially expandable endoprostheses, which are adapted to be implanted in a bodily lumen. An "endoprosthesis" corresponds to an artificial implantable medical device that is placed inside the body. A "lumen" refers to a cavity of a tubular organ such as a blood vessel. A stent is an example of these endoprostheses. Stents are generally cylindrically shaped devices, which function to hold open and sometimes expand a segment of a blood vessel or other anatomical lumen such as urinary tracts and bile ducts. Stents are often used in the treatment of atherosclerotic stenosis in blood vessels. "Stenosis" refers to a narrowing or constriction of the diameter of a bodily passage or orifice. In such treatments, stents reinforce body vessels and prevent restenosis following angioplasty in the vascular system. "Restenosis" refers to the reoccurrence of stenosis in a blood vessel or heart valve after it has been treated (as by balloon angioplasty, stenting, or valvuloplasty) with apparent success.
The treatment of a diseased site or lesion with a stent involves both delivery and deployment of the stent. "Delivery" refers to introducing and transporting the stent through a bodily lumen to a region, such as a lesion, in a vessel that requires treatment. "Deployment" corresponds to the expansion of the stent within the lumen at the treatment region. Delivery and deployment of a stent are accomplished by positioning the stent about one end of a catheter, inserting the end of the catheter through the skin into a bodily lumen, advancing the catheter in the bodily lumen to a desired treatment location, expanding the stent at the treatment location, and removing the catheter from the lumen. In the case of a balloon expandable stent, the stent is mounted about a balloon disposed on the catheter. Mounting the stent typically involves compressing or crimping the stent onto the balloon. The stent is then expanded by inflating the balloon. The balloon may then be deflated and the catheter withdrawn. In the case of a self-expanding stent, the stent may be secured to the catheter via a retractable sheath or a sock. When the stent is in a desired bodily location, the sheath may be withdrawn which allows the stent to self-expand.
Stents have been made of many materials including metals and polymers. Polymeric materials include both nonbioerodable and bioerodable plastic materials. The cylindrical structure of stents is typically composed of a scaffolding that includes a pattern or network of interconnecting structural elements or struts. The scaffolding can be formed from wires, bars, tubes, or planar films of material rolled into a cylindrical shape. Furthermore, the pattern that makes up the stent allows the stent to be radially expandable and longitudinally flexible. Longitudinal flexibility facilitates delivery of the stent, and rigidity is needed to hold open a body lumen. The pattern should be designed to maintain the longitudinal flexibility and rigidity required of the stent.
Stents are used not only for mechanical intervention but also as vehicles for providing biological therapy. Biological therapy can be achieved by medicating the stents. Medicated stents provide for the local administration of a therapeutic substance at the diseased site. In order to provide an efficacious concentration to the treated site, systemic administration of such medication often produces adverse or even toxic side effects for the patient. 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 thus produces fewer side effects and achieves more favorable results.
A medicated stent may be fabricated by coating the surface of either a metallic or polymeric scaffolding to produce a drug reservoir layer on the surface. The drug reservoir layer typically includes a polymeric carrier that includes an active agent or drug. To fabricate a coating, a polymer, or a blend of polymers, can be applied on the stent using commonly used techniques known to those having ordinary skill in the art. A composition for application to a stent may include a solvent, a polymer dissolved in the solvent, and an active agent dispersed in the blend. The composition may be applied to the stent by immersing the stent in the composition, by direct application, by roll coating, or by spraying the composition onto the stent. The solvent is allowed to evaporate, leaving on the stent strut surfaces a coating of the polymer and the active agent impregnated in the polymer.
A drug delivery stent coating should meet several well-known criteria including mechanical integrity, controlled release of the drug, and biocompatibility. Active agents within polymer-based coating layers can interfere with the mechanical integrity of a coating since active agents negatively impact the coating mechanical properties, and the ability of a polymer matrix to adhere effectively to the surface of the stent. Increasing the quantity of the active agent reduces the effectiveness of the adhesion. A primer layer can serve as a functionally useful intermediary layer between the surface of the device and an active agent-containing or reservoir coating, or between multiple layers of reservoir coatings. The primer layer provides an adhesive tie between the reservoir coating and the device. In addition, successful treatment of a diseased site with a medicated stent often requires that the rate of release of the active agent or drug be within a prescribed range. A barrier or polymeric topcoat layer above a reservoir layer serves the purpose of controlling the rate of release of an active agent or drug.
Furthermore, since the presence of foreign polymers can adversely affect the body, it is generally desirable to limit exposure of the polymer on a coating to the body. Therefore, a stent may also include a biobeneficial coating over a reservoir layer and/or topcoat layer to improve the biocompatibility of the coating. However, in general, it is appropriate to use no more polymer than is necessary to hold the drug on the stent and to control its release. This is particularly the case for coatings that include bioabsorbable polymers since the polymer is absorbed in vivo. Therefore, it would be advantageous to reduce the amount of coating material on a stent without adversely impacting the stent's treatment capabilities.
Additionally, the presence of a topcoat layer, such as a poly(ester amide) (PEA) layer, on a luminal stent surface can have a detrimental impact on a stent's deliverability and coating mechanical integrity. The PEA coatings change the coefficient of friction between the stent and the delivery balloon. In addition, some PEA polymers have structures that cause them to be sticky or tacky. If the PEA either increases the coefficient of friction or adheres to the catheter balloon, the smooth release of the stent from the balloon after deflation is compromised. PEA stent coatings often exhibit extensive balloon shear damage post-deployment as well, which could result in a thrombogenic luminal stent surface. Therefore, it would be desirable to limit exposure of the balloon to the PEA topcoat layer.
Embodiments of the present invention are directed to coatings for implantable medical devices, such as stents. The devices may include a structural element having a surface with an abluminal side, a luminal side, and two sidewalls extending between the abluminal side and the luminal side. The coating may include a continuous first layer disposed above all or a majority of the abluminal side and optionally above a portion of at least one of the side-walls extending from the abluminal side. The luminal side and portions of the sidewalls are free from the first layer. The coating may further include a continuous second layer covering the first layer such that no portion of the first layer is not covered by the second layer. The luminal side of the structural element is free from the second layer.
A further embodiment of the invention may a include a coating for the structural element including a continuous first layer disposed above all or a majority of the abluminal side and optionally above a portion of at least one of the side-walls extending from the abluminal side. The luminal side and portions of the sidewalls are free from the first layer. The coating may further include a continuous second layer covering a portion of the first layer such that at least a portion of the first layer is not covered by the second layer.
Embodiments of the invention described herein relate to drug delivery implantable medical devices. In particular, various embodiments of devices with abluminal, multilayer coating constructs for drug-delivery are described. The embodiments of devices described herein relate to implantable medical devices that include an underlying scaffolding or substrate with a coating such as a polymer-based coating. The polymer-based coating may contain, for example, an active agent or drug for local administration at a diseased site. The active agent can be any substance capable of exerting a therapeutic or prophylactic effect. The underlying substrate that is coated can be polymeric, metallic, ceramic, or made from any suitable material. "Implantable medical device" is intended to include self-expandable stents, balloon-expandable stents, stent-grafts, grafts (e.g., aortic grafts), artificial heart valves, cerebrospinal fluid shunts, pacemaker electrodes, and endocardial leads (e.g., FINELINE and ENDOTAK, available from Guidant Corporation, Santa Clara, Calif.). The underlying structure or substrate of the device can be of virtually any design.
The underlying structure or substrate of an implantable medical device, such as a stent can be completely or at least in part be made from a biodegradable polymer or combination of biodegradable polymers, a biostable polymer or combination of biostable polymers, or a combination of biodegradable and biostable polymers. Additionally, a polymer-based coating for a surface of a device can be a biodegradable polymer or combination of biodegradable polymers, a biostable polymer or combination of biostable polymers, or a combination of biodegradable and biostable polymers.
To fabricate the coating, the polymer, or a blend of polymers, can be applied on the stent using commonly used techniques known to those having ordinary skill in the art. For example, the polymer can be applied to the stent by dissolving the polymer in a coating solvent, or a mixture of solvents, and applying the resulting solution on the stent by spraying, "ink-jet-type" deposition methods, brushing, roll coating, plasma deposition, and the like. "Solvent" is defined as a substance capable of dissolving or dispersing one or more other substances or capable of at least partially dissolving or dispersing the substance(s) to form a uniformly dispersed mixture at the molecular- or ionic-size level. The solvent should be capable of dissolving at least 0.1 mg of the polymer in 1 ml of the solvent, and more narrowly 0.5 mg in 1 ml at ambient temperature and ambient pressure.
Polymers can be biostable, bioabsorbable, biodegradable, or bioerodable. Biostable refers to polymers that are not biodegradable. The terms biodegradable, bioabsorbable, and bioerodable are used interchangeably and refer to polymers that are capable of being completely degraded and/or eroded 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 eventual absorption and elimination of the polymer can be caused by, for example, hydrolysis, metabolic processes, bulk or surface erosion, and the like. For coating applications, it is understood that after the process of degradation, erosion, absorption, and/or resorption has been completed, no polymer will remain on the device. In some embodiments, very negligible traces or residue may be left behind. For stents made from a biodegradable polymer, the stent 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.
Representative examples of polymers that may be used in the embodiments of the substrate of implantable medical devices or coatings for implantable medical devices disclosed herein include, but are not limited to, poly(N-acetylglucosamine) (Chitin), Chitosan, poly(hydroxyvalerate), poly(lactide-co-glycolide), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polyorthoester, polyanhydride, poly(glycolic acid), poly(glycolide), poly(L-lactic acid), poly(L-lactide), poly(D,L-lactic acid), poly(D,L-lactide), poly(D-lactic acid), poly(D-lactide), poly(D,L-lactide-co-L-lactide), poly(caprolactone), poly(trimethylene carbonate), polyester amide, poly(glycolic acid-co-trimethylene carbonate), co-poly(ether-esters) (e.g. PEO/PLA), 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 other than polyacrylates, 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), poly(methacrylates), poly(acrylates), acrylonitrile-styrene copolymers, ABS resins, polyamides (such as Nylon 66 and polycaprolactam), polycarbonates, polyoxymethylenes, polyimides, polyethers, polyurethanes, rayon, rayon-triacetate, cellulose, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, cellophane, cellulose nitrate, cellulose propionate, cellulose ethers, and carboxymethyl cellulose. Additional representative examples of polymers that may be especially well suited for use in embodiments of the substrate of implantable medical devices or coatings for implantable medical devices disclosed herein include ethylene vinyl alcohol copolymer (commonly known by the generic name EVOH or by the trade name EVAL), poly(butyl methacrylate), poly(vinylidene fluoride-co-hexafluoropropene) (e.g., SOLEF 21508, available from Solvay Solexis PVDF, Thorofare, N.J.), polyvinylidene fluoride (otherwise known as KYNAR, available from ATOFINA Chemicals, Philadelphia, Pa.), ethylene-vinyl acetate copolymers, and polyethylene glycol.
In addition, polymers containing moieties derived from poly(lactic acid) can be also used in addition to or instead of, poly(lactic acid), for fabricating and coating devices. Polymers based on poly(lactic acid) include derivatives of poly(lactic acid), for example, hydrolyzed or carboxylated poly(lactic acid), or a blend thereof. Using hydrolyzed or carboxylated poly(lactic acid) is expected to result in an increased rate of degradation of the coating. Another type of polymer based on poly(lactic acid) that can be used for fabricating and coating implantable medical devices includes graft copolymers, and block copolymers, such as AB block-copolymers ("diblock-copolymers") or ABA block-copolymers ("triblock-copolymers"), or mixtures thereof.
Examples of active agents include antiproliferative 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. The bioactive 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., TAXOL� by Bristol-Myers Squibb Co., Stamford, Conn.), docetaxel (e.g., Taxotere�, from Aventis S.A., Frankfurt, Germany), 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 aspirin, 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 � (Biogen, Inc., Cambridge, Mass.). Examples of such cytostatic or antiproliferative agents 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.), calcium channel blockers (such as nifedipine), coichicine, proteins, peptides, 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), and nitric oxide. An example of an antiallergic agent is permirolast potassium. Other therapeutic substances or agents which may be appropriate agents include cisplatin, insulin sensitizers, receptor tyrosine kinase inhibitors, carboplatin, alpha-interferon, genetically engineered epithelial cells, steroidal anti-inflammatory agents, non-steroidal anti-inflammatory agents, antivirals, anticancer drugs, anticoagulant agents, free radical scavengers, estradiol, antibiotics, nitric oxide donors, super oxide dismutases, super oxide dismutases mimics, 4-amino-2,2′,6,6′-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), tacrolimus, dexamethasone, ABT-578, clobetasol, cytostatic agents, prodrugs thereof, co-drugs thereof, and a combination thereof. Other therapeutic substances or agents may include rapamycin and structural derivatives or functional analogs thereof, such as 40-O-(2-hydroxy)ethyl-rapamycin (known by the trade name of EVEROLIMUS), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.
A non-polymer substrate of the device may be made of a metallic material or an alloy such as, but not limited to, cobalt chromium alloy (ELGILOY), stainless steel (316L), high nitrogen stainless steel, e.g., BIODUR 108, cobalt chrome alloy L-605, "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.
Embodiments of the devices described herein may be illustrated by a stent.
Additionally, a surface of an implantable medical device may also be characterized by the relative location of the surface with respect to a bodily lumen. The device may include luminal surfaces or inner portions, abluminal surfaces or outer portions, and surfaces between the luminal and abluminal surfaces or side-wall surfaces. For example, struts 15 of stent 10 include luminal surfaces 35, abluminal surfaces 40, and side-wall surfaces 45. A strut may also be described by axes, a longitudinal axis and a latitudinal axis.
As indicated above, a drug delivery coating for a stent with a structural element like that depicted in
(a) a primer layer, which may improve adhesion of subsequent layers on the implantable substrate or on a previously formed layer;
(b) a reservoir or agent layer, which may include a polymer and an agent or, alternatively, a polymer free agent;
(c) a topcoat layer, which may serve as a way of controlling the rate of release of an agent from a reservoir layer; and
(d) a biobeneficial or biocompatible finishing layer containing a biobeneficial agent, which may improve the biocompatibility of the coating.
The reservoir layer can be applied directly to at least a part of a surface of an implantable medical device as a pure agent to serve as a reservoir for at least one active agent. The agent can be combined with a biodegradable polymer as a matrix, wherein the agent may or may not be bonded to the polymer. The primer layer can be applied between the surface of the device and the agent layer to improve adhesion of the agent layer to the surface or between layers and can optionally include an agent. A layer of pure or substantially pure active agent can be sandwiched between layers including biodegradable polymer. For example, it has been observed that a reservoir layer containing principally EVEROLIMUS has very poor adhesion to metallic struts. A primer layer, including, for example, poly(butyl methacrylate) (PBMA) enables an EVEROLIMUS reservoir layer to remain on the stent. The topcoat layer can be applied over at least a portion of the reservoir layer to serve as a membrane to control the rate of release of the active agent and can optionally comprise an agent.
The biobeneficial finishing layer can also be applied to increase the biocompatibility of the coating by, for example, increasing acute hemocompatibility and can also include an active agent. A "biobeneficial agent" is an agent linked to a polymer that provides a biological benefit within a mammal without necessarily being released from the polymer. A biological benefit may be that the polymer or coating is modified with the biobeneficial agent to be non-thrombogenic, such that protein absorption is inhibited or prevented to avoid formation of a thromboembolism; to promote healing, such that endothelialization of the luminal stent surfaces is rapid and forms a healthy and functional endothelial layer; or to be non-inflammatory, such that the biobeneficial agent acts as a biomimic to passively avoid attracting monocytes and neutrophils, which leads to the cascade of events creating inflammation. The biobeneficial agent can also be combined, mixed or blended with a polymer. Representative examples of biobeneficial agents include, but are not limited to, poly(alkylene glycols), poly(N-vinyl pyrrolidone), poly(acrylamide methyl propane sulfonic acid), poly(styrene sulfonate), sulfonated dextran, polyphosphazenes, poly(orthoesters), poly(tyrosine carbonate), hyaluronic acid, heparin and any derivatives, hirudin, analogs, homologues, congeners, salts, copolymers and combinations thereof.
Coating configurations on stents with one or more of the above types of layers are typically conformal, which is a coating that covers all or most of the surfaces of the struts, including the abluminal surface, luminal surface, and side-wall surfaces.
It would be desirable to have a drug delivery coating restricted completely or substantially to an abluminal surface of a stent that also addresses one or more of the criteria discussed above including mechanical integrity, controlled release, and biocompatibility. There are several advantages of having a drug delivery coating restricted completely to an abluminal surface region of a strut. From a therapeutic standpoint, an abluminal coating can be as efficacious as a conformal coating. Furthermore, an abluminal coating allows a reduction in the total polymer load on a stent, which may improve the biocompatibility of the stent. A lower polymer loading reduces the form factor of the stent which reduces the disturbance of the local blood flow, and hence, the thrombogenecity of the stent. Additionally, a decreased polymer load for biodegradable coatings reduces the likelihood of embolization due to particles of degrading polymer in the blood stream.
Another advantage of a coating restricted completely or substantially to the abluminal surface is that interactions between a topcoat layer and the catheter balloon are reduced or eliminated. It has been observed that use of an outermost topcoat layer, in particular poly(ester amide), on a luminal stent surface can have a detrimental impact on a stent's deliverability and coating mechanical integrity. The PEA coating changes the coefficient of friction between the stent and the delivery balloon. Additionally, some PEA polymers have structures that cause them to be sticky or tacky. If the PEA either increases the coefficient of friction or adheres to the catheter balloon, the smooth release of the stent from the balloon after deflation is compromised. PEA stent coatings have been observed to exhibit extensive balloon shear damage post-deployment as well, which could increase the thrombogenicity of the luminal stent surface.
The abluminal, multilayer coating configurations described herein possess the advantages discussed above and meet one or more of the criteria of mechanical integrity, controlled release, and biocompatibility. Additionally, the coatings allow controlled release from an abluminal reservoir layer without the use of reservoirs embedded in cavities or indentations in the abluminal surface. The surfaces of the structural members of the implantable medical devices used for conformal coatings are identical to those used in the presently described abluminal coating embodiments.
Embodiments of polymer coatings are illustrated by FIGS. 5-15A-B. The figures have not been drawn to scale, and the thickness of the various layers have been over or under emphasized for illustrative purposes. The polymers used for the primer material should have a high capacity of adherence to the surface of an implantable device, such as a metallic surface of a stent, or a high capacity of adherence to a polymeric surface such as the surface of a stent made of polymer, or a previously applied layer of polymeric material. The polymer in primer layers may be a homopolymer, copolymer, terpolymer, etc. The polymer may also include random, alternating, block, cross-linked, blends, and graft variations thereof. For instance, a primer layer may include PEA, poly(butyl methacrylate), or a poly(lactic acid). The active agent may be, for example, 40-O-(2-hydroxy)ethyl-rapamycin, known by the trade name of EVEROLIMUS, available from Novartis as Certican™. The active agent may be dispersed in a polymer such as poly(vinylidene fluoride-co-hexafluoropropene) (Solef). A topcoat or barrier layer may be any polymer that controls the migration of active agent. For example, the topcoat layer may include PEA.
By way of example, and not limitation, a primer layer can have any suitable thickness, examples of which can be in the range of about 0.1 to about 10 microns, or more narrowly about 0.1 to about 2 microns. A reservoir layer can have a thickness of about 0.1 microns to about 20 microns, or more narrowly about 0.5 microns to 15 microns. The amount of the active agent to be included on an implantable medical device can be further increased by applying a plurality of reservoir layers on top of one another. A topcoat layer can have any suitable thickness, examples of which can be in the range of about 0.1 to about 20 microns, or more narrowly about 0.1 to about 10 microns.
"Above" a surface or layer is defined as higher than or over a surface or layer measured along an axis normal to a surface, but not necessarily in contact with the surface or layer. "Below" is defined as the opposite of "above." "Cover" is defined as above and in contact with. "Continuous" is defined as marked by uninterrupted extension in space. As used herein, an "edge" of a layer refers to a line or region on a surface delineating where the layer ends.
A structural element of an implantable medical device, such as a stent, suitable for coating embodiments disclosed herein may include a surface having an abluminal side, a luminal side, and two sidewalls extending between the abluminal side and the luminal side. Several embodiments include coating layers above the abluminal side, and optionally over a minor portion of one or both of the sidewalls adjacent to the abluminal side. Some of these abluminal or substantially abluminal coating embodiments include controlled release of active agents from a reservoir layer and/or improved adhesion due to primer layer(s). In the embodiments of the coatings described below, the surface of the structural element below the coating is cavity free.
One embodiment of a coating on a structural element of an implantable medical device may include a continuous first layer disposed above a majority of the abluminal side. The continuous first layer may optionally be above a portion of at least one of the side-walls extending from the abluminal side. The luminal side and portions of the sidewalls may be free from the first layer.
The coating may further include a continuous second layer covering the first layer such that no portion of the first layer is not covered by the second layer. The luminal side of the structural element may be free from the second layer. In some embodiments, the second layer may cover a portion of the structural element not covered by the first layer. In one embodiment of the coating, a majority of the sidewalls may be free from the first layer and the second layer.
It may be advantageous to have a third layer above the reservoir layer that may function as a topcoat layer, primer layer, and/or biobeneficial layer. A topcoat layer may control the release of active agent from the reservoir layer. Additionally, a third layer functioning as a primer layer may improve the adhesion between a second layer and another layer above the second layer. In some embodiments, a continuous third layer may cover the second layer such that no portion of the second layer is not covered by the third layer. Additionally, the third layer may cover a portion of the structural element not covered by the second layer.
In one embodiment, a majority of the sidewalls may be free from the third layer. Alternatively, the third layer may cover a portion of or all of the sidewalls.
In a further embodiment, the luminal side of the structural element may be free from the third layer. Alternatively, the third layer may cover a portion of or the entire luminal side.
In certain embodiments, at least one of the first or second layers may be a reservoir layer that includes a pure or substantially pure active agent. In one such embodiment, the first layer may be a reservoir layer. In this embodiment, the second layer may be a topcoat or barrier layer that functions to control the release of active agent from the reservoir layer. The second layer may additionally or alternatively function as a primer layer that improves adhesion between the reservoir layer and another layer above the second layer.
In certain embodiments, coating layers in an abluminal or substantially abluminal coating may be strip-shaped with at least one edge of a coating layer parallel to a longitudinal axis of the structural element. As an illustration,
In alternate embodiment, the second layer may be a reservoir layer. In this embodiment, the first layer may then be primer layer that improves adhesion between a reservoir layer and a surface or another layer.
As discussed above, it may be advantageous to have third layer above the reservoir layer that functions as a topcoat and/or biobeneficial layer.
Other embodiments of a coating on a structural element may include a continuous first layer disposed above a majority of the abluminal side of the structural element and optionally above a portion of at least one of the side-walls extending from the abluminal side. The luminal side and portions of the sidewalls may be free from the first layer. The coating may also include a continuous second layer covering a portion of the first layer such that at least a portion of the first layer is not covered by the second layer. A majority of the sidewalls may be free from the first layer and the second layer. In an embodiment, the second layer may be a reservoir layer and the first layer may be a primer layer that improves adhesion of the reservoir layer to the surface of the structural element.
Additionally, an embodiment exemplified in
The structural member may further include a fourth layer covering the third layer such that no portion of the third layer is not covered by the fourth layer. The fourth layer may be a biobeneficial coating layer that increases biocompatibility of the coating.
Furthermore, numerous variations of the coating embodiments described above are possible. Such variations may be configured to achieve release control of active agent from a reservoir layer, improve adhesion between layers, and/or improve biocompatibility of the coating. In certain embodiments, abluminal or substantially abluminal coating embodiments may have multiple primer and reservoir layers with the layers alternating between the two types of layers through the thickness of the coating. Such embodiments may be useful, for example, for a course of treatment that occurs in stages where each stage requires the use of a different type or types of active agents.
Moreover, multiple primer and reservoir embodiments may utilize the release control topcoat-reservoir embodiment exemplified in
One embodiment of a multiple primer and reservoir layer coating may include repeat units of the embodiment exemplified in
Another embodiment of a multiple primer and reservoir layer coating may include repeat units of the embodiment exemplified in
A further embodiment of a multiple primer and reservoir layer coating may include the embodiment exemplified in
Additionally, the embodiment exemplified in
In addition, a multiple primer and reservoir coating may include the coating shown in
Various methods may be used to form coatings as described herein including, but not limited to, ink-jet-type coating, electrostatic coating, roll coating, thermal deposition with masking, plasma polymerization with masking, direct application of polymer/solvent solution by micro-syringe, direct polymer melt application, and spray coating with photomasking. For example, a controlled deposition system ink-jet-type coating method can be used that applies various substances only to certain targeted portions of an implantable medical device. A representative example of such a system, and a method of using the same, is described in U.S. Pat. No. 6,395,326 to Castro et al. A controlled deposition system can be capable of depositing a substance on an implantable medical device having a complex geometry, and otherwise apply the substance so that coating is limited to particular portions of the device. The system can have a dispenser and a holder that supports the medical substrate. The dispenser and/or holder can be capable of moving in very small intervals, for example, less than about 0.001 inch. Furthermore, the dispenser and/or holder can be capable of moving in the x-, y-, or z-direction, and be capable of rotating about a single point.
The controlled deposition system can include a dispenser assembly. The dispenser assembly can be a simple device including a reservoir, which holds a composition prior to delivery, and a nozzle having an orifice through which the composition is delivered. One exemplary type of dispenser assembly can be an assembly that includes an ink-jet-type printhead. Another exemplary type of a dispenser assembly can be a microinjector capable of injecting small volumes ranging from about 2 to about 70 nL, such as NanoLiter 2000 available from World Precision Instruments or Pneumatic PicoPumps PV830 with Micropipette available from Cell Technology System. Such microinjection syringes may be employed in conjunction with a microscope of suitable design.
Furthermore, selective coating of an implantable medical device may be performed using photomasking techniques. Deposition and removal of a mask can be used to selectively coat surfaces of substrates. Masking deposition is known to one having ordinary skill in the art.
Additionally, the substances of the present invention can also be selectively deposited by an electrostatic deposition process. Such a process can produce an electrically charged or ionized coating substance. The electric charge causes the coating substance to be differentially attracted to the device, thereby resulting in higher transfer efficiency. The electrically charged coating substance can be deposited onto selected regions of the device by causing different regions of the device to have different electrical potentials.
An electrostatic coating method was used to coat the stent with a total solid of 328 μg using a 2% by weight solution of PEA-TEMPO in ethanol. PEA-TEMPO may be obtained from Guidant Corporation. The stent was translated and rotated under an electrospray nozzle. A different electrical potential on the luminal and abluminal surfaces was created by using a plastic sleeve over a spray mandrel. The plastic sleeve repelled the same charged droplets which prevented the droplets from depositing onto the luminal side of the stent. This resulted in a thinner coating layer on the luminal surface than the abluminal surface. A syringe pump was controlled at 1 cc/hr, and voltage was set at 5 kV. The coated stent was oven dried at 50� C. for 30 minutes.
Another of the same type of stent was coated using conventional spray coating to compare with the electrostatically coated stent. The stent was coated with 300 μg of 2% by weight solution of PEA-TEMPO in ethanol. The coated stent was oven dried at 50� C. for 30 minutes.
While particular embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that changes and modifications can be made without departing from this invention in its broader aspects. Therefore, the appended claims are to encompass within their scope all such changes and modifications as fall within the true spirit and scope of this invention.
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|U.S. Classification
|International Classification
|Cooperative Classification
|European Classification
|Apr 7, 2005
Owner name: ADVANCED CARDIOVASCULAR SYSTEMS, INC., CALIFORNIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:PACETTI, STEPHEN D.;DESNOYER, JESSICA;CHEN, YUNG-MING;AND OTHERS;REEL/FRAME:016448/0920;SIGNING DATES FROM 20041223 TO 20050105
|Dec 21, 2010
|Certificate of correction
|Mar 18, 2013
|Fee payment
Year of fee payment: 4
|May 25, 2017
|Fee payment
Year of fee payment: 8


text:
Separate names with a comma.
Discussion in 'Trials' started by Brewtus, Dec 12, 2010.
Only when it rains!
Reminds me of the Tuttle creek spillway after the summer of '93
This was after a 15 mile ride from the event.
I didn't take that pic.
Oh. My. Gawd. No.
It's extremely rare that we get enough rain in the San Ysidro slot canyon to flood that entire surface, but parts of it can get a good washing now and then. The summer monsoon can really pour down the deeper, narrower part of the canyon. It's exciting to see.
I had so many clothes on that I was burning up. My snow pants were falling down under my rain pants so I cold hardly move around on the bike. But the worst part is fogged up glasses and not being able to see half the time.
Hey Neil, how did you do? How did you like the new bike? Were the sections all in the same areas as the November event?
I thought about going down for the event but didn't want to drive that far after seeing the weather forecast. The pics of the bike make me glad I stayed home.
No, we were at a different area. 1st on Sat., 2nd on Sunday. Fortunatly when we got on 35 and headed south we had no problem getting home. There was a rollover in the north bound lane(can't remember if it was south or north of Ft Worth) and it was a parking lot.
Congrats! You must be pleased with the new bike with a 1st and a 2nd on its 1st outing.
Well, it's quite a bit different than the 270. If I learn how to ride it, its going to be awsome! The stearing lock is crazy sharp and easy to tuck if your not careful. It's easy to overshoot in 2nd gear and first seems too low at times. And now that I've ridden in the wet at Muenster the brakes don't work, but thats normal.
The Muenster mud will quickly ruin a set of brake pads.
as well as chain, wheel bearings, shock linkage and fork seals... that sand is MISERABLE and 3 times i been there, 3 times it rains like hell! lol
Well, at least it wasn't your fault, this time.
Oh, arent you funny! :huh hope next year it is dry...
should be a UTE cup year this year, for me. crossing my fingers.
I loaded mine onto my truck, so I can move up to Rio Rancho!!! NMTB Here I come!!!
Bring it Nigel!! Looking forward to your arrival! I may go practice this weekend in anticipation of your arrival!!
Another soon-to-be NMTA member?
Kinda wish I could get my job I have here, out there, lol Winter stinks sometimes... it was -8f tuesday am when I started the car to goto work I think the high for the day was 5f?

subset: commoncrawl


text:
This one's different: How about making a surfboard with a tail that flexes for better snap through turns? That's just what Rusty has developed with its new Flextail model.
The design premise isn't that new actually. "The whole idea started early during the shortboard revolution when Midget Farley developed a stringerless board," says Rusty Surfboards General Manager Peter Johnson. "It felt really alive, but didn't last very long. People have tried to get a different flex with epoxy boards, but those didn't catch on because they just didn't feel right. Now we've developed a board with a tapered stringer. It's got a different flex pattern and makes the board feel alive. This board really snaps through turns."
In the Flextail, Rusty worked with Clark Foam to develop the foam blank with the disappearing stringer. It actually starts as a standard double stringer at the nose and then tapers to an end at the fins of the board. With a unique look, there's actually no stringer — just foam — across the back of the board. However, strength was added by using a heavier S Cloth fiberglass. And to compensate for the added flex, the rocker is flatter.
To develop the board, Rusty has shaped more than 150 versions in the last year. Southern California local pros like Matt Coleman have been testing them extensively, and Rusty took the new design on its shop demo tour, which made 32 stops around the country this summer. Locals in each area tried the boards and gave tons of feedback.
Johnson says Clark Foam actually gave Rusty the structural characteristics of the boards so they could quantify what was going on with the designs. The company has been playing with the flexes of the boards for a while. In standard production models, it shifted to double stringers about eight years ago to make the boards stronger, but most pros felt this made the boards to stiff, so they still get mostly single stringer boards.
Rusty won't come out with production Flextail models until the spring of 2001, in regular thruster or C-5 versions, but the C-5 model is the preferred.
"We're always pushing the technical and innovative level of surfboards," says Johnson. From the board manufacturer that developed the C-5 and backed it up with two contests and tons of cash prizes, it's good to see the development continues. Johnson promises more is on the way from Rusty.


text:
Manny energizes LA with first homer
Ramirez goes 2-for-4; Blake also goes deep for new team
By Ken Gurnick / MLB.com
He homered. He hustled. He high-fived every teammate in sight while receiving a hero's welcome in the dugout and acknowledged another frenzied sellout crowd with a quick curtain-call wave. He had two hits, scored two runs and drove in two.
His dreadlocks were all over the Dodgers' 4-2 victory against Arizona, trimming the deficit back to two games, infusing the lineup with the threat of his lethal bat and the energy of his presence.
"I feel like we just hit the lottery with him in the lineup," catcher Russell Martin said.
Living up to his image of difference maker, Ramirez overshadowed some other pretty important events, like Casey Blake's first homer as a Dodger, starter Hiroki Kuroda's return to form with 7 1/3 solid innings and a save by Chan Ho Park as Jonathan Broxton's weary arm was shut down for a day.
But there was no overlooking Ramirez, whose first Dodgers homer was his 21st of the season and 511th of his career, tying Mel Ott for 22nd all-time. He drove in Juan Pierre, who led off with a bunt that was ruled a single by plate umpire Derryl Cousins when Arizona catcher Miguel Montero gloved the ball before it had completely entered foul territory.
"To be honest, I'm still kind of nervous, kind of shy to settle in," Ramirez said. "The crowd really made me feel good. I like that they got my back and I got their back. The fans just want me to go out there and play hard."
It was a huge 428-foot blast to center, but home runs are the expectation. The surprise was Ramirez creating the Dodgers' fourth run in the sixth inning after a single by hustling -- that's right, hustling -- from first to third on James Loney's single to right and scoring on Jeff Kent's single to left.
Kent, who had two hits, was batting sixth for the first time in his Dodgers career and Andruw Jones was out of the starting lineup indefinitely, further examples of how dramatically the focus of this offense, and team, has changed.
Another example was the behavior in a normally subdued dugout, which absolutely erupted when Ramirez launched his home run, and the celebration went off the charts when he returned from his trot around the bases.
"It's Manny. All Manny," Martin said of the new atmosphere. "He's just fun to have around. He's energetic and outspoken. He wants to have fun. After the home run, I told him to go out [for the curtain call]. The crowd was going crazy. He's a great hitter. You saw in the first inning, with one swing of his bat he can lift a team. It's what he does."
But as manager Joe Torre reminded, the club still relies on its pitching and Kuroda's first win since July 7 was a welcome change. After staggering to a 13.11 ERA in three starts since the All-Star break, he allowed only four hits and no walks while striking out six. The only Diamondbacks run off him came on No. 8 hitter Montero's home run into the right-field box seats leading off the third inning.
Kuroda (6-8) retired the next 12 batters and finally gave way in the eighth after an error by Kent and a bloop single by pinch-hitter Jamie D'Antona.
Torre said the difference was Kuroda finishing off his breaking pitches. After returning from a sore shoulder before the All-Star break, he had been recoiling on sliders.
"That was the big factor," Kuroda said of the mechanical adjustment. "I worked on that with [pitching coach Rick] Honeycutt. I felt I had been a burden on the team."
Hong-Chih Kuo pitched the next 1 1/3 innings, coming within one out of his first career save, but Alex Romero singled home Conor Jackson. Torre then brought in Park, who got Chris Young on a fielder's choice grounder for his second save of the year.
Broxton, 5-for-5 in saves since taking over for the injured Takashi Saito, never warmed up.
"I've thrown nine straight days," Broxton said. "I'm sore like you'd expect. But they asked me if I could close and I said I could. They decided to give me a break."
Ken Gurnick is a reporter for MLB.com. This story was not subject to the approval of Major League Baseball or its clubs.


text:
Angels easing Pujols in to Cactus League
By Alden Gonzalez / MLB.com
TEMPE, Ariz. -- Albert Pujols had a normal offseason and has pronounced himself completely healthy, but Angels manager Mike Scioscia will not be playing him at first base on an everyday basis once Cactus League games start.
"He's not at that point," Scioscia said. "And we wouldn't do it anyway. If he felt great, there's no doubt about getting him in the flow in little bits. You're not going to just throw him out there and have him play 15 straight Spring Training games because he feels good, because I think by Game 16 you might be facing a problem."
Pujols, whose 2013 season ended after 99 games with a partial tear of his left plantar fascia, stayed mostly away from arduous activity Wednesday during the Angels' first full workout.
Scioscia said the goal was for Pujols to play first base "on a regular basis" when the season starts but that they would take it slow and have backup plans if the 34-year-old is not ready by Opening Day on March 31.
Veteran first baseman Carlos Pena is in camp, and his chances of making the team as a reserve could hinge largely on Pujols' health.
Raul Ibanez, the 41-year-old designated hitter who has spent the vast majority of his career in the outfield, will get plenty of reps this spring at first base -- a position he has not spent much time at since 2005.
"We'll see," Scioscia said of Ibanez playing first base. "We're not talking about on an everyday basis, but we'll see what his proficiency is, his comfort level, and hopefully we'll be able to tap into that."
Owner Moreno to Angels: Have fun
TEMPE, Ariz. -- Arte Moreno addressed the entire team Wednesday morning prior to the Angels' first full workout, on the heels of a frustrating four-year absence from the playoffs.
The owner's words, simply: "Have fun."
The pre-practice meeting usually runs a little longer on the first day position players and pitchers are together. The entire front office and public-relations staff is in the room; everybody introduces themselves, and Moreno is usually in attendance.
The Angels' owner said he does not normally say anything that day but aims to convey a sense of calmness when he speaks -- no matter how affected he really is by sub-.500 seasons.
"Most people know me," Moreno said. "It might be the younger guys, or the guys we just picked up, but I go around the room and say hello to as many as I can. And during Spring Training, I always try to get over and talk to them a little bit, just so they're not intimidated by that. I tell them I go by my first name.
"I really try to be positive and optimistic. But don't get me wrong, everybody has areas on a team you look at and say, 'Where can I go? Who can we add, or what can we do to improve what you're trying to accomplish?'"
Veteran Lyon facing unfamiliar battle for spot
TEMPE, Ariz. -- Veteran right-handed reliever Brandon Lyon, 34, is on his first Minor League contract, and, for pretty much the first time in his 12-year career, he will have to battle to win a spot in a Major League bullpen.
"People are fighting to push you out of the game," Lyon said, "and you have to keep fighting to stay in the game."
From 2006-12, Lyon made at least 60 appearances in six out of seven seasons, compiled a 3.59 ERA and spent two seasons -- '08 and '10 -- as a closer. With the Mets last season, though, he struggled through a 4.98 ERA, a 1.63 WHIP and a 1.77 strikeout-to-walk ratio in 34 1/3 innings.
Lyon never went on the disabled list last year, but he had a back issue he did not know how to deal with, which might have caused his average fastball velocity to drop to 88 mph in 2013 from 89.7 mph in 2012.
"I didn't know how to maintain it; I didn't know how to take care of it at all," Lyon said. "It didn't bother me, but I wasn't able to go out there and be 100 percent. I was guarding it more than pushing it. So I pushed it to see how it goes [in the offseason], and everything felt great."
Now Lyon, obtained Feb. 10, is competing with at least nine other relievers for two spots in the Angels' bullpen. Asked if he would be willing to go to the Minors if he does not win a job out of Spring Training, Lyon said: "I haven't really thought about that. My focus is here, to get ready for a Major League season. When the time comes, I'll think about that then."
Worth noting
• Special guest instructors for Angels Spring Training will include Chuck Finley (Feb. 17-21), Tim Salmon (Feb. 19-21), David Eckstein (Feb. 24-27 and March 17-20), Jim Abbott (March 10-13), Adam Kennedy (March 11-14), Garret Anderson (March 14-15) and Bobby Grich (March 15-20).
• Third baseman Luis Jimenez (from the Dominican Republic) and catcher Anderson De La Rosa (Venezuela) have yet to arrive in camp because of issues entering the country, but they are expected to report in the coming days.
Alden Gonzalez is a reporter for MLB.com. Read his blog, Gonzo and "The Show", and follow him on Twitter @Alden_Gonzalez. This story was not subject to the approval of Major League Baseball or its clubs.


text:
SOC Course Descriptions
Listed below are the course descriptions for School of Communication Summer Sessions courses.
School of Communication
COMM 101 Public Speaking and Critical Thinking
This introductory course is designed to supply students with the skills of public address, a fundamental understanding of critical thinking practices, foundational tenets of communication theory, a grasp of the relationship between context and communication, and a sense of the social responsibility that comes with the capacity for communication.
COMM175 Introduction to Communication
This course gives a general historical and theoretical overview of communication. By looking at communication through a critical, historical, and theoretical lens, students will acquire an intellectual framework for further study and practice in communication. This course will also increase basic communication literacy.
COMM 200 Communication and New Media
Prerequisites: CMUN/COMM 150, 160, or 175. This course explores the ways technology affects personal, cultural, and mass communication through examining the historical, societal, and ethical implications of newer and interactive forms of media. Students use audio, video, and digital tools to research and produce essays, projects, and presentations that analyze the impact of technology on communication.
COMM 205 Reporting and Writing Across Platforms
Prerequisite UCRW110
This course is designed to teach students to report, write, and create stories for print, broadcast, and the Internet. While learning the basics through lectures and the textbook, students also will spend time doing research, interviews, and writing print news stories, broadcast scripts, and articles for the Internet.
COMM 211 Principles of Advertising
Prerequisites: CMUN/COMM 150, 160, or 175. This introduction to advertising provides an overview of the theory and hands-on practice of advertising including planning, strategy, creative development, and media planning. Elements of direct response, promotion, Internet, and public relations are also presented. Students will be able to demonstrate an understanding of the principles of advertising and practice creative and decision-making skills in developing an advertising campaign.
COMM 215 Ethics and Communication
Prerequisites: CMUN/COMM 150, 160, or 175. This course explores various approaches to ethical decision-making and applies that process to diverse aspects of every day, contemporary life. Students learn to discern a wide variety of ethical issues concerning communication behavior, apply systematic ethical analysis to various communication situations, and explain their analyses clearly.
COMM 274 Introduction to Cinema
This course is an introduction to the study of cinema as a complex medium of communication. Students will be provided with the basic terminology, observational skills, and theoretical background for the study of film aesthetics, language, cultural analysis, history, and the production of cinematic texts. Students will be able to demonstrate an understanding of the basic approaches to film studies such as formal analysis, critical practices, and narrative studies.
COMM 315 Advanced Reporting Topics
Prerequisite: CMUN 271 or COMM 205 and Junior or Senior Standing; advanced reporting topics; engaged learning
This course offers in-depth attention to the challenges of writing complex stories characterized by careful research, use of sources, interviewing, and reporting and writing. Students examine writing for a "lay" audience in such areas as science and technology, finance, government, and religion. Students will broaden their writing and research experience
COMM 373 Digital Storytelling Abroad (Santiago, Chile)
Please see the program description listed on the Study Aboard website www.luc.edu/studyabroad/chile/
COMM 381 Communication Practicum
Department consent required
Students gain advanced practical experience in service experiential learning projects.
COMM 382 Journalism Practicum
Department consent required
Students gain hands-on practical experience in developing Journalism projects.
Department consent required
Students will gain advanced practical experience creating digital cinema projects.
COMM 391 Advertising & Public Relations Internship
Prerequisites: Permission from Advertising & Public Relations internship director, Junior status, and attending an internship orientation. This supervised field experience enables students to have hands-on professional learning at a wide range of agency, corporate, and non-profit organizations as the basis for learning and refining professional communication skills.
COMM 392 Journalism Internship
Prerequisites: Permission from Journalism internship director, Junior status, and attending an internship orientation. This supervised field experience enables students to have hands-on professional learning at a wide range of agency, corporate, and non-profit organizations as the basis for learning and refining professional communication skills. Students gain proficiency in professional conduct and industry skills while systematically reflecting on their experiences.
COMM 393 Communication Studies Internship
Prerequisites: Permission from Communication Studies internship director, Junior status, and attending an internship orientation. This supervised field experience uses experiential learning at a wide variety of corporate, professional, and non-profit organizations as the basis for learning and refining communication skills. Students will be able to demonstrate skill proficiency as required at their sites, professional conduct, and systematic reflection on their experiences.
COMM 398 Directed Study
Prerequisites: Instructor and departmental approval. Independent research under the supervision of a designated faculty member. May be repeated for a total of 9 hours, but only 6 may count toward the major. Students gain experience and use skills they have developed in their field of interest to work on independent research.