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|Número de publicación
|Tipo de publicación
|Número de solicitud
|Fecha de publicación
|3 Jul 2001
|Fecha de presentación
|10 Jun 1998
|Fecha de prioridad
|10 Jun 1998
|También publicado como
|Número de publicación
|Aron B. Anderson, Ralph A. Chappa, Terrence P. Everson
|Cesionario original
|Surmodics, Inc.
|Exportar cita
|BiBTeX, EndNote, RefMan
|Citas de patentes (12), Otras citas (4), Citada por (113), Clasificaciones (21), Eventos legales (4)
|Enlaces externos: USPTO, Cesión de USPTO, Espacenet
The present invention relates to the use of compounds such as functional silicone polymer formulations, and in particular hydride functional siloxane polymer formulations, for treating surfaces. In another aspect, the invention relates to methods for coating substrate surfaces, such as the surfaces of medical articles such as stents and guidewires, in order to provide the surfaces with different or desired properties.
Implantable medical articles are instrumental in saving patients' lives and enhancing the quality of life for many others. However, a significant barrier to the use of such implantable articles is the possibility of adverse reactions of the body such as thrombogenic and immune responses. Common materials used to manufacture implantable medical articles include metals, minerals or ceramics, and polymers. It is generally desirable to modify the surface of such materials in order to provide the surface with properties that are different from the properties of the material, e.g., in terms of infection resistance, thromboresistance, biodeposition, friction, radiopacity, conductivity and/or biocompatibility. Other desired properties include hydrophilicity, lubricity, ability to mimic natural tissue, and ease of insertion into the body without tissue damage. In addition, it is desirable to have a coating that is durable and abrasion resistant.
Various synthetic techniques have been used to impart desired chemical, physical and biological properties to materials used to manufacture implantable medical articles. One current method of coating medical devices involves application of a parylene coating to devices. For example, parylene C, one of the three primary variants of parylene, can be used to create a moisture barrier on the surface of a medical device. Parylene C is a para-xylylene containing a substituted chlorine atom, which can be coated by delivering it in a vacuum environment at low pressure as a gaseous polymerizable monomer. The monomer condenses and polymerizes on substrates at room temperature, forming a matrix on the surface of the medical device. The coating thickness is controlled by pressure, temperature, and the amount of monomer used. The parylene coating provides an inert, non-reactive barrier.
However, the coating of medical articles with polymers such as parylene C has a number of limitations. For example, parylene C cannot be used to form a thin (e.g., less than 0.1 micron) film with uniform thickness on a medical article. The parylene C application procedure is influenced by the vapor flow through the vacuum chamber, such that areas with different lines of sight, either on a single device or among different devices, receive varying amounts of deposited polymer. Moreover, parylene C requires vacuum conditions to apply the coating, and this requirement complicates the processability of a medical device to be coated using this method. Additionally, the thicker polymer coating, when applied to a metal medical device, such as, for example a stent, will have different physical properties than the underlying metal and, consequently, may not respond similarly to tensile, shear, or compression forces, causing the coating to crack, flake, or delaminate.
Other current methods of coating medical articles typically involve the coupling of compounds directly to surfaces of such articles by ionic or covalent binding. One approach has been to couple biochemical materials, such as heparin or albumin, directly to the surface of the article in order to enhance thromboresistance. For example, albumin has been covalently bound to polymer surfaces in order to improve the biocompatibility of the article by reducing thrombogenicity. See Nicholas A. Peppas et al., "New Challenges in Biomaterials," Science, 263: 1715-1720 (1994).
Medical articles have also been coated with polyurethane or polyethylene terephthalate (PET). See, for example, European Patent Application No. EP 0 769 306 A2, describing a surgical instrument coated with a non-hydrophilic lubricious polymer on the majority of its length located proximally and a hydrophilic polymer located at the majority of the remaining distal length of the instrument. Such coating processes can include, for example, encapsulation of the article with the desired coating. The result of encapsulation is generally a thick layer of polymer surrounding the article. However, the lack of a bond between the polymeric coating and the surface of the article can result in the polymer coating being easily lost.
On a separate subject, silicone-based polymer coatings are currently used to provide controlled modification of surface properties. For example, a siloxane trimonomer film can be used to coat silicone rubber and other materials in order to provide biocompatible coatings with high affinity for albumin. See, for example, Chi-Chun Tsai et al., "Biocompatible Coatings with High Albumin Affinity," ASAIO Transactions, 36: M307-M310 (1990). The siloxane trimonomer is formed by substituting hydroxyl or acyl groups in siloxane side chains, and the resulting siloxane coating preferentially adsorbs albumin from plasma.
Another surface modification technique employing silicone-containing polymers involves direct binding of functional groups to the surfaces of such materials as glass and titanium, using long chains of SiCl3 terminated amphiphiles. In this method, long-chain alkyltrichlorosilane bearing a remote functionality are bound directly to the material surfaces. The SiCl3 terminated amphiphiles react with a surface oxide layer (or silanol group on glass), forming a siloxane-anchored network. See, e.g., Sukenik et al., "Modulation of Cell Adhesion by Modification of Titanium Surfaces with Covalently Attached Self-assembled Monolayers," Journal of Biomedical Materials Research, 24: 1307-1323 (1990).
In a broader view, the chemical modification of surfaces to achieve desired chemical and/or physical characteristics has been previously described. See U.S. Pat. Nos. 4,722,906; 4,973,493; 4,979,959; 5,002,582; 5,414,075; and 5,512,329 (each of which are assigned to the present assignee, and the disclosure of each is incorporated herein by reference). These patents generally relate to surface modification by the use of latent reactive groups to achieve covalent coupling of reagents such as biomolecules and synthetic polymers to various substrates. The preferred latent reactive group is typically described as a photochemically reactive functional group (also known as a "photoreactive group") that, when exposed to an appropriate energy source, undergoes a transformation from an inactive state (i.e., ground state) to a reactive intermediate capable of forming a covalent bond with an appropriate material.
Applicants have found that using photoreactive groups to coat polymer layers directly onto a substrate may produce polymer layers that have a tendency to crack when subjected to contortions movement involved in fabricating those substrates into medical devices and/or thereafter, in the course of extended use within the body. This cracking, in turn, may result in the loss of some or all of the coating. The use of thicker coatings does not generally prevent this problem, and in fact can exacerbate this and other problems. What is needed is a way to provide coatings and coating methods for use with such devices, where the coatings exhibit an improved combination of such properties as coating stability, uniformity, and thickness.
The present invention provides an article (e.g., in the form of an implantable medical article) comprising a support material bearing an intermediate layer comprising a functional silicone polymer formulation, the intermediate layer having photoimmobilized thereon a target compound. In a preferred embodiment, the functional silicone polymer formulation comprises a hydride functional siloxane polymer formulation. Surprisingly, substrates coated in the manner of the present invention, that is, with an intermediate layer and photoimmobilized target compound, are particularly well suited to undergo contortions movement in the course of implantation and/or use within the body.
Photoimmobilization of the target compound onto an intermediate layer can be accomplished by the activation of one or more photoreactive groups. In one embodiment, the target compound is itself derivatized with one or more photoreactive groups. In an alternative embodiment, the target compound is attached to the intermediate layer via a coupling compound, wherein the coupling compound provides at least one photoreactive group for photoimmobilizing the coupling compound to the intermediate layer, and either a photoreactive or thermoreactive group for a photochemical or thermochemical reaction between the coupling compound and target compound. Alternatively, the coupling compound provides a thermochemical group for thermochemically covalently attaching the coupling compound to the intermediate layer, and a photoreactive group for photoimmobilizing the coupling compound to the target compound. In another alternative embodiment, the intermediate layer itself provides one or more photoreactive groups for attachment of the target compound.
Preferably, the article of the present invention, when provided in the form of an implantable medical article, provides an improved combination of such properties as durability and tenacity of the target compound attachment, and overall thickness of the coating comprising the intermediate layer and target compound, as compared to a comparable implantable medical article lacking the intermediate layer.
In another aspect, the invention provides a method of fabricating an article, the method comprising the steps of providing a support material, applying an intermediate layer and photoimmobilizing a target compound onto the intermediate layer. Optionally, the support material can be reformed into a final desired article, such as a medical stent. The steps of fabricating (e.g., coating and reforming) the article can be performed in any suitable manner and sequence. Support materials coated in the manner described herein provide improved performance, as compared to materials lacking an intermediate layer, for instance, in the course of being implanted (e.g., by twisting or bending) or used within the body.
In yet another aspect, the invention provides a method of using an article of the present invention, the method comprising the steps of fabricating an article in the manner described herein, and positioning the article in or upon the body. In yet another aspect, the invention provides an article coated with an intermediate attachment layer and photoimmobilized target compound, the article being positioned in permanent or temporary, bonded or touching contact with, or in apposition to a body part.
Implantable medical articles are generally manufactured of metals, minerals or ceramics, polymers, or combinations thereof. It is often desirable to modify the surface properties of these articles in order to provide such properties as biocompatibility and lubricity. The article of the present invention provides a support material (e.g., a material useful for fabrication of medical articles), bearing an intermediate layer having photoimmobilized thereon molecules of a target compound. In another aspect, the present invention provides a method of attaching target molecules to support surfaces.
Suitable support materials for use in the present invention include materials commonly used to fabricate implantable medical articles, and particularly those that are contorted (e.g., by bending or twisting) in the course of implantation and/or use within the body, such as stents and guidewires. The surface of the support material is optionally intended to function in contact with tissue and/or fluids of the body. The intermediate layer includes a functional silicone polymer formulation, and preferably, a hydride functional siloxane polymer formulation. A particularly preferred hydride functional siloxane polymer formulation is in the form of methylhydrosiloxane-dimethylsiloxane copolymers.
A target compound of the present invention can include one or more latent reactive groups that respond to specific applied external stimuli to undergo active specie generation with resultant covalent bonding to an adjacent support. Latent reactive groups include groups of atoms in a molecule which retain their covalent bonds unchanged under conditions of storage but which, upon activation, form covalent bonds with other molecules.
The present invention further provides a method of fabricating an article, the method comprising the steps of providing a support material, applying an intermediate layer and photoimmobilizing a target compound onto the intermediate layer.
Suitable support materials of the present invention are capable of being coated with a functional silicone polymer formulation or are capable of being treated so as to be coated. Additionally, suitable support materials can be used as, or fabricated into, a medical article, e.g., twisted or bent into the form of an expandable stent. Such materials are generally not able to be attached directly to desired compounds by photochemistry, in a manner sufficient for their intended use.
Examples of suitable support materials include those materials commonly used to fabricate stents and other medical articles, including metals, minerals or ceramics, and polymers. Suitable metals include reactive metals, such as, for example, aluminum, chromium, cobalt, iron, tantalum, titanium, and alloys thereof, as well as nitinol and other nickel-titanium alloys, and stainless steels. Examples of suitable minerals or ceramics include alumina, hydroxyapatite, quartz, sapphire, silica and glasses.
Other suitable support materials include polymers such as, for example, polycarbonate, polyester, polyethylene, polyethylene terephthalate (PET), polyglycolic acid (PGA), polyolefin, poly-(p-phenyleneterephthalamide), polyphosphazene, polypropylene, polytetrafluoroethylene, polyurethane, polyvinyl chloride, polyacrylate (including polymethacrylate), and silicone elastomers, as well as copolymers and combinations thereof.
Examples of alternative support materials include human tissue such as bone, skin and teeth; organic materials such as wood, cellulose and compressed carbon; and other suitable natural and synthetic materials.
Preferred support materials are capable of being coated with a functional silicone polymer formulation or are capable of being treated so as to be coated. For example, the surface of the support material can be treated to provide a hydroxide or amine derivatized surface. Preferably, support materials of the present invention are capable of being fabricated into a medical article while subjected to contortions movements and other processes involved during their fabrication or use, e.g., twisting, bending, heating and curing. Preferred materials can be used to form a final desired article that can be sterilized, e.g., prior to use in surgery. Examples of preferred support materials include stainless steel, nickel-titanium alloys, cobalt, tantalum, and combinations and/or alloys thereof.
Intermediate layers are preferably capable of being applied to a support material and covalently attached to a target compound (e.g., by the activation of photoreactive groups), in order to provide a durable and tenacious coating in a cost effective manner. When applied, a preferred intermediate layer forms a thin layer of functional silicone polymer formulation on the surface of a support material. This layer, in turn, is stably retained upon the surface and serves as the attachment site for binding target compounds to the surface. The word "layer," as used in this respect herein, will refer to a coating of sufficient dimensions (e.g., thickness and area) for its intended use, e.g., over all, or a portion, of the support material surface.
Preferred intermediate layers provide a film of functional silicone polymer formulation on the surface of the support materials, the intermediate layer having a thickness of approximately 100 Å (Angstrom) or less. By measuring ESCA (Electron Spectroscopy for Chemical Analysis) spectra at varying detection angles, the thickness of the intermediate layer can be estimated.
Examples of suitable intermediate layers include functional (i.e., reactive) silicone containing polymers. Suitable intermediate layers are selected from the group consisting of hydride functional siloxanes, silanol functional siloxanes, epoxy functional siloxanes, polymers with hydrolyzeable functionality, polysilanes, polysilazanes and polysilsesquioxanes.
Suitable hydride functional siloxanes include: hydride terminated polydimethylsiloxanes; methylhydrosiloxane-dimethylsiloxane copolymers; polymethylhydrosiloxanes; polyethylhydrosiloxanes; hydride terminated polyphenyl-(dimethylhydrosiloxy)siloxanes; and methylhydrosiloxane-phenylmethylsiloxane copolymers.
Examples of suitable silanol functional siloxanes include: silanol terminated polydimethylsiloxanes; silanol terminated diphenylsiloxane-dimethylsiloxane copolymers; and silanol terminated polydiphenylsiloxanes. Suitable epoxy functional siloxanes include epoxypropoxypropyl terminated polydimethylsiloxanes and (epoxycyclohexylethyl)methylsiloxane-dimethylsiloxane copolymers. Examples of suitable polymers with hydrolyzeable functionality include: diacetoxymethyl terminated polydimethylsiloxanes; and dimethylamino terminated polydimethylsiloxanes.
Preferred functional silicone polymer formulations are capable of being applied to a support material in order to provide abstractable hydrogen atoms that can be used for covalent bonding to target compounds, e.g., by activation of photoreactive groups such as aryl ketones. Such preferred functional silicone polymer formulations form layers that are durable and abrasion resistant and provide a tenacious bond with the target compound through the residue of the photoreactive group. In turn, support materials having an intermediate layer of the present invention typically bond target compounds longer than support materials lacking an intermediate layer. Moreover, since functional silicone polymers are able to form a thin, uniform layer coating the support, the overall thickness of the final desired article is reduced.
In a preferred embodiment, an intermediate layer includes one or more hydride functional siloxane polymers. Hydride functional siloxane polymers can be characterized according to chemical characteristics and reactivity. Preferred hydride functional siloxane polymers are selected from the group consisting of: hydride terminated polydimethylsiloxanes; methylhydrosiloxane-dimethylsiloxane copolymers; polymethylhydrosiloxanes; polyethylhydrosiloxanes; hydride terminated polyphenyl-(dimethylhydrosiloxy)siloxanes; hydride terminated methylhydrosiloxane-phenylmethylsiloxane copolymers; and methylhydrosiloxane-octylmethylsiloxane copolymers.
Particularly preferred hydride functional siloxane polymers include methylhydrosiloxane-dimethylsiloxane copolymers, e.g., having about 1 to about 100 mole percent MeHSiO (based on total moles siloxane used to prepare the polymer). Examples of particularly preferred polymers have about 25 to about 100 mole percent MeHSiO, and have viscosity about 1 cSt (centistokes) to about 15,000 cSt, preferably about 10 cSt to about 50 cSt (as are available from Gelest Inc., Tullytown, Pa., e.g., under Product No. HMS 301). The hydride functional siloxane polymers of the present invention tend to be preformed polymers, since the preferred molecular weight of the polymers can be adapted to the particular application. An example of a particularly preferred methylhydrosiloxane-dimethylsiloxane copolymer has a molecular weight of about 1500 Daltons to about 2200 Daltons.
Preferred hydride functional siloxane polymers of the present invention further include those capable of undergoing any of three classes of reactivity, including dehydrogenative coupling, hydride transfer (e.g., reduction), and hydrosilylation. Dehydrogenative coupling occurs when hydroxyl functional materials react with hydride functional siloxanes in the presence of metal salt catalysts. Reduction reactions involve the transfer of hydrogen and are catalyzed by palladium or dibutyltin oxide. The hydrosilylation of vinyl functional siloxanes by hydride functional siloxanes is the basis of addition cure chemistry used in two-part Room Temperature Vulcanizing cures (RTVs, which cure below 50° Celsius) and Low Temperature Vulcanizing cures (LTVs, which cure between 50° Celsius and 130° Celsius). The most widely used materials for these addition cure applications are methylhydrosiloxane-dimethylsiloxane copolymers which have more readily controlled reactivity than the homopolymers and result in tougher polymers with lower crosslink density.
Functional silicone polymers can be used to form an intermediate layer on a support surface by any suitable means, for example, by dipping or immersing the support material in a diluted or undiluted formulation of functional silicone polymer, or by spraying or brush coating the functional silicone polymer formulation onto the support material.
Preferably, and particularly in the case of a metallic support material, the metal is pretreated, e.g., by exposing it to a base such as sodium hydroxide, to provide a hydroxide layer on the surface of the metal. Pretreatment in this manner provides a layer of hydroxyl groups for the subsequent reaction with the intermediate layer. In an alternative embodiment, a support material (e.g., in the form of a polymer surface) can be derivatized by plasma treatment using a mixture of methane and ammonia gases. The resulting amine derivatized surface exhibits improved reactivity with the intermediate layer.
The functional silicone polymer formulation can be used neat or optionally solubilized or diluted. A preferred amount of methylhydrosiloxane-dimethylsiloxane copolymer is in the range of 0.1%-99% (by weight of the final solution) dissolved in solvents such as toluene, tetrahydrofaran (THF), ethyl acetate, benzene, or chloroform.
Optionally, the support material bearing an intermediate layer is then washed, e.g., with toluene or other suitable solvent, to remove excess functional silicone polymer formulation. The support material bearing an intermediate layer can optionally be dried before photoimmobilizing a target compound onto the intermediate layer. Drying and/or curing the article can be performed in any suitable fashion, e.g., sequentially or simultaneously.
Reagents of the invention carry one or more pendent latent reactive (preferably photoreactive) groups covalently bonded to the residue of the molecule. Photoreactive groups are defined herein, and preferred groups are sufficiently stable to be stored under conditions in which they retain such properties. See, e.g., U.S. Pat. No. 5,002,582, the disclosure of which is incorporated herein by reference. Latent reactive groups can be chosen that are responsive to various portions of the electromagnetic spectrum, with those responsive to ultraviolet, infrared and visible portions of the spectrum (referred to herein as "photoreactive") being particularly preferred.
Photoreactive groups respond to specific applied external stimuli to undergo active specie generation with resultant covalent bonding to an adjacent chemical structure, e.g., as provided by the same or a different molecule. Photoreactive groups are those groups of atoms in a molecule that retain their covalent bonds unchanged under conditions of storage but that, upon activation by an external energy source, form covalent bonds with other molecules.
The photoreactive groups generate active species such as free radicals and particularly nitrenes, carbenes, and excited states of ketones upon absorption of electromagnetic energy. Photoreactive groups may be chosen to be responsive to various portions of the electromagnetic spectrum, and photoreactive groups that are responsive to e.g., ultraviolet, infrared and visible portions of the spectrum are preferred and may be referred to herein occasionally as "photochemical group" or "photogroup."
Photoreactive aryl ketones are preferred, such as acetophenone, benzophenone, anthraquinone, anthrone, and anthrone-like heterocycles (i.e., heterocyclic analogs of anthrone such as those having N, O, or S in the 10-position), or their substituted (e.g., ring substituted) derivatives. The functional groups of such ketones are preferred since they are readily capable of undergoing the activation/inactivation/reactivation cycle described herein. Benzophenone is a particularly preferred photoreactive moiety, since it is capable of photochemical excitation with the initial formation of an excited singlet state that undergoes intersystem crossing to the triplet state. The excited triplet state can insert into carbon-hydrogen bonds by abstraction of a hydrogen atom (from a support surface, for example), thus creating a radical pair. Subsequent collapse of the radical pair leads to formation of a new carbon-carbon bond. If a reactive bond (e.g., carbon-hydrogen) is not available for bonding, the ultraviolet light-induced excitation of the benzophenone group is reversible and the molecule returns to ground state energy level upon removal of the energy source. Photoactivatible aryl ketones such as benzophenone and acetophenone are of particular importance inasmuch as these groups are subject to multiple reactivation in water and hence provide increased coating efficiency. Hence, photoreactive aryl ketones are particularly preferred.
The azides constitute a preferred class of photoreactive groups and include arylazides (C6R5N3) such as phenyl azide and particularly 4-fluoro-3-nitrophenyl azide, acyl azides (—CO—N3) such as benzoyl azide and p-methylbenzoyl azide, azido formates (—O—CO—N3) such as ethyl azidoformate, phenyl azidoformate, sulfonyl azides (—SO2—N3) such as benzenesulfonyl azide, and phosphoryl azides (RO)2PON3 such as diphenyl phosphoryl azide and diethyl phosphoryl azide. Diazo compounds constitute another class of photoreactive groups and include diazoalkanes (—CHN2) such as diazomethane and diphenyldiazomethane, diazoketones (—CO—CHN2) such as diazoacetophenone and 1-trifluoromethyl-1-diazo-2-pentanone, diazoacetates (—O—CO—CHN2) such as t-butyl diazoacetate and phenyl diazoacetate, and beta-keto-alpha-diazoacetates (—CO—CN2—CO—O—) such as t-butyl alpha diazoacetoacetate. Other photoreactive groups include the diazirines (—CHN2) such as 3-trifluoromethyl-3-phenyldiazirine, and ketenes (—CH═C═O) such as ketene and diphenylketene.
Upon activation of the photoreactive groups, the reagent molecules are covalently bound to each other and/or to the intermediate layer by covalent bonds through residues of the photoreactive groups. Exemplary photoreactive groups, and their residues upon activation, are shown as follows.
Residue Functionality
aryl azides
acyl azides
sulfonyl azides
phosphoryl azides
new C—C bond
new C—C bond
and ketone
new C—C bond
and ester
new C—C bond
and beta-ketoester
aliphatic azo
new C—C bond
new C—C bond
new C—C bond
photoactivated ketones
new C—C bond
and alcohol
Suitable target molecules for use in the present invention encompass a diverse group of substances. Target molecules can be immobilized singly or in combinations with other types of target molecules. Typically, target molecules are selected so as to confer one or more particular desired properties to the surface and/or to the device or article incorporating or bearing the surface. Examples of suitable target molecules, and the surface properties they are typically used to provide, is represented by the following non-limiting list:
Synthetic Polymers
Sulfonic acid-substituted
Lubricity, negatively charged surface,
Lubricity, protein repulsion, hydrophilicity
Polyethylene glycol
Lubricity, cell and protein repulsion,
Positively charged surface
Polylactic acid
Bioerodible surface
Polyvinyl alcohol
Lubricity, hydrophilicity
Polyvinyl pyrrolidone
Lubricity, hydrophilicity
Quaternary amine-substituted
Lubricity, positively charged surface
Lubricity, hydrophobicity
Conductive polymers (e.g.,
Electric conductivity
polyacetylene, polypyrrole)
Alginic acid
Lubricity, hydrophilicity
Lubricity, hydrophilicity, biodegradable
glucose source
Positively charged surface,
Hydrophilicity, biodegradable glucose
Antithrombogenicity, hydrophilicity,
cell attachment
Hyaluronic acid
Lubricity, negatively charged surface
Lubricity, hydrophilicity
Mono-, di- saccharides
Dextran sulfate
Chromatography media
Antigen binding
Antithrombotic agents (e.g.,
Antithrombogenic surface
antithrombin III)
Nonthrombogenic surface
Attachment proteins/peptides
Cell attachment
(e.g. collagen)
Catalytic surfaces
Extracellular matrix proteins/
Cell attachment and growth
Growth factors,
Cell growth
Antithrombogenic surface
Thrombolytic proteins (e.g.,
Thrombolytic activity
streptokinase, plasmin,
Fatty acids
Hydrophobicity, biocompatibility
Mono- , di- and triglycerides
Hydrophobicity, lubricity, biodegradable
fatty acid source
Hydrophobicity, lubricity, biodegradable
fatty acid source
Nonthrombogenic surface/immobilized
Nucleic Acids
Substrate for nucleases/affinity binding
Substrate for nucleases/affinity binding
Nucleosides, nucleotides
Source of purines, pyrimidines, enzyme
Enzyme cofactors
Immobilized enzymes
Heme compounds
Globin bindings/surface oxygenation
Drug activity
Non-polymeric Materials
Dyes (e.g., azo dyestuffs)
Coloring agents
Fluorescent compounds
(e.g., fluorescein)
The target compound can be photoimmobilized onto the intermediate layer in any suitable manner. In one embodiment, the target compound is itself prederivatized with one or more latent photoreactive groups, and covalent bonding with the intermediate layer occurs upon activation of the photoreactive group in the presence of the intermediate layer. The target molecule is spatially oriented so as to enable one or more of its photoreactive groups to come into covalent bonding proximity with the intermediate layer. Thereafter, external stimulation is applied to covalently bond the target molecule to the intermediate layer. (See, for example, U.S. Pat. No. 5,002,582, the disclosure of which is incorporated herein by reference).
In an alternative embodiment, the target compound is photoimmobilized onto the intermediate layer via a coupling compound, wherein the coupling compound provides one or more latent photoreactive groups and/or one or more latent thermoreactive groups. In one such embodiment, the coupling compound possesses a photochemically reactive group capable, upon activation, of covalently bonding to the intermediate layer and possessing a different reactive group that is capable of covalently bonding, e.g., through thermochemical reaction, to molecules of the target compound. Each of the reactive groups of the coupling compound is responsive to activation by a different stimulus. For instance, stimulus can be applied to sequentially activate the groups to photochemically covalently bind the coupling compound, and to thermochemically covalently bind the reactive group of the coupling compound to the target molecules.
In yet another alternative embodiment, the intermediate layer itself provides one or more photoreactive groups. In this embodiment, the intermediate layer is itself prederivatized with one or more photoreactive groups that are activated to form a covalent bond with the target compound. For example, in a preferred embodiment, the hydrosiloxane intermediate layer is prederivatized with photoreactive groups such as benzophenone. This modification can be done prior to, during, or after application of the intermediate layer. The benzophenone groups can then be activated by external stimulation, to allow covalent bonding between the intermediate layer and a target molecule.
Optionally, the support material can be fabricated by reforming it into a final desired article. In view of the present teaching, the support material can be reformed into a medical article using techniques within the skill of those in the art. This reformation can be done in any suitable manner, e.g., prior to, during, or after photoimmobilization of the target compound. In the event the support material is reformed after photoimmobilization of the target compound, techniques well known in the art can be used to determine that such reformation does not cause cracks or fissures in the coating. Suitable methods for determining the absence of cracking include, for example, the use of fluorescence, stains or scanning electron microscopy (SEM). In a preferred embodiment, the support material is reformed into a final desired article prior to application of the intermediate layer and subsequent photoimmobilization of a target compound.
Examples of suitable articles that can be fabricated according to the present invention include stents, guidewires, orthopedic prostheses, catheters, surgical instruments, dental implants, and various medical devices that are used within or are inserted into the body. For example, suitable stents include coronary, intraluminal, frontal sinus, urethral, nasal, and other stents. Suitable insertable medical devices include, for example, tubing (e.g., vascular graft tubing); balloons (e.g., intra aortic); prostheses (e.g., soft or hard tissue prosthesis, synthetic prosthesis, artificial organs, or heart valves); lenses (e.g., lenses for the eye such as contact and intraocular lenses). Other suitable medical devices include dialysis tubing, blood oxygenator tubing, blood bags, catheters, sutures, blood oxygenator membranes, and ultrafiltration membranes.
An experiment was performed to demonstrate the effect of applying a hydrosiloxane formulation (methylhydrosiloxane-dimethylsiloxane copolymer) to the surface of 316L stainless steel stents, followed by photoimmobilization of heparin to provide a hemocompatible coating.
The hydrosiloxane formulation was applied to the stainless steel stents in the following manner. A stent made of 316L stainless steel was initially cleaned with hexane followed by cleaning in isopropyl alcohol (IPA). The stent was then heated at 90° C. in 1N NaOH for 30 minutes, rinsed with deionized water and dried. The stent was dipped into a nondiluted solution of methylhydrosiloxane-dimethylsiloxane copolymer (H-siloxane, 25-35 Mole % MeHSiO, Product No. HMS-301, Gelest, Inc., Tullytown, Pa.) and reacted in an oven at 150° C. for 30 minutes. The coated portion of the stent was then thoroughly washed three times with toluene for five minutes each wash, on an orbital shaker at 100 rpm, to remove any unbound H-siloxane. The coated stent was then air dried prior to proceeding to photochemistry.
Photoheparin was then photoimmobilized onto the H-siloxane-treated stent in the following manner. The treated portion of the stent was immersed in a water solution containing 20 mg/ml photolabelled heparin (HP01, available from SurModics, Inc., Eden Prairie, Minn.). The stent was allowed to soak one hour at room temperature, and the sample was illuminated with an Oriel Series Q Arc Lamp (Oriel Instruments, Stratford, Conn.) which contained an Osram HBO 100 W/cm2, mercury short arc doped bulb (Germany). The sample was illuminated for 2 minutes at an intensity of 8-10 mW/cm2 in the wavelength range of 330 nm-340 nm. This photoheparin coating procedure was repeated four more times with a 10 minute dwell instead of an hour, for a total of five coats of photoheparin. The resulting coated part was air dried for 15 minutes.
In order to remove excess photoheparin, the stent was then washed by placing it in phosphate buffered saline (PBS, 10 mM phosphate, 150 mM NaCl, pH 7.2) solution overnight at 37° C. on an orbital shaker at 150 rpm.
After washing, the coated stent was assayed for heparin activity by a thrombin inhibition activity assay as follows: the stents were incubated with mild agitation for two hours at 37° C. in a PBS solution containing 1 mg/ml bovine serum albumin (BSA, Product No. A-2153, Sigma, St. Louis, Mo.), 0.01 U/ml human thrombin (ATIII, Product No. T-6884, Sigma, St. Louis, Mo.), 0.5 U/ml Antithrombin III (ATIII, Product No. 603-20, Bayer, W. New Haven, Conn.), and 0.2 mM of the chromogenic thrombin substrate H-D-phenylalanyl-L-pipecoyl-L-arginine-p-nitroanilide (S-2238, Product No. 820324, Kabi, Glendale, Calif.). After incubation, the absorbance of the solutions was read at 405 nm using a Beckman DU-30 spectrophotometer. The color generated by thrombin-mediated cleavage of the substrate is directly related to the activity of the thrombin, and thus, inversely related to the amount of activation of antithrombin induced by the surface. The absorbance of the solution in the stent tubes was compared to the absorbances in a set of standard heparin solutions having a range of soluble activity. The activity on the stents was calculated based on the standard curve of absorbance versus heparin activity.
Also tested was a stent coated with parylene C in a manner analogous to that described above with respect to the H-siloxane stent. Parylene C was used as a positive control in the present experiment. A bare stainless steel stent was also coated using only three coats of photoheparin as compared to five coats for the parylene C and H-siloxane precoated stents.
Results indicate that the H-siloxane stent and parylene C stent had improved heparin bonding strength as compared to the bare metal control stent. The H-siloxane stent gave a positive heparin result of 10.5 mU/cm2, while the parylene C treated stent gave a positive heparin result of 8.7 mU/cm2. The bare metal stent (control) gave a negative heparin result, i.e., no heparin activity was observed on the control stent.
An experiment was performed to demonstrate the effect of applying an H-siloxane copolymer to the surface of stainless steel and nitinol wires, followed by photoimmobilization of lubricious coatings.
Stainless steel and nitinol (nickel/titanium) wires (30 cm in length) were cleaned and H-siloxane was applied in a manner analogous to that described in Example 1; that is, wires were initially cleaned with hexane followed by cleaning in IPA. The wires were heated at 90° C. in 1N NaOH for 30 minutes, rinsed with deionized water and then dried. Next, the wires were dipped into a undiluted solution of H-siloxane (25-35 Mole % MeHSiO, Product No. HMS-301, Gelest, Inc., Tullytown, Pa.) and reacted in an oven at 150° C. for 30 minutes. The wires were then thoroughly washed three times, five minutes each wash, on an orbital shaker at 100 rpm, with toluene to remove any unbound H-siloxane. The wires were then air dried.
Immobilization of photoreagents onto the wires bearing H-siloxane was performed as follows. The stainless steel and nitinol wires were dip coated at 0.5 cm/second in a solution containing 15 mg/ml photolabeled polyvinyl pyrrolidone (PV01, available from SurModics, Inc., Eden Prairie, Minn.) and 35 mg/ml photolabeled polyacrylamide (PA05, available from SurModics, Inc., Eden Prairie, Minn.) in 30% IPA/H2O. The coated wires dried for 30 minutes at room temperature, followed by illumination with a Dymax lamp (model no. PC-2, Dymax Corporation, Torrington, Conn.) which contained a Heraeus bulb (W. C. Heraceus GmbH, Hanau, Federal Republic of Germany) to activate the photogroups present in each polymer, and produce covalent bonding to the wire. The coated wires were illuminated for 3 minutes at an intensity of 1-2 mW/cm2 in the wavelength range of 330-340 nm. This dip coating process was then repeated for a total of two coats per wire. Photoreagents were also photoimmobilized onto parylene C coated stainless steel wire (positive control) and a bare stainless steel wire (negative control) using the above procedure.
Friction testing of the resulting wires was performed in the following manner. Each wire was hydrated in isotonic saline and was pulled between two silicone pads exerting 200 g force on the wire. The grams of pull force exerted on the wire were then measured. Pull force (g) is equal to the coefficient of friction (COF) multiplied by pinch force (g). The pull force was averaged over a 20 cm section and the pulls were repeated 15 times.
No. of Pulls
Pull Force (g)
Parylene C Stainless Steel
H-Siloxane Stainless Steel
H-Siloxane Nitinol
These results indicate that applying H-siloxane to the wires prior to photorimmobilization of photoreagents enables the photoreagents to bind more tightly as compared to wires lacking the H-siloxane intermediate layer (i.e., bare wire).
For bare wire, the grams of pull force increased considerably from pull 1 to pull 15, indicating that the lubricious coating was not well bound to the surface and was coming off easily. In contrast, the wire treated with H-siloxane prior to coating with photoreagents showed no significant change in pull force, indicating a well-bonded lubricious coating. As a positive control, the wire treated with parylene C prior to coating with photoreagents also showed no significant change in pull force. The H-siloxane treatment resulted in improved bonding of the photoreagents, as compared to bare wire.
A methylhydrosiloxane-dimethylsiloxane copolymer was modified to contain a substituted benzophenone.
A reactive, substituted benzophenone was prepared in the following manner. 4-hydroxybenzophenone, 20 g (0.10 mol), was dissolved in 200 ml of acetone with stirring in a round bottom flask equipped with a reflux condenser. Potassium carbonate, 34.86 g (0.25 mol), was added, followed by 13.43 g (0.11 mol) of allyl bromide. The mixture was refluxed gently for 6 hours and stirred overnight at room temperature. The reaction was quenched with water and the product was extracted with chloroform. After washing the combined extracts with brine, the organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the solvent was removed under reduced pressure to give an oil. This residue was dissolved in a minimum amount of chloroform and the solution was passed through a one inch silica gel filter bed using a 1/3 (v/v) hexane/ether solvent as eluant. The filtrate was collected and the solvents were removed under reduced pressure. The oil was again dissolved in a minimal amount of chloroform and treated with 150 ml of ether. The product slowly crystallized as the solution cooled giving a white, crystalline solid after filtration, washing with hexane, and drying. The yield of 4-allyloxybenzophenone was approximately 98.5%.
A methylhydrosiloxane-dimethylsiloxane copolymer containing a photogroup was then prepared in the following manner. Methylhydrosiloxane-dimethylsiloxane copolymer, 20 g (30% methylhydrosiloxane in the copolymer, 85.8 mmoles containing hydride; product no. HMS-301, Gelest Inc., Tullytown, Pa.), was added to a 250 ml round bottom flask. 4-Allyloxybenzophenone, 2.9 g (12.2 mmoles), was dissolved in 150 ml of inhibitor-free tetrahydrofuran and added to the flask. Argon was bubbled through the reaction mixture, followed by the addition of 80 mg of chloroplatinic acid (H2PtCl6-xH2O) dissolved in one milliliter of isopropanol. The argon bubbling was discontinued, the flask lightly capped, and the reaction was stirred with a magnetic stir bar overnight at room temperature. The next morning, the dark yellow reaction solution was filtered through a Celite bed and the solvent was removed under vacuum to give a yellow oil. The product was diluted to 25% solids with isopropanol and stored in a plastic bottle. The result was a H-siloxane copolymer modified so as to contain a substituted benzophenone.
An experiment is described to demonstrate the application of a modified methylhydrosiloxane-dimethylsiloxane copolymer to a stent, followed by photoimmobilization of polyvinylpyrrolidone (PVP) to provide a lubricious, hydrophilic coating.
The methylhydrosiloxane-dimethylsiloxane copolymer containing a substituted benzophenone as prepared in Example 3 is applied to the stent as follows. A stainless steel stent is cleaned and base treated as in Example 1. The stent is dipped into a neat solution of benzophenone modified H-Siloxane and reacted at 150° C. for 30 minutes. The stent is then washed with toluene, 3 times, 5 minutes each wash on an orbital shaker at 100 rpm with toluene. The stent is then air dried. Next, the stent is placed into a 10 mg/ml solution of PVP in H2O. The stent is illuminated with an Oriel Series Q Arc Lamp (Oriel Instruments, Stratford, Conn.) which contains an Osram HBO 100 W/cm2, mercury short arc doped bulb (Germany) to activate the photogroups present in each polymer, and produce covalent bonding to the H-siloxane modified layer. The illumination duration is for 2 minutes at an intensity of 8-10 mW/cm2 in the wavelength range of 330-340 nm to activate the latent benzophenone reaction to photocouple the PVP to the H-siloxane-benzophenone treated stent. The stent is removed and rinsed with deionized water to remove any unbound PVP. The stent is then stained with Congo Red and is evaluated for a uniform coated hydrophilic surface.
Although the present invention has been described in detail, the foregoing description is illustrative of the present invention but not considered to be limiting. Numerous variations and modifications may be effected without departing from the true scope and spirit of the invention, all of that are contemplated as falling within the scope of the appended claims. Unless otherwise indicated, all percentages are by weight.
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Owner name: SURMODICS, INC., MINNESOTA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:ANDERSON, ARON B.;CHAPPA, RALPH A.;EVERSON, TERRENCE P.;REEL/FRAME:009281/0113
Effective date: 19980610
|8 Dic 2004
|Fee payment
Year of fee payment: 4
|4 Dic 2008
|Fee payment
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|5 Dic 2012
|Fee payment
Year of fee payment: 12


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More information
Learn more about your child's right to carry an asthma inhaler or injectable epinephrine at school, including a clickable list of each state's law from the Allergy and Asthma Network/Mothers of Asthmatics website.
SOURCES: Maureen George, Ph.D., R.N., assistant professor, University of Pennsylvania School of Nursing, Philadelphia; Nancy Sander, president, Allergy and Asthma Network/Mothers of Asthmatics
|Copyright©2010 ScoutNews,LLC.
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Celestial-inspired poetry at Misty Valley Books SundayMay 18,2013CHESTER Misty Valley Books will present an evening of celestially-inspired poetry at 7 p.m. Sunday on the green in Chester. The featured poets are Kate Gleason, Becky Sakellariou and Patrice Pinette.
Gleason is the author of a full-length collection of poetry and two chapbooks. Her work has appeared in Best American Poetry and she is a Pushcart Prize nominee.
Pinette was a featured poet in the New Hampshire Poets Showcase and has been published in a number of literary journals and anthologies. Sakellariou was raised in New England and lived her adult life in Greece and her works have been published in several literary journals.
A reception, book signing and stargazing will take place after the readings.
The event is free to the public.
For more information call 875-3400 or visit www.mvbooks.com.MORE IN This Just InMONTPELIER The states highest court has upheld a jury conviction for a Lyndon man charged with... Full StoryST. ALBANS The American Red Cross says it responded to a house fire in St. Full StoryBERLIN- Officials say a school bus was hit by a truck and overturned in Berlin, shortly after... Full Story
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text: When i was a month pregnant things started to change with me and my then fiance (husband now). I lost all sexual interest in him and everything he did was irritating. We broke it off until i decided to keep the baby/ But I started to realize we dont have anything in commen other then sex. We have only had sex once in the last 3 almost 4 months. We decided to get married back in january even though we were not together. I know it doesnt make sense to most people. But he is military and going to afganistan in april. We thought getting married would be best just in case anything happened. Plus I needed the insurance and he needed the housing and extra money. We both are 19 and I feel like we were sercame by puppy love at first. I do love him. But the night we got married we had sex for the 1st time in months and it was horrible. I was so devistated. I called my best friend crying. I know that if it wasnt for this baby we would never have stayed together and probably wouldnt even be talking. He is a good guy. Has a issue with lying and hiding things... especially about financial things. But I just dont know what to do. I feel so trapped sometime. Its acquired between us now. How do I be a supportive wife when i dont even want to sleep in the same bed with him... Has being pregnant changed anyone elses relationships?


text:
ADA Info
Looking for a free way for your family to enjoy the last few days of summer vacation? Join us this Thursday, August 20 at 2:30 pm for a superhero movie! This movie is about a dog with superpowers. Tickets are required. They are free and given out starting 30 minutes before the program. Just a reminder--Freeman is open 1-9 pm on Thursdays.
Love Elvis but can't make it to Graceland this year? Then come in your best Hawaiian print shirt and join us for a showing of the movie "Blue Hawaii" starring the King himself. The movie will be shown Monday, August 10, at 4:00 pm. Hawaiian themed treats will be served!
He overcame adversity and changed the world of medicine. Who is this man Dr. Ben Carson? Growing up in a broken home amongst poverty and prejudice, his grades suffered and his temper flared, and yet his mother never lost her faith in him. We will be showing this movie on Saturday February 21, 2015 at 3:00 pm. Come and enjoy this movie with us.
There is a great national program that is giving a way tickets to see the movie Selma to interested 7th 8th and 9th graders. #SelmaForStudents has gotten a number of movie theaters around the country to give 7th 8th and 9th grade students free tickets to screenings of Selma if they show their student ids at the box office.
Practicing for the Spelling Bee?
Join us for an afternoon movie that will surely entertain you and who knows, maybe you will pick up a few tips as well.
Date: Tuesday, January 20
Time: 4:00 pm
Ages: 12 & older
Rating: PG
Celebrate the chilly weather outside by coming inside the North Channel Library to watch Frozen! We'll be
Book to movie adaptations happen fairly regularly, although nonfiction adaptations are a bit less common. A round of movies based on nonfiction will debut this month. Here's your chance to read (or re-read) the books before they hit the big screen:
MovieYou all know about the Tremendous Tuesdays, right? If you don't, not a problem. I'll tell you. We have something cool planned for the school age children on Tuesdays at 4:30 PM. Now the first Tuesday is Movie Tuesday. So if you like enjoying an amazing and popular movie with your friends, join us for the show on first Tuesday of every month at 4:30 PM. All the movies are rated G or PG.
You will want to bring your friends to see this movie! Recent release, second in popular series.
Call 713-464-1633 for more information. Date: Monday, August 4, 3:00pm, Ages: 13 and older, Rating: PG13. Snacks provided.
Copyright © 2014 Vital Imagery Ltd.
TGIF Programs invites adults of all ages this Friday, March 7 to see a movie. The movie will start at 10:30 AM in the Marge Jacobson Community Room. We will be showing a 1998 adventure film starring Uma Thurman and Ralph Fiennes. Thurman and Fiennes portray two British agents (John Steed and Emma Peel) who team up to stop Sir August De Wynter from destroying the world with a weather changing machine.
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text:
Posted January 29, 2013 on AP on Fox
Greg Oden's next comeback could be with the Cavaliers. A person with knowledge of Cleveland's interest said the team is exploring the possibility of signing Oden, the former No. 1 overall pick whose NBA career has been sabotaged by injuries. The Cavs are doing their due diligence while looking at Oden, said the person who spoke to The Associated Press on condition of anonymity Tuesday because the team's interest is contingent upon the center's health. CBSSports.com first reported the Cavs and Miami Heat were leading the pursuit of Oden, who hasn't played since 2009 and has undergone three microfracture knee surgeries - two on his left knee. Before watching No. 11 Ohio State's 58-49 win over Wisconsin on Tuesday night in Columbus, Ohio, Oden said he hopes to be healthy enough to take another shot at pro ball. ''I don't know when, but I'm taking this year off. I'll play next year,'' said Oden, who led the Buckeyes to the Final Four as a freshman in 2007. Oden's agent, Mike Conle...
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It: Controparte Culturale Fantasy
We don't have an article named It/ControparteCulturaleFantasy. If you want to start this new page, just click the edit button above. Be careful, though, the only things that go in the Main namespace are tropes. Don't put in redirects for shows, books, etc.. Use the right namespace for those.


text:
The Bible Cure for Allergies: Ancient Truths, Natural
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Product Description
Product Information
|Format: Paperback
Number of Pages: 96
Vendor: Siloam
Publication Date: 2000
Dimensions: 6 1/2 X 4 (inches)
Availability: In Stock
Series: Bible Cure
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Author Bio
Dr. Don Colbert is a board-certified family practice medical doctor who specializes in nutritional medicine, treating over 17,000 patients. Since 1984, Dr. Colbert has helped thousands of patients regain good health and live pain free after years of suffering. A graduate of Oral Roberts School of Medicine, he has received extensive training in nutritional medicine. As a result, he has founded and developed his own nutritional supplement line, Divine Health Nutritional Products. Dr. Colbert also co-hosts Golden Eagle Network's "Your Health Matters" with his wife, Mary. They frequently lead health seminars at home and abroad, the address health and nutrition issues as guests on national talk shows and news broadcasts. Don and Mary make their home in Central Florida.


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October 5, 2015 Some colleges give big discounts based on family income. Some don't. Play with Planet Money's interactive graphic to see the average price families pay at 1,550 four-year colleges.
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October 3, 2015 To the three Rs, the schools in the nation's capital have added a fourth: Riding. Bicycles, that is.
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President Obama has selected Deputy Education Secretary John B. King Jr. to replace Arne Duncan. King is a former New York state education commissioner.
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October 2, 2015 John King Jr. is Arne Duncan's deputy and was New York's education commissioner before heading to Washington. Like the man he's replacing, he's no stranger to controversy.
Secretary of Education Arne Duncan takes the stage at North High School in Des Moines, Iowa, on Sept. 14 to discuss college access and affordability.
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October 2, 2015 A list of the major benchmarks of Arne Duncan's seven years in the Obama Administration — and what they mean for what's coming next.
Arne Duncan, U.S. Secretary of Education, will step down in December — after nearly seven years in the job.
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October 2, 2015 After nearly seven years in office, Duncan bows out, leaving behind a remarkable legacy of achievement and controversy.
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Education Secretary Arne Duncan said in a letter to his staff that he will step down to spend more time with his family, who live in Chicago.
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October 2, 2015 Duncan has been with Obama from the beginning of his administration. His tenure has been marked by reform — and controversy over initiatives like Common Core and an embrace of charter schools.
The official graduation numbers that Chicago Mayor Rahm Emanuel touted through his first term and his re-election campaign have been revised.
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October 2, 2015 The school district revised its numbers down 2 to 3 percentage points for every year dating back to 2011.
October 1, 2015 A federal judge has ruled that a child's exposure to traumatic events could lead to disability. The decision allows a case against the Compton Unified School District to move forward.
A brain at play.
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October 1, 2015 Why do we humans like to play so much? Play sports, play tag, play the stock market, play duck, duck, goose? We love it all. And we're not the only ones.
The winning IMPCT team poses with former President Bill Clinton and (at far right) Philip Hult, co-chairman, EF Education First. The team members (from left) are Andres Escobar, Juan Diego Prudot, Taylor Scobbie and An-Nung Chen
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September 30, 2015 The challenge to university students around the world: Come up with a way to provide quality education to slum kids under age 6. And the winner of the $1 million Hult Prize is ...
September 30, 2015 A coalition of colleges and universities aims to level the admissions playing field between rich and poor, and to make the whole process more creative, engaging and less daunting.
Fernando Aguilar plays with his 8-year-old son Isaac. He worries that Isaac isn't enrolled in the gifted and talented program in Houston.
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September 30, 2015 Whites and Asians get most of the spots in the city's gifted and talented program. One researcher describes it as being "segregated by race and income."
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September 29, 2015 A new Vanderbilt University study found that Tennessee's Voluntary Pre-K for low-income children has no lasting benefits, stirring up an age-old debate in education circles.
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September 29, 2015 That's the conclusion of a new poll of 30,000 graduates of four-year colleges.
September 28, 2015 The controversies over gifted education start with identifying who qualifies for that title.
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September 27, 2015 Molly Pollak was a middle and high school teacher. When she retired this year, former students gave her a book filled with their letters. It reads like a textbook for great teaching.
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Jeff Zlotnik leads meditation near the San Diego State University campus. Members of the new fraternity and sorority won't have to be Buddhist, he says; they'll have house rules based on Buddhist teachings, but also normal Greek activities like parties — "hopefully with some mindful behavior and mindful activities and mindful action."
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September 26, 2015 New Buddhist fraternity and sorority houses at San Diego State will have meditation, and will stress compassion. They'll also have typical Greek activities, like parties — with mindfulness mixed in.
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September 24, 2015 Many public school students get 15 minutes or less to eat. A study finds that kids who get less than 20 minutes for lunch end up eating less of everything on their tray.
September 24, 2015 At the annual Schools for Tomorrow conference in New York, some themes stood out: college graduation rates, training teachers and doing more for low-income, high-achieving students.
September 23, 2015 The right text or email message can help students get enrolled, find the right payment plan and remind them to pay, White House research shows.
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text:
Days Inn
Today:Open 24 Hours
11100 New Georges Creek Rd SW,
Frostburg, MD 21532
(301) 689-2050
Hotel Rooms
Secure online booking with Expedia Affliate Network Call 866-761-3335 to book by phone
The room rates listed are double occupancy per room unless otherwise stated and exclude tax recovery charges and service fees.
Business Details
in Business
- Hours:
Regular Hours
- General Info:
Property Location Located in Frostburg, Days Inn And Suites is convenient to Maplehurst Country Club and Noah's Ark. This motel is within close proximity of Frostburg Library and Palace Theater.
Rooms Make yourself at home in one of the air-conditioned guestrooms. Complimentary wireless Internet access keeps you connected, and cable programming is available for your entertainment. Private bathrooms with shower/tub combinations feature complimentary toiletries and hair dryers. Conveniences include safes and coffee/tea makers, as well as phones with free local calls.
Rec, Spa, Premium Amenities Enjoy recreational amenities such as a sauna and a fitness center. This motel also features complimentary wireless Internet access and barbecue grills.
Dining A complimentary continental breakfast is served daily.
Business, Other Amenities Featured amenities include complimentary newspapers in the lobby, a 24-hour front desk, and ATM/banking services. Free self parking is available onsite.
- Extra Phones:
Fax: (301) 689-5933
TollFree: (800) 615-3107
- Services/Products:
- Fitness Center
- Payment method:
- amex, debit, discover, master card, visa
- Location:
- Located in Frostburg, Days Inn And Suites is convenient to Maplehurst Country Club and Noah's Ark. This motel is within close proximity of Frostburg Library and Palace Theater.
Days Inn & Suites Frostburg
Days Inn And Suites
- Other Link:
- Other Email:
- Categories:
- Hotels, Lodging, Motels


text:
The IRCTC stated the Bharat Darshan train will conduct service from Madurai to locations in north India, via Thiruvananthapuram, Kollam, Kottayam, Ernakulam, Thrissur, Shoranur, Palakkad, Podanur, Erode, Salem and Vijayawada.
The trip covers tourist places for example Haridwar, Varanasi, Gaya, Puri, Konark and Visakhapatnam. The train will convey just Bharat Darshan vacationers.
The train will begin from Madurai on May 23, and can go through Kerala on May 24. The price of the tour package is 7,500, comprising non AC sleeper class ticket, non-AC residence, non AC buses for excursion and vegetarian food.
The initial options that come with the package include tourist pads and guards on each one of the 10 coaches, including the kitchen vehicle, sound system for important bulletins, music, and off and on-board catering services. The service no. are Ernakulam:- 04846464849, Thiruvananthapuram:-
For more information visit: http://www.onlinepnrstatus.in/


text: We booked this small Hotel because of the location. very handy to Las Ramblas and the action in the city centre. Our hotel was positioned above a "chic" winebar and opposite a popular Restaurant. The noise was loud and went well into the morning. The rooms are not airconditioned and leaving the window open is not recommended (thieves) and noise.... More


text:
Outdoor Stainless Steel Knife + Bottle Opener + Wrench Tool - Black + Silver
Color: Black + Silver + Multi-Colored Material: Stainless steel Quantity: 1Set Shade Of Color: Black Tools Include: Knife, bottle opener, wrench Other Features: N A
free shipping
(0 Review)
» Multi-Tools
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Multi-functional Stainless Steel Bottle Opener Wrench Screwdriver Rope Cutter Tool - Silver
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(2 Reviews)
Multi-functional Stainless Steel Bottle Opener Wrench Screwdriver Rope Tightener Tool - Silver
Aluminum Alloy Bicycle 15mm Pedal Wrench
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REWIN HCRJ-313 Chrome-Vanadium Steel 2-in-1 13mm Open End + Double Box End Combination Wrench
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(1 Review)
» Wrenches
REWIN RJ-317 Chrome-Vanadium Steel 2-in-1 17mm Open End + Double Box End Combination Wrench
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- Type: Combination Wrench
REWIN RJ-313 Chrome-Vanadium Steel 2-in-1 12mm Open End + Double Box End Combination Wrench
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(3 Reviews)
10-Piece Metal Wrench Tools Set
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EDCGEAR Compact Multifunctional Wrench Tool w/ 4 Screwdriver - Black + Silver
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Portable Stainless Steel Spanner Wrench Lens Repair Tools for DLSR Camera - Silver
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» Maintenance & Tools
Multi-functional Tool Metric Folding Hex Set w/ Open Wrench / Key Chain - Deep Pink + Silver
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LRT-02H Stainless Steel Lens Spanner Wrench Lens Range Repair Tools for SLR DSLR lens - Silver
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Tips: Pointed & Flat tips
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REWIN RJ-319 Chrome-Vanadium Steel 2-in-1 19mm Open End + Double Box End Combination Wrench
11-in-1 Multi-functional Tool SAE Folding Hex Set w/ Open Wrench / Key Chain - Orange + Silver
Color: Orange + Silver Model: RAF-02 Quantity: 1Piece Material: Aluminum + iron
LRT-02C Stainless Steel Lens Spanner Wrench Lens Range Repair Tools for SLR DSLR lens - Silver
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C1658 Portable Stainless Steel Spanner Wrench Lens Repair Tool for DLSR Camera - Silver
pointed tip and one flat tip; Adjustable opening from 5mm to 125mm; Fits grip ring of telescope camera lens, optical lens; Opens grip ring of camera body; Fits some two lens
Stainless Steel Tubular Civil Lock Pick Open Tools - Black + Silver
Model 71127 Quantity 1 piece s per pack Color Black + Silver Material Stainless steel Specification Outer diameter: 9.6mm; inner diameter: 8mm Packing List 1 x Lock open
» Lock Picks and Tools
6" 150mm Spanner Wrench with Measurement Scale
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Copper Open Toilet Paper Tissue Towel Roll Paper Holder - Silver
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Strong Lock Pick Gun Locksmith Tool Door Lock Opener - Blue + Silver
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LWD-GS-181-04 Quick Opening Stainless Steel Lock Picks Tools Set - Blue + Silver
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Stainless Steel Lens Spanner Wrench 8-130mm Lens Range Repair Tools for SLR DSLR lens -Silver
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Multi-function 11-in-1 Stainless Steel Card Style Knife Tool - Silver
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(18 Reviews)
Folding Retractable Desktop Tripod Stand Holder for Microphone - Black
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» Microphone
MM6020 5mW 650nm Red Laser Refile Scope Sight w/ CREE XR-E Q5 White Flashlight - Black
» Gun Scopes & Sights
Multi-function Portable Stainless Steel Card Style Tool Kits - Black (2 PCS)
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(35 Reviews)
HSS Hex Shank Countersunk Drill Bit Tapper Tool Set - Black (6# / 8# / 10# / 12#)
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Stainless Steel 11-in-1 Multi-Functional Tool Card (2-Pack)
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(197 Reviews)
» Other Instruments
Genuine LEGO Star Wars A-wing Starfighter 75003
features 4 flick missiles, opening cockpit and removable engine Weapons include a blaster pistol Accessories include mug and a wrench Collect the A-wing pilot helmet, being
» Anime & Movie Figures
SAHOO 23824 Steel Alloy Crank Removal Tool Kit for Bike - Silver
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Fotopro X4i-E Outdoor Travel Aluminum-Magnesium Alloy Telescopic Tripod for SLR Camera
cm Certification CE Other Features 5-section telescopic design, easily hang onto your bag; Portable and convenient; 23 68 88 degrees opening angles, to suit different
» Tripods & Holders
NexTool KT5006A Multifunction Sea Horse Style Stainless Steel Keychain Tool - Silver
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AML020134 Stainless Steel Saw Rake Lock Picking Tools Set - Dark Grey + Silver (3 PCS)
of quality stainless steel; Lightweight and portable; Can open most crescent locks Packing List 3 x Lock picks 1 x Z-shape torsion wrench
Fotopro M-5 Folding 4-Section Portable Tripod for SLR Camera - Black
tripod can achieve the minimum height; Four-section retractable, easily open and tighten; Comes with shoulder band which prevents camera falling down; Easy to carry; Suitable
G002 Compact Portable Outdoor Multifunction Emergency Kit Tools - White (6 PCS)
ruler bottle opener 4 position wrench butterfly wrench saw blade direction ancillary indication 2 position wrench lanyard hole key ring hole ; The fretsaw can use for single
AML020125 7-in-1 Aluminum Alloy Auto Car Lock Picking Scope w/ 2-LED Set - Blue (1 x AAA)
Model AML020125 Quantity 1 Color Blue Material Aluminum alloy + stainless steel Specification Able to open most of the car and house locks; The blue handle is made of
Elegant Water Resistant IR Surveillance Security Camera with 36-LED Night Vision - White (8mm Lens)
wrench, mounting screws & English manual
- Widely used for theft prevention, home, office & public places security etc.
» CCTV Cameras
Anti-Explosion Fixed Focus 1/4 Sharp CCD Security Camera w/ 24-LED IR Night Vision (3.6mm Lens)
security etc.
- Comes with 4 x mounting screws, 1 x wrench and 1 x Chinese manual
FEREI B5 Water Resistant 4-Mode 480-Lumen Memory LED White Bike Light w/ CREE MC-E / Battery Pack
x AC 100~240V power adapter 2-flat-pin plug 1 x Velcro nylon strap 1 x Wrench 1 x Chinese English manual
» Bike Lights
Ultrafire Stainless Steel Bottle Opener (with Screw Driver and Wrench Tools)
The bottle opener is completely stainless steel construction. The opener is with cross screw driver and wrench tools for other function. The opener is convenient to
(67 Reviews)
Multi-Purpose Strap Wrench Bottle Opener (Random Color)
- Material: Plastic + rubber
- Rubber strap fits most objects of any shape to loosen, tighten or hold without surface damage
- Ideal for oil filters, jar lids, and plumb
» Opener & Stopper
Rewin Open End Spanner Wrench Set - Silver (8-Piece)
- Color: Silver
- Model: HCRB-K5524
- Material: High carbon steel
- Double-ended wrench set
- Package includes: 22x24 + 19x22 + 17x19 + 17x14 + 14x12 + 10x12 + 8x10 + 7x
GUB HIN-181 Portable Bicycle Stainless Steel Repair Tool Kit Wrench Set - Black
: 2 2.5 3 4 5 6 8mm hex wrench, PH2 SL5 T25 screwdriver, chain cutter Best Use Cycling Packing List 1 x Bike repair wrench set
keith KR1302 8,10,12mm Wrench Ruler Bottle Opener Flat Screwdriver Tool - Silver
Color: Silver Grey Brand: keith Model: KR1302 Quantity: 1Piece Material: Titanium Best Use: Mountaineering , Travel , Cycling , Family & car camping Carabiner type: Other
Pro'skit HW-7509B Open-end Wrenches Kit - Silver (9 PCS)
Open-end Wrenches 1 x Canvas bag
EDCGEAR Multi-functional Bottle Opener Hex Wrench Key Chain - Silver
Color: Silver Brand: EDCGEAR Model: N A Quantity: 1Piece Material: Stainless steel
AOTDDOR D92 Multifunctional Stainless Steel Hex Wrench / Screwdriver / Bottle Opener Tool - Silver
Color: Silver Brand: AOTDDOR Model: D92 Quantity: 1Piece Material: Stainless steel
Tench Wrench Quick Opener for China WangLi Mini Locks
Manufacturer's product descriptions: - This tench wrench can be used to open WangLi Mini Lock technically.
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text:
Things to see and do - Rome
Leaving for Italy
Rome :
Unmissable tourist sites
Where to sleep?
Rome Hotel tips
Hotel Cosmopolita from99 €Book
Hotel Trecento from150 €Book
Hotel Mancino 12 from150 €Book
Rome Leisure tips
Rome Walking Tour and Cooking Class
- 72.0 €
- Book
Skip the Line: Borghese Gallery and Gardens Walking Tour
- 48.0 €
- Book
- 130.0 €
- Book
Reports Rome
Results 1 to 2 on 2
Rome's Colosseum hosts new historical exhibition
Piazza del Colosseo I I - 00184 Roma Rome
Tourists visiting the Colosseum in Rome can now sample an extra slice of history. The "Roma Caput Mundi" exhibition has opened inside the monument and explores the historical and political expansion of the ancient city.
[to know more]
Pizzarium and Roman pizza
I - Rome
In Rome, pizza lays claim to a specific identity. It is available not only in numerous classic establishments, but also "by the slice" in hundreds of little shops.
[to know more]


text:
Dwyane Wade: LeBron James Is On Michael Jordan's Level, But Still Has More Work To Do
With a ring, three MVPs and a whole bunch of other achievements under LeBron James' belt, many a...
Miami Heat shooting guard Dwyane Wade says James is already on the level, but the debate seems premature.
"He's on that level," Wade told Ira Winderman of the South Florida Sun-Sentinel, "but he has a lot more to do to get there. I think he understands he has an unbelievable opportunity to be one of the greatest to play this game. But that's when he gets done playing, he can say that.
"Right now, he has so much more to cover in his career. He's just getting started at the same time when Michael kind of just got started. We'll see how it all shakes out. I hope it shakes out the same way. I'll be a very happy man."
Wade has a solid point here. James is still in his prime, and at 27, he still has a lot of years left in his career. Maybe after a decade or so, we can come to a solid conclusion on where James stands among the greats, or maybe just next to MJ.
Josh Dhani is the founder of FootBasket. You can read more about him at his website. Follow him on Twitter @joshdhani.