text:
|Publication number
|Publication type
|Application number
|Publication date
|Mar 17, 2005
|Filing date
|Jul 19, 2004
|Priority date
|Aug 5, 1999
|Publication number
|Ed Roschak, Loc Phan, Patrick Massetti
|Original Assignee
|Ed Roschak, Loc Phan, Massetti Patrick John
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (99), Referenced by (35), Classifications (74), Legal Events (1)
|External Links: USPTO, USPTO Assignment, Espacenet
This application is a continuation in part of U.S. patent application Ser. No. 10/633,902 filed on Aug. 4, 2003 which is continuation of application Ser. No. 09/633,651 now U.S. Pat. No. 6,692,494B1 which is a non-provisional of 60/147,528 filed Aug. 5, 1999 and a non-provisional of 60/176,141 filed Jan. 14, 2000. This application is also a continuation-in-part of U.S. patent application Ser. No. 10/458,085, filed Jun. 9, 2003. The entirety of each of the above are hereby incorporated by reference.
The American Lung Association (ALA) estimates that nearly 16 million Americans suffer from chronic obstructive pulmonary disease (COPD) which includes diseases such as chronic bronchitis, emphysema, and some types of asthma. The ALA estimated that COPD was the fourth-ranking cause of death in the U.S. The ALA estimates that about 14 million and 2 million Americans suffer from emphysema and chronic bronchitis respectively.
Those inflicted with COPD face disabilities due to the limited pulmonary functions. Usually, individuals afflicted by COPD also face loss in muscle strength and an inability to perform common daily activities. Often, those patients desiring treatment for COPD seek a physician at a point where the disease is advanced. Since the damage to the lungs is irreversible, there is little hope of recovery. Most times, the physician cannot reverse the effects of the disease but can only offer treatment and advice to halt the progression of the disease.
To understand the detrimental effects of COPD, the workings of the lungs requires a cursory discussion. The primary function of the lungs is to permit the exchange of two gasses by removing carbon dioxide from arterial blood and replacing it with oxygen. Thus, to facilitate this exchange, the lungs provide a blood gas interface. The oxygen and carbon dioxide move between the gas (air) and blood by diffusion. This diffusion is possible since the blood is delivered to one side of the blood-gas interface via small blood vessels (capillaries). The capillaries are wrapped around numerous air sacs called alveoli which function as the blood-gas interface. A typical human lung contains about 300 million alveoli.
The air is brought to the other side of this blood-gas interface by a natural respiratory airway, hereafter referred to as a natural airway or airway, consisting of branching tubes which become narrower, shorter, and more numerous as they penetrate deeper into the lung. Specifically, the airway begins with the trachea which branches into the left and right bronchi which divide into lobar, then segmental bronchi. Ultimately, the branching continues down to the terminal bronchioles which lead to the alveoli. Plates of cartilage may be found as part of the walls throughout most of the airway from the trachea to the bronchi. The cartilage plates become less prevalent as the airways branch. Eventually, in the last generations of the bronchi, the cartilage plates are found only at the branching points. The bronchi and bronchioles may be distinguished as the bronchi lie proximal to the last plate of cartilage found along the airway, while the bronchiole lies distal to the last plate of cartilage. The bronchioles are the smallest airways that do not contain alveoli. The function of the bronchi and bronchioles is to provide conducting airways that lead air to and from the gas-blood interface. However, these conducting airways do not take part in gas exchange because they do not contain alveoli. Rather, the gas exchange takes place in the alveoli which are found in the distal most end of the airways.
The mechanics of breathing include the lungs, the rib cage, the diaphragm and abdominal wall. During inspiration, inspiratory muscles contract increasing the volume of the chest cavity. As a result of the expansion of the chest cavity, the pleural pressure, the pressure within the chest cavity, becomes sub-atmospheric. Consequently, air flows into the lungs and the lungs expand. During unforced expiration, the inspiratory muscles relax and the lungs begin to recoil and reduce in size. The lungs recoil because they contain elastic fibers that allow for expansion, as the lungs inflate, and relaxation, as the lungs deflate, with each breath. This characteristic is called elastic recoil. The recoil of the lungs causes alveolar pressure to exceed atmospheric pressure causing air to flow out of the lungs and deflate the lungs. 'If the lungs' ability to recoil is damaged, the lungs cannot contract and reduce in size from their inflated state. As a result, the lungs cannot evacuate all of the inspired air.
In addition to elastic recoil, the lung's elastic fibers also assist in keeping small airways open during the exhalation cycle. This effect is also known as "tethering" of the airways. Tethering is desirable since small airways do not contain cartilage that would otherwise provide structural rigidity for these airways. Without tethering, and in the absence of structural rigidity, the small airways collapse during exhalation and prevent air from exiting thereby trapping air within the lung.
Emphysema is characterized by irreversible biochemical destruction of the alveolar walls that contain the elastic fibers, called elastin, described above. The destruction of the alveolar walls results in a dual problem of reduction of elastic recoil and the loss of tethering of the airways. Unfortunately for the individual suffering from emphysema, these two problems combine to result in extreme hyperinflation (air trapping) of the lung and an inability of the person to exhale. In this situation, the individual will be debilitated since the lungs are unable to perform gas exchange at a satisfactory rate.
One further aspect of alveolar wall destruction is that the airflow between neighboring air sacs, known as collateral ventilation or collateral air flow, is markedly increased as when compared to a healthy lung. While alveolar wall destruction decreases resistance to collateral ventilation, the resulting increased collateral ventilation does not benefit the individual since air is still unable to flow into and out of the lungs. Hence, because this trapped air is rich in CO2, it is of little or no benefit to the individual.
Chronic bronchitis is characterized by excessive mucus production in the bronchial tree. Usually there is a general increase in bulk (hypertrophy) of the large bronchi and chronic inflammatory changes in the small airways. Excessive amounts of mucus are found in the airways and semisolid plugs of this mucus may occlude some small bronchi. Also, the small airways are usually narrowed and show inflammatory changes.
Currently, although there is no cure for COPD, treatment includes bronchodilator drugs, and lung reduction surgery. The bronchodilator drugs relax and widen the air passages thereby reducing the residual volume and increasing gas flow permitting more oxygen to enter the lungs. Yet, bronchodilator drugs are only effective for a short period of time and require repeated application. Moreover, the bronchodilator drugs are only effective in a certain percentage of the population of those diagnosed with COPD. In some cases, patients suffering from COPD are given supplemental oxygen to assist in breathing. Unfortunately, aside from the impracticalities of needing to maintain and transport a source of oxygen for everyday activities, the oxygen is only partially functional and does not eliminate the effects of the COPD. Moreover, patients requiring a supplemental source of oxygen are usually never able to return to functioning without the oxygen.
Lung volume reduction surgery is a procedure which removes portions of the lung that are over-inflated. The portion of the lung that remains has relatively better elastic recoil, providing reduced airway obstruction. The reduced lung volume also improves the efficiency of the respiratory muscles. However, lung reduction surgery is an extremely traumatic procedure which involves opening the chest and thoracic cavity to remove a portion of the lung. As such, the procedure involves an extended recovery period. Hence, the long term benefits of this surgery are still being evaluated. In any case, it is thought that lung reduction surgery is sought in those cases of emphysema where only a portion of the lung is emphysematous as opposed to the case where the entire lung is emphysematous. In cases where the lung is only partially emphysematous, removal of a portion of emphysematous lung which was compressing healthier portions of the lung allows the healthier portions to expand, increasing the overall efficiency of the lung. If the entire lung is emphysematous, however, removal of a portion of the lung removes gas exchanging alveolar surfaces, reducing the overall efficiency of the lung. Lung volume reduction surgery is thus not a practical solution for treatment of emphysema where the entire lung is diseased. Moreover, conventional lung volume reduction surgery is an open surgical procedure which carries the risk of surgical complications and requires a significant period of time for recuperation.
Both bronchodilator drugs and lung reduction surgery fail to capitalize on the increased collateral ventilation taking place in the diseased lung. There remains a need for a medical procedure that can alleviate some of the problems caused by COPD. There is also a need for a medical procedure that alleviates some of the problems caused by COPD irrespective of whether a portion of the lung, or the entire lung is emphysematous. The production and maintenance of collateral openings through an airway wall allows air to pass directly out of the lung tissue responsible for gas exchange. These collateral openings serve to decompress hyper inflated lungs and/or facilitate an exchange of oxygen into the blood.
Methods and devices for creating and maintaining collateral channels are discussed in U.S. patent application Ser. No. 09/633,651, filed on Aug. 7, 2000; U.S. patent application Ser. Nos. 09/947,144, 09/946,706, and 09/947,126 all filed on Sep. 4, 2001; U.S. Provisional Application No. 60/317,338 filed on Sep. 4, 2001; U.S. Provisional Application No. 60/334,642 filed on Nov. 29, 2001; U.S. Provisional Application No. 60/367,436 filed on Mar. 20, 2002; and U.S. Provisional Application No. 60/374,022 filed on Apr. 19, 2002 each of which is incorporated by reference herein in its entirety.
Although creating an opening through an airway wall may overcome the shortcomings associated with bronchodilator drugs and lung volume reduction surgery, various problems can still arise. When a hole is surgically created in tissue the healing cascade is triggered. This process is characterized by an orderly sequence of events, which can be broadly classified into distinct phases. These phases proceed in a systematic fashion, with a high degree of integration, organization, and control. However, the various stages are not sharply delineated, but overlap considerably, and factors affecting one phase have a stimulatory or inhibitory effect on the overall process.
The result of this wound healing process is tissue proliferation that can occlude or otherwise close the surgically created opening. Additionally, in the event an implant is deployed in the surgically created opening to maintain the patency of the opening, the implant may become encapsulated or filled with tissue thereby occluding the channel.
Drug eluting coronary-type stents are not known to overcome the above mentioned events because these stents are often substantially cylindrical (or otherwise have a shape that conforms to the shape of a tubular blood vessel). Hence, they may slide and eject from surgically created openings in an airway wall leading to rapid closure of any channel. Additionally, the design and structure of the coronary-type stents reflect the fact that these stents operate in an environment that contains different tissues when compared to the airways not to mention an environment where there is a constant flow of blood against the stent. Moreover, the design of coronary stents also acknowledges the need to place the stent within a tubular vessel and avoid partial re-stenosis of the vessel after stent placement so that blood may continue to flow. In view of the above, implants suited for placement in the coronary are often designed to account for factors that may be insignificant when considering a device for the airways.
Not surprisingly, experiments in animal models found that placement of coronary drug eluting stents (i.e., paclitaxel drug eluting vascular stents and sirolimus drug eluting stents) into the airway openings did not yield positive results in maintaining the patency of the opening. The shortcomings were both in the physical structure of the stent which did not lend itself to the airways as well as the inability of those drug eluting devices to control the healing cascade caused by creation of the channel. The majority of these devices filled with tissue at an early stage and an inspection of the remainder of the implanted devices indicated imminent closure.
An understanding of the distinctions between the healing response in the coronary versus the airways may explain this outcome. For purposes of our discussion, the healing response in both the coronary and the lungs may be divided into approximately four stages as measured relative to the time of the injury: 1) acute phase; 2) sub-chronic phase; 3) chronic phase; and 4) late phase.
In the coronary, after trauma caused by the placement of a coronary stent, the healing process begins in the acute phase with thrombus and acute inflammation. During the sub-chronic phase, there is an organization of the thrombus, an acute/chronic inflammation and early neointima hyperplasia. In the following chronic phase, there is a proliferation of smooth muscle cells along with chronic inflammation and adventitial thickening. In the late stage of the healing process there is chronic inflammation, neointimal remodeling, medial hypertrophy and adventitial thickening.
Based upon the observations in a rabbit model, the healing response in the airway begins with a fibrinous clot, edema hemorrhage, and fibrin deposition. In the sub-chronic phase there is re-epithelialization, mucosal hypertrophy, squamous metaplasia, fibroplasias and fibrosis. In the chronic phase, while the epithelium is intact and there is less mucosal hypertrophy, there is still fibroplasia and fibrosis. In the late stage the respiratory epithelium is intact and there is evidence of a scar.
Accordingly, the unique requirements of the airways and collateral channels calls for specific features for any implant used in collateral channels. For example, these implants/conduits are often placed across three different tissue zones; namely the parenchyma, the newly sectioned airway wall, and the interior of the airway surface. Each different zone may have a different reaction to the presence of the implant/conduit. The parenchyma may build up a layer of scar tissue around the conduit, which may eventually eject the implant or block the air path on the parenchyma side of the conduit. The airway wall may undergo a healing response as a result of the trauma of the procedure. This healing response and associated tissue growth may restrict air-flow through the implant. Furthermore, mucus from the airways may deposit in to the conduit thereby further occluding the conduit.
In addition, placement of an implant or conduit within the collateral channel may present additional structure requirements for the devices. For example, surgeons often use radiological imaging to place coronary stents within the vasculature. In most cases, placement of coronary stents is critical so that the ends of the coronary stent straddle the vascular obstruction. In contrast, a surgeon placing an implant in collateral channels is often using a remote access device such as a bronchoscope or endoscope that allows for direct observation of the device during placement. For proper placement of the implant, and in cases where it is important to "sandwich" the airway wall, it is necessary to identify the center and/or edges of the conduit or implant prior to expansion of the device. It follows that failure to properly place the implant may result in detachment of the implant (via insufficient attachment to the airway wall), pneumothorax (if the implant is advanced too distally and breaches the pleural cavity), or deployment of the implant wholly in the lung parenchyma exterior to the airway wall. Accordingly, such devices may require a visual indicator to assist the medical practitioner during placement and to offer a measure of safety so that the device is not improperly advanced/deployed thus creating additional complications.
Accordingly, there remains a need for devices and methods that specifically address the requirements discussed herein.
The devices and methods described herein serve to maintain the patency of a channel surgically created in an organ such as an airway wall. In particular, the devices and methods are suited for placement within a channel created within the airway wall and prevent closure of the channel such that air may flow through the channel and into the airway.
It is noted that the devices and methods described herein have particular use for individuals having emphysema and COPD. However, the devices and methods could also benefit any individuals having hyperinflation of the lungs.
Delivery devices for delivering the implants and/or creating the opening are described in U.S. Provisional Application No. 60/488,33, filed Jul. 18, 2003, the entirety of which is herein incorporated by reference.
Implants of the present invention may include a support member having a structure that is adapted for placement within a wall of a body organ, especially an airway wall.
When used in the lungs implants of the present invention modifies he healing response of the lung tissue (e.g., at the site of newly created hole/channel) for a sufficient time until the healing response of the lung tissue subsides or reduces such that the hole/channel becomes a persistent air path. For example, the implant and bioactive substance will modify the healing response for a sufficient time until the healing response is reduced and, from a visual observation, the body treats the opening essentially as a natural airway passage rather than as an injury to the airway wall.
Variations of the invention include implants having compositions comprising a polymer which either serves as a carrier for the agent or as a delivery barrier for the agent. In those variations of the implant used in the airways, the composition may provide a steady release rate of bio-active substance as well as have a sufficient amount of available bio-active substance to modify the healing response of the lung tissue. As described herein, such a delivery system takes advantage of the tissue environment surrounding the airways.
The antiproliferative agent of the present invention is one that modifies a healing response. Various agents are discussed below, examples include a microtubule stabilizing agent such as taxol or paclitaxel, or a microtubule destabilizing agent such as vincristine, vinblastine, podophylotoxin, estramustine, noscapine, griseofulvin, dicoumarol, a vinca alkaloid, or a combination thereof. Furthermore, the agent may include steroids, non-steroidal anti-inflammatories, rapamycin, dactinomycin, sirolimus, everolimus, Abt-578, tacrolimus, and a combination thereof. It is noted that the composition or implant may also include additional substance as required by the location of the implant. Such substances may affect/suppress mucus production, provide protection against bacteria, or maintain sterility of the implant site or surrounding tissue. It is contemplated that the bio-active substances listed herein includes all forms of the substances (e.g., analogs, derivatives, salt forms and crystalline forms.)
Variations of the invention also may include visualization features which provide assistance when attempting to place the implant from within an organ and having no or little direct visibility outside of the organ.
The invention may also include additional features such as valves within the implant to regulate flow or provide a protective barrier.
This application is also related to the following application 60/420,440 filed Oct. 21, 2002; 60/387,163 filed Jun. 7, 2002; Ser. No. 10/235,240 filed Sep. 4, 2002; Ser. No. 09/947,144 filed Sep. 4, 2001; Ser. No. 09/908,177 filed Jul. 18, 2001; Ser. No. 09/633,651 filed Aug. 7, 2000; and 60/176,141 filed Jan. 14, 2000; Ser. No. 10/080,344 filed Feb. 21, 2002; Ser. No. 10/079,605 filed Feb. 21, 2002; and Ser. No. 10/280,851 filed Oct. 25, 2002. Each of which is incorporated by reference herein. Accordingly, where not inconsistent with the principles described herein, features and aspects of the invention may be combined with the various implants and conduits described in the above related applications.
Described herein are devices (and methods) for improving the gas exchange in the lung. In particular, methods and devices are described that serve to maintain and extend the patency of collateral openings or channels through an airway wall so that air is able to pass directly out of the lung tissue and into the airways. This facilitates exchange of oxygen into the blood and decompresses hyper inflated lungs.
By "channel" it is meant to include, but not be limited to, any opening, hole, slit, channel or passage created in the tissue wall (e.g., airway wall). The channel may be created in tissue having a discrete wall thickness and the channel may extend all the way through the wall. Also, a channel may extend through lung tissue which does not have well defined boundaries such as, for example, parenchymal tissue.
Although not shown, the airway comprises an internal layer of epithelial pseudostratified columnar or cuboidal cells. Mucous secreting goblet cells are also found in this layer and cilia may be present on the free surface of the epithelial lining of the upper respiratory airways. Supporting the epithelium is a loose fibrous, glandular, vascular lamina propria including mobile fibroblasts. Deep in this connective tissue layer is supportive cartilage for the bronchi and smooth muscle for the bronchi and bronchioles.
As noted above, the implant is suited for placement about an opening in the wall of an organ. In some cases, the implant is suited to placement in an organ having a thin wall. Through observation, applicants noted that airway wall thickness is fairly proportional to the diameter of the airway lumen by approximately a factor of ⅙. While the invention is not limited to use in any particular sized airway, on average the implant is placed in airways ranging from 3 mm to 15 mm in diameter with respective airway wall thicknesses of 0.5 mm to 2.5 mm. Therefore, in many variations of the invention, the implant 200 and associated tissue retaining members 226 and 228 will be suitable to retain itself on the relatively thin airway wall tissue.
As described below, the implants of the present invention include a support member and a composition that maintain patency of the channel. Variations of the invention include support members selected from a mesh or woven structure either of which are comprised of a metal alloy (e.g., stainless, a shape-memory alloy, etc.), a polymer, a ceramic, or a combination thereof. The support member provides a structure that mechanically maintains patency of the channel as well as provides a delivery means for the composition or other substances as described herein. It is specifically noted that while the variations of the present invention are suited for use in the airways, the invention is not limited to such applications. Rather, the variations of the present invention may be used in various applications as appropriate.
In those cases where the implant 200 of
The implants of
The implant described herein may be manufactured by a variety of manufacturing processes including but not limited to laser cutting, chemical etching, punching, stamping, etc. For example, the implant may be formed from a tube that is slit to form extension members and a center section between the members. One variation of the implant may be constructed from a metal tube, such as stainless steel, 316L stainless steel, titanium, tantalum, titanium alloy, nitinol, MP35N (a nickel-cobalt-chromium-molybdenum alloy), etc. Also, the implant may be formed from a rigid or elastomeric material that is formable into the configurations described herein. Also, the implant may be formed from a cylinder with the passageway being formed through the implant. The implant may also be formed from a sheet of material in which a specific pattern is cut. The cut sheet may then be rolled and formed into a tube. The materials used for the implant can be those described above as well as a polymeric material, a biostable or implantable material, a material with rigid properties, a material with elastomeric properties, or a combination thereof. If the implant is a polymeric elastic tube (e.g. a thermoplastic elastomer), the implant may be extruded and cut to size, injection molded, or otherwise formed.
Additionally, the implants described herein may be comprised of a shape memory alloy, a super-elastic alloy (e.g., a NiTi alloy), a shape memory polymer, or a shape memory composite material. The implant may be constructed to have a natural self-assuming deployed configuration, but is restrained in a pre-deployed configuration. As such, removal of the restraints (e.g., a sheath) causes the implant to assume the deployed configuration. A implant of this type could be, but is not limited to being, comprised from an elastic polymeric material, or shape memory material such as a shape memory alloy. It is also contemplated that the implant could comprise a shape memory alloy such that, upon reaching a particular temperature (e.g., 98.5� F.), it assumes a deployed configuration.
The implant's surface may be modified to affect tissue growth or adhesion. For example, an implant may comprise a smooth surface finish in the range of 0.1 micrometer to 0.01 micrometer. Such a finish may serve to prevent the implant from being ejected or occluded by tissue overgrowth. On the other hand, the surface may be roughened or porous. The implant may also comprise various coatings and polymeric layers as discussed below.
As discussed above, the implants of the present invention may include a composition or polymeric layer that includes a bio-active substance or combination of bioactive substances. In some cases, the implant itself may be formed from a polymeric composition or a polymer having the bio-active substance; The purpose of the composition is to assists in modifying the healing response as a result of the trauma to lung tissue resulting from creation of the collateral channel. The term lung tissue is intended to include the tissue lining the airway, the tissue beneath the lining, and the tissue within the lung but exterior to the airway (e.g., lung parenchyma.) In modifying the healing response it is fundamentally desirable to further the patency of the channel to allow sufficient flow of trapped gasses through the implant into the airways. A discussion of the bio-active substances is found below.
The composition may comprise a polymeric layer which acts as a carrier for various bioactive or other agents as described herein. Alternatively, or in combination, the polymeric layer may function as a tissue barrier to inhibit growth of tissue into the conduit/implant. In an additional variation, the support member may be fabricated from a polymeric material having the bio-active substance incorporated directly therein. The composition 212 prevents tissue in-growth from occluding the collateral channel or passage of the implant 200. The polymeric layer 212 may coaxially cover the center section from one end to the other or it may only cover one or more regions of the implant 200. The composition 212 may completely or partially cover the implant 200. The composition 212 may be located about an exterior of the implant's surface, about an interior of the implant's surface.
Alternatively, or in combination, as shown in
The composition should be selected to accommodate the significant expansion of the implant. Examples of such polymers include, but are not limited to, thermoplastic polymers, thermoset polymers, acrylate polymers, a blend of acrylate-methacrylate polymers, silicone elastomers, urethane elastomers, ethylene vinyl acetate polymers, polyethylene, polypropylene, PLA-PGA, PLA, PGA, polyorthoester, polycapralactone, polyester, hydrogels, polystyrene, co-polymers of styrene-isobutylene-styrene, and combinations or blends thereof.
Examples of bioabsorbable polymers include but are not limited to poly(L-lactic acid), polycaprolactone, poly(lactide-co-glycolide), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester, polyanhydride, poly(glycolic acid), poly(D,L-lactic acid), poly(glycolic acid-co-trimethylene carbonate), polyphosphoester, polyphosphoester urethane, poly(amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate), copoly(ether-esters) (e.g., PEO/PLA), polyalkylene oxalates, polyphosphazenes and biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic acid. Also, biostable polymers with a relatively low chronic tissue response such as polyurethanes, silicones, fluorosilicones, and polyesters could be used. Also, hydrogels may be used to carry the drug.
Examples of other types of polymers that may be useful include but are not limited to polyolefins, polyisobutylene and ethylene-alphaolefin copolymers; acrylic polymers and copolymers, vinyl halide polymers and copolymers, such as polyvinyl chloride; polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene halides, such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile, polyvinyl ketones; polyvinyl aromatics, such as polystyrene, polyvinyl esters, such as polyvinyl acetate; copolymers of vinyl monomers with each other and olefins, such as ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetate copolymers; polyamides, such as Nylon 66 and polycaprolactam; alkyd resins, polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxy resins, polyurethanes; rayon; rayon triacetate; cellulose, cellulose acetate, cellulose butyrate; cellulose acetate butyrate; cellophane; cellulose nitrate; cellulose propionate; cellulose ethers; and carboxymethyl cellulose. It may be possible to dissolve and cure (or polymerize) these polymers on the implant so that they do not leach into the tissue and cause any adverse effects on the tissue.
The coatings may be applied, for example, by either dip coating, molding, spin-coating, painting, transfer molding or liquid injection molding. Alternatively, the polymeric layer may be a tube of a material and the tube is placed either over and/or within the implant. The polymeric layer may then be bonded, crimped, heated, melted, shrink fitted or fused to the implant. The polymeric layer may also be tied to the implant with a filament of, for example, a suture material.
Still other techniques for attaching the polymeric layer include: solvent swelling applications and extrusion processes; wrapping a sheet of material about the implant, or placing a tube of the material about the implant and securing the tube to the implant. The polymeric layer may be secured on the interior of the implant by positioning a sheet or tube of material on the inside of the center section and securing the material therein.
The composition may also be formed of a fine mesh with a porosity or treatment such that tissue may not penetrate the pores. For example, a ChronoFlex™ DACRON� or TEFLON� mesh having a pore size of 100-300 microns may be saturated with collagen or another biocompatible substance. This construct may form a suitable polymeric layer. The mesh may be coaxially attached to a frame such as the open frame structures disclosed above. Still other suitable frames include a continuous spiral metallic or polymeric element.
Bioactive Substances:
As discussed above, the bio-active substance or combination of bioactive substances is selected to assists in modifying the healing response as a result of the trauma to the lung tissue resulting from creation of the collateral channel. As noted above, the term lung tissue is intended to include the tissue lining the airway, the tissue beneath the lining, and the tissue within the lung but exterior to the airway (e.g., lung parenchyma.) The purpose of modifying the healing response is to further extend the patency of the channel or implant to increase the duration which trapped gasses may exit through the implant into the airways. The term antiproliferative agent is intended to include those bioactive substances that directly modify the healing response described herein.
The bioactive substances are intended to interact with the tissue of the surgically created channels and in particular, lung tissue. These substances may interact with the tissue in a number of ways. They may, for example, 1.) accelerate cell proliferation or wound healing to epithelialize or scar the walls of the surgically-created channel to maintain its patent shape or 2.) the substances may inhibit or halt tissue growth when a channel is surgically created through an airway wall such that occlusion of the channel due to tissue overgrowth is prevented. Additionally, other bioactive agents may inhibit wound healing such that the injury site (e.g., the channel or opening) does not heal leaving the injury site open and/or inhibit infection (e.g., reduce bacteria) such that excessive wound healing does not occur which may lead to excessive tissue growth at the channel thereby blocking the passageway.
A variety of bioactive substances may be used alone or in combination with the devices described herein. Examples of bioactive substances include, but are not limited to, antimetabolites, antithrobotics, anticoagulants, antiplatelet agents, thorombolytics, antiproliferatives, antinflammatories, agents that inhibit hyperplasia and in particular restenosis, smooth muscle cell inhibitors, growth factors, growth factor inhibitors, cell adhesion inhibitors, cell adhesion promoters and drugs that may enhance the formation of healthy neointimal tissue, including endothelial cell regeneration. The positive action may come from inhibiting particular cells (e.g., smooth muscle cells) or tissue formation (e.g., fibromuscular tissue) while encouraging different cell migration (e.g., endothelium, epithelium) and tissue formation (neointimal tissue).
Still other bioactive agents include but are not limited to analgesics, anticonvulsives, anti-infectives (e.g., antibiotics, antimicrobials), antineoplastics, H2 antagonists (Histamine 2 antagonists), steroids, non-steroidal anti-inflammatories, hormones, immunomodulators, mast cell stabilizers, nucleoside analogues, respiratory agents, antihypertensives, antihistamines, ACE inhibitors, cell growth factors, nerve growth factors, anti-angiogenic agents or angiogenesis inhibitors (e.g., endostatins or angiostatins), tissue irritants (e.g., a compound comprising talc), poisons (e.g., arsenic), cytotoxic agents (e.g., a compound that can cause cell death), various metals (silver, aluminum, zinc, platinum, arsenic, etc.), epithelial growth factors or a combination of any of the agents disclosed herein.
Examples of agents include pyrolitic carbon, titanium-nitride-oxide, taxanes, fibrinogen, collagen, thrombin, phosphorylcholine, heparin, rapamycin, radioactive 188Re and 32P, silver nitrate, dactinomycin, sirolimus, everolimus, Abt-578, tacrolimus, camptothecin, etoposide, vincristine, mitomycin, fluorouracil, or cell adhesion peptides. Taxanes include, for example, paclitaxel, 10-deacetyltaxol, 7-epi-10-deacetyltaxol, 7-xylosyl-10-deacetyltaxol, 7-epi-taxol, cephalomannine, baccatin III, baccatin V, 10-deacetylbaccatin III, 7-epi-10-deacetylbaccatin III, docetaxel.
Of course, bioactive materials having other functions can also be successfully delivered in accordance with the present invention. For example, an antiproliferative agent such as methotrexate will inhibit over-proliferation of smooth muscle cells and thus inhibit restenosis. The antiproliferative is desirably supplied for this purpose until the tissue has properly healed. Additionally, localized delivery of an antiproliferative agent is also useful for the treatment of a variety of malignant conditions characterized by highly vascular growth. In such cases, an implant such as a implant could be placed in the surgically created channel to provide a means of delivering a relatively high dose of the antiproliferative agent directly to the target area. A vasodilator such as a calcium channel blocker or a nitrate may also be delivered to the target site. The agent may further be a curative, a pre-operative debulker reducing the size of the growth, or a palliative which eases the symptoms of the disease. For example, tamoxifen citrate, Taxol� or derivatives thereof. Proscar�, Hytrin�, or Eulexin� may be applied to the target site as described herein.
Variations of the invention may also include fibrinolytics such as tPA, streptokinase, or urokinase, etc. Such fibrinolytics prevent or reduce the accumulation of fibrin within the opening. Accumulation of fibrin in the opening may result from inflammation of the tissue. The fibrin may form a structure which makes it easier for tissue to grow into the opening using the fibrin structure as a framework. Use of fibrinolytics, either topically, locally, or on the implant, serves to remove or hinder the network of fibrin from forming within the opening (or implant) and therefore aids in modifying the healing response.
In the event that poisonous and toxic compounds are delivered, they should be controlled to avoid substantial cytotoxicity so that inadvertent death of tissue does not occur, pneumothorax, unacceptable systemic levels, etc. The poisonous agent should be delivered locally or only be effective locally. One method for delivering the bioactive agent locally is to associate the bioactive agent with an implant. For example, the implants described herein may include a bioactive substance or medicine deposited onto the interior, the exterior, or both the interior and exterior surfaces of the implant. The bioactive substance may remain on the implant so that it does not leach. Cells that grow into the surgically created channel contact the poison and die. Alternatively, the bioactive agent may be configured to gradually elute as discussed below.
When used in the lungs, the implant modifies the healing response of the lung tissue (e.g., at the site of newly created hole/channel) for a sufficient time until the healing response of the lung tissue subsides or reduces such that the hole/channel becomes a persistent air path. For example, the implant and bioactive substance will modify the healing response for a sufficient time until the healing response is reduced and, from a visual observation, the body treats the opening essentially as a natural airway passage rather than as an injury to the airway wall.
To illustrate the above,
In one variation of the invention which modifies the healing response as describe above, the implant provides a steady release rate of bio-active substance as well as has a sufficient amount of available bio-active substance to modify the healing response of the lung tissue. As noted herein, the term lung tissue is intended to include the tissue lining the airway, the tissue beneath the lining, and the tissue within the lung but exterior to the airway (e.g., lung parenchyma.) Such a delivery profile allows for a concentration gradient of drug to build in these tissues adjacent to the delivery site of the implant.
It is believed that forming the concentration gradient affects the healing response of the lung tissue so that the implant does not become occluded as a result of the healing response. Because the implant is often placed in the airway wall it is exposed to the healing process of the multiple tissues. Providing a sufficient amount of bio-active substance allows for the formation of a concentration of the bio-active substance across these various tissues. In one variation of the invention it is believed that the fluids from these tissues enter into the composition layer of the device. The fluids then combine with the bio-active substances and migrate out of the composition layer to settle into the lung tissue. A concentration gradient forms when the drug 'saturates' local tissue and migrates beyond the saturated tissues. Furthermore, by providing a sufficient delivery rate, the healing response may be affected or suppressed during the critical time immediately after the wounding caused by creation of the collateral channel when the healing response is greatest.
To select a proper combination of drug and polymer, it is believed that the solubility parameter of the polymer must be matched with the bio-active substance to provide an acceptable slow elution rate from the polymer. Next, the polymer itself must be selected to have the proper attributes, such as a proper diffusion coefficient (to slow fluid entering and departing from the implant), and proper mechanical expansion properties (to allow for the significant expansion of the polymer to accommodate formation of the grommet shape.)
The solubility parameter is defined as the square root of the cohesive energy of the molecules in a compound. The level of control that a polymer has over the elution of a drug is the difference between the solubility parameters of the polymer and the solubility parameter of the drug. To select a polymer with the approximate diffusion a polymer with a high internal density could be selected to be less permeable to a complex molecule such as paclitaxel. Using a polymer with high internal density also accommodated the significant expansion required of the polymer to form the structure necessary to grommet about the airway wall. An example of the polymer selection is found below.
It is also important to note that paclitaxel is a taxane that is regarded as a microtubule stabilizer. The benefits of a microtubule stabilizing substance for use in vascular drug eluting stents is discussed, for example, in U.S. Pat. No. 5,616,608 to Kinsella et al. This type of drug operates to enhance microtubule polymerization which inhibits cell replication by stabilizing microtubules in spindles which block cell division. In contrast to the vascular applications, the implant for use in the present invention may use microtubule stabilizing substances such as taxanes (e.g., paclitaxel) as well as those microtubule destabilizing substances that are believed to promote microtubule disassembly in preventing cell replication. Such destabilizing substances include, but are not limited to vincristine, vinblastine, podophylotoxin, estramustine, noscapine, griseofulvin, dicoumarol, a vinca alkaloid, and a combination thereof.
Additionally, the exterior surface of the implant may be treated via etching processes or with electrical charge to encourage binding of the bioactive substances to the implant. The exterior surface may also be roughened to enhance binding of the medicine to the surface as discussed in U.S. Patent Application Publication No. 2002/0098278. See also U.S. Patent Application Publication Nos. 2002/0071902, 2002/0127327 and U.S. Pat. No. 5,824,048 which discuss various techniques for coating medical implants.
Although the implant may comprise a frame or body with a bioactive matrix disposed or otherwise associated therewith, the invention is not so limited. In one variation, the support member is formed from a polymer and the composition is joined to the polymeric support member. Alternatively, the bioactive substances may be placed directly onto the polymeric support member.
Various additional substances may be used incorporated into the device to reduce an adverse reaction resulting from possible contact with the implant and the airway wall. Adverse reactions include, but are not limited to, granulation, swelling, and mucus overproduction. These substance may may also be inhaled, injected, orally applied, topically applied, or carried by the implant. These substances may include anti-inflammatory, infection-fighting substances, steroids, mucalytics, enzymes, and wound healing-accelerating substances. Examples of these substances include but are not limited to, acetylcysteine, albuterol sulfate, ipratropium bromide, dornase alfa, and corticosteroids.
As noted above, conventional vascular drug eluting devices are not designed for exposure multiple tissue environments. Moreover, those devices are placed in an environment where a constant flow of blood creates an environment requiring a different delivery mechanism and rate. As noted herein, experiments with conventional coronary drug eluting implants demonstrated that such devices were unsuitable.
It is important to note that, to obtain data and histology, applicants terminated QT-304 at 7 weeks (42 days), QT-362 at 12 weeks, and QT-345 at 18 weeks. Yet, based on the trend and closure of the devices, full closure would have occurred soon after 7 weeks for all devices in QT-304. In contrast, based on the stabilization of both the trend and relative patency of the devices in QT-362 and QT-345, patency of the devices in these trials would have extended well beyond the respective 12 and 18 weeks. In the above protocols, patency of the implants were determined visually using a bronchoscope advanced to the implant site.
Visualization Feature
As discussed above, when placed into an airway wall, the implant of the present invention is usually placed using a bronchoscope under direct visualization. In such a procedure, the direct visualization only permits viewing of the interior of the airway and care must be taken to place the implant such that during expansion, the implant properly deploys about the airway wall. Also, care must be taken not to advance the implant/delivery catheter too far into the opening into the airway wall. Improper advancing of the implant/delivery catheter could potentially result in a pneumothorax.
To address the above problem, as illustrated in previous figures, the implant 200 may also includes a visualization mark 218. The visualization marker 218 is visually apparent during a procedure and gives the medical practitioner an indication when the implant/delivery catheter is advanced to the proper location. In this manner, the visualization mark 218 facilitates alignment and deployment of the implants into collateral channels.
The visualization mark 218 may be a ring of biocompatible polymer and may be selected to provide contrast so that it may be identified as the medical practitioner views the device through a endoscope or bronchoscope. For example, the bronchoscope will usually contain a light-source that illuminates the target area. Therefore, the visualization mark may be something that reflects or refracts the light in a different manner from the remainder of the implant. In one variation, the visualization mark may be the same color as the remainder of the device, or partially transparent, or entirely transparent, but is identifiable because the mark reflects or refracts light differently than the remainder of the device. Also, the visualization feature may protrude from the center section or it may be an indentation(s). The visualization mark may also be a ring, groove or any other physical feature on the implant. Moreover, the visualization feature may be continuous or comprise discrete segments (e.g., dots or line segments).
The visualization feature may be made using a number of techniques. In one example, the mark is a ring formed of silicone and is white. The polymeric ring may be spun onto the polymeric layer. For example, a clear silicone barrier may be coated onto the implant such that it coaxially covers the implant. Next, a thin ring of white material such as a metal oxide suspended in clear silicone may be spun onto the silicone coating. Finally, another coating of clear silicone may be applied to coat the white layer. The implant thus may include upwards of 1-3 layers including a polymeric layer, a visualization mark layer, and a clear outer covering. In another example the mark is a ring formed of silicone and is black. In another example the mark is a ring formed by suspending gold particulates in the polymer as shown in
The shape of the visualization mark is not limited to a thin ring. The visualization mark may be large, for example, and cover an entire half of the implant as shown in
In most variations of the invention, the visualization mark is made to stand out when viewed with, for example, an endoscope. The implants may also have additional imaging enhancing additives to increase non-direct imaging, such as fluoroscopic or radioscopic viewing It is also contemplated that other elements of the implant can include visualization features such as but not limited to the extension members, polymeric layer, control segments, etc.
In some variations of the invention, it was found that incorporation of a bioactive or other substance into the coating caused a coloration effect in the composition layer (e.g., the polymer turns white). This coloration obscures the support member structure in the layer making it difficult to identify the edges and center of the support member or implant. As discussed herein, placement of the implant may depend upon positioning the center of the implant within the opening in tissue. If the support member structure is identifiable, then one is able to visually identify the center of the implant. When the composition colors obscures the support member or renders the implant otherwise opaque, it may become difficult to properly place the device. This may be especially true when the composition layer extends continuously over the support member.
Additionally, the coloration may render the visualization mark difficult to identify especially under direct visualization (e.g., using a scope) In some cases it was undesirable to simply add additional substances on or in the composition layer for marking because such substances could possibly interfere with the implant's ability to deliver the substance as desired. To address these issues, a variation of the invention includes a delivery device for delivering an the implant (such as those described herein and in the cases referenced herein), where the delivery device and the implant are of different visually identifiable colors or shades such that they distinction is easy to identify under endoscopic or bronchoscopic viewing. Such a feature permits identification of the proximal end of implant and assists in preventing too much advancement of the implant into the tissue beyond the airway wall.
In one example, as shown in
In another variation, the visualization mark may comprise providing a contrast between the implant and a delivery catheter. In one example because the implant appears mostly white and is mounted delivery catheter, it is difficult to identify the location of implant under visualization. In this example the implant would be placed over a blue colored catheter. The proximal and distal areas of the implant would be flanked by the blue color, thus giving the appearance of a distinct distal and proximal end of the implant. This would allow a physician to place the implant properly by using the blue flanks as a guide for placing the central white portion in the tissue wall. Similarly, a colored flexible sheath covering the catheter would also suffice.
It is noted that while the visualization features described above are suitable for use with the implants described herein, the inventive features are not limited as such. The features may be incorporated into any system where placement of an implant under direct visualization requires clear identification of the implant regardless of whether the implant is opaque or colored.
Valves and Barriers within Implants
The implants may further comprise various structures deposited within the passageway. For example, as shown in
One example of the one-way valve 224 is a valve as shown in
Additionally, a valve could be used to prevent fluid such as mucus from flowing into the passage and into the parenchyma. Such a valve could be configured and could operate similarly to the one described above for gas flow.
The above illustrations are examples of the invention described herein. Because of the scope of the invention, it is specifically contemplated that combinations of aspects of specific embodiments or combinations of the specific embodiments themselves are within the scope of this disclosure.
Implants comprising stainless steel mesh frame fully encapsulated with a composition comprising silicone (as described below) and paclitaxel were implanted in several canine models. Visual observation indicated that, on average, the passage through the implants of the present invention remained unobstructed and were associated with significantly reduced fibrotic and inflammatory responses, in canine models, at a considerably higher rate than an implant without any drug adjunct or coronary drug eluting stents (as shown in
The composition comprised approximately a 9% paclitaxel to silicone ratio with approximately 400 micrograms of paclitaxel per implant. Measurements found that approximately 30% of the paclitaxel released after 60 days. In general, for implants with the paclitaxel/silicone composition, observations of chronic inflammation, epithelial metaplasia and fibrosis were all very mild.
For paclitaxel as the bioactive substance, polymers with solubility parameters between 5-25 (MPa) {circumflex over ( )} � were believed to provide sufficient elution rates. The polymer used in the example device has good diffusivity for lipophilic drug (such as paclitaxel) because the side methyl group on the silicone may be substituted with more lipophilic hydrocarbon molecules containing vinyl group or groups for polymerization by platinum catalyst.
The composition for the example may be as follow: polymer part: polydimethylsiloxane, vinyldimethyl terminated, any viscosity; and/or polydimethylsiloxane, vinylmonomethyl terminated, any viscosity. The cross-linker part: polydimethylsiloxane, any viscosity; and/or polymonomethylsiloxane, any viscosity. Platinum catalyst part and/or cross-linker part: platinum; and/or platinum-divinyltetramethyldisiloxane complex in xylene, 2-3% Pt; and/or platinum-divinyltetramethyldisiloxane complex in vinyl terminated polydimethylsiloxane, 2-3% Pt; and/or platinum-divinyltetramethyldisiloxane complex in vinyl terminated polydimethylsiloxane, ˜1% Pt; platinum-Cyclovinylmethylsiloxane complex, 2-3% Pt in cyclic vinyl methyl siloxane.
These components may be combined in different ratios to make the polymer. The hydrocarbon side chain off the silicone back bone makes this polymer system unique and may result in a "zero-order"-like release profile. The amount of vinyl siloxane cross-linker may determine the rate of the drug release and diffusivity of the polymer to the drug. There are other types of polydimethylsiloxanes such as: trimethylsiloxy terminated polydimethylsiloxane in various viscosities, (48-96%) dimethyl (4-52%) diphenylsiloxane copolymer in various viscosities, dimethylsiloxane-ethylene oxide copolymer, dimethyl diphenylsiloxane copolymer, polymethylhydrosiloxane, trimethylsilyl terminated at various viscosities, (30-55%) methyldro-(45-70%) dimethylsiloxane copolymer at various viscosities, polymethylphenylsiloxane, polydimethylsiloxane silanol terminated at various viscosities, polydimethylsiloxane aminopropyldimethyl terminated at various viscosities. For paclitaxel a release profile was found to be acceptable with a polymer system consisting of polydimethylsiloxane vinyl terminated at various viscosity and a range of platinum-mono, di, tri and/or tetramethyldisiloxane complex.
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|Jun 3, 2014
|Holaira, Inc.
|Delivery devices with coolable energy emitting assemblies
|Jun 28, 2013
|Jul 15, 2014
|Holaira, Inc.
|Delivery devices with coolable energy emitting assemblies
|Jun 18, 2007
|Oct 21, 2014
|Cook Medical Technologies Llc
|Self-cleaning stent
|Nov 11, 2010
|Dec 16, 2014
|Holaira, Inc.
|Non-invasive and minimally invasive denervation methods and systems for performing the same
|Sep 26, 2011
|Jan 13, 2015
|Holaira, Inc.
|Delivery devices with coolable energy emitting assemblies
|Sep 26, 2011
|Apr 14, 2015
|Holaira, Inc.
|Delivery devices with coolable energy emitting assemblies
|Jun 28, 2013
|Apr 28, 2015
|Holaira, Inc.
|Delivery devices with coolable energy emitting assemblies
|Jun 9, 2003
|Apr 15, 2004
|Broncus Technologies, Inc.
|Methods and devices for maintaining patency of surgically created channels in tissue
|Apr 27, 2004
|Nov 11, 2004
|Don Tanaka
|Localized pleurodesis chemical delivery
|May 20, 2004
|Dec 2, 2004
|Don Tanaka
|Methods and devices to assist pulmonary decompression
|May 24, 2004
|Dec 9, 2004
|Don Tanaka
|Intra-thoracic collateral ventilation bypass system
|Jun 30, 2004
|Feb 3, 2005
|Don Tanaka
|Methods and devices to accelerate wound healing in thoracic anastomosis applications
|Oct 15, 2004
|Mar 3, 2005
|Broncus Technologies, Inc.
|Methods for treating chronic obstructive pulmonary disease
|Jul 19, 2004
|Mar 17, 2005
|Broncus Technologies, Inc.
|Methods and devices for maintaining surgically created channels in a body organ
|Nov 1, 2004
|May 5, 2005
|Broncus Technologies, Inc.
|Methods for treating chronic obstructive pulmonary disease
|Sep 28, 2004
|Jun 23, 2005
|Broncus Technologies, Inc.
|Devices for maintaining surgically created openings
|Oct 22, 2004
|Jun 23, 2005
|Michael Biggs
|Devices for maintaining surgically created openings
|U.S. Classification
|623/23.65, 424/424, 623/23.7
|International Classification
|Cooperative Classification
|European Classification
|Mar 3, 2005
Owner name: BRONCUS TECHNOLOGIES, INC., CALIFORNIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:ROSCHAK, ED;PHAN, LOC;MASSETTI, PATRICK;REEL/FRAME:016322/0391
Effective date: 20041013


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Warsaw, the capital of Poland, was severely damaged by bombs and shells during the Second World War. Fortunately, this has not caused the city to lose much of its grandeur.
The River Vistula divides the city of Warsaw into two different parts. The district on the left bank is more attractive to tourists, with the modern city centre and the Old Town. The Old Town is lively and atmospheric, full of outdoor cafés and surrounded by mediaeval fortified walls.
Warsaw suffered greatly during the Second World War. Many historic buildings were destroyed, including the magnificent Warsaw Royal Castle. Fortunately, this castle has been renovated and it is now once again accessible to the public. Visitors can wander through magnificent royal chambers, such as the Marble Room, the Throne Room and the Ballroom and enjoy works from the early Baroque, Gothic and Rococo periods. The oldest monument in Warsaw is the statue of King Sigismund II Wasa. Also worth a visit is the market square, which is surrounded by beautiful mansions, alternating with cafés and restaurants.

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Get longer, thicker, bouncier hair with hair plus! Clinically proven to increase hair growth up to 123% in just 28 days! European-made, specially formulated shampoo and conditioner stimulate growth while giving hair a healthier, more lustrous look. Rich in Keratin, soy proteins, Vitamin B6 and emollients, the shampoo and conditioner when used together strengthen and protect hair, plus increase growth, gloss, texture. 8-1/2 oz. ea.
Welcome to Harriet Carter - Distinctive Gifts Since 1958. Find a large selection of products for organizing your life, as well as As Seen On TV products, household gadgets and problem solvers, unique gifts and gift ideas. Buying online is the fastest and most convenient way to shop! We have created this website just for you; everything is arranged by product category for quick, easy selection. In addition to our selection of gift ideas, you'll find products for organizing, As Seen On TV items, New Arrivals, Web Exclusive Gifts, Household Gadgets and products for your Pets.
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Commemorate the UConn Huskies as the 2014 NCAA Men's and Women's Basketball Champions with this framed collectible. Each piece comes designed with both 2014 Final Four logos, both tournament schedules, laser-cut team logo, and a descriptive plate. Each collectibles contains a piece of game-used basketball (not from any specific game or event) from the 2013-14 men and women's championship season. It has suede matting and is framed in black wood. It measures 23.5'' x 27.5'' x 1'' and comes ready to hang in your home or office. The product is officially licensed by the CLC and the University of Connecticut. This collectible is a limited edition of 100.
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Berlin '36
Based on the true story of Gretel Bergmann who unwittingly became the biggest threat to the Nazi Party in 1936. Berlin was hosting the summer Olympic Games and Gretel was one of Germany's best gold medal contenders. She was also Jewish. Her skill and ethnicity undermined the Nazi belief that Aryans were the superior race, so the German authorities schemed to replace Gretel with another woman -- but "she" had a secret that, if uncovered, could be even more embarrassing to the Nazis.
Cast: Karoline Herfurth, Axel Prahl, August Zirner, Sebastian Urzendowsky, Maria Happel
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Directed by: Kaspar Heidelbach
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Running time: 1hr 50min
Opens: Sep 16, 2011 NY/LA
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The Grace Card
Everything can change in an instant ... and take a lifetime to unravel. When Mac McDonald loses his son in an accident, years of bitterness and pain erode his love for his family and leave him angry with God ... and everyone else. Can Mac and his new patrol partner, Sgt. Sam Wright, somehow join forces to help one another when it's impossible to look past their differences -- especially the most obvious one? Every day, we have the opportunity to rebuild relationships and heal wounds by extending and receiving God's grace. Offer "The Grace Card" ... and never underestimate the power of God's love.
Cast: Louis Gossett Jr., Cindy Hodge, Mike Higgenbottom, Rob Erickson, Michael Joiner
Produced by:
Directed by: David G. Evans
Written by: Howard Klausner
Running time: 1hr 41min
Opens: Feb 25, 2011 Limited
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Looking for a safe alternative to Teflon that still packs a punch in the kitchen? GreenPan produces high-quality cooking items that are non-stick without the sketchiness. Its cookware incorporates Thermolon, a mineral-based non-stick coating that's free of dangerous chemicals and won't blister, peel, or release toxic fumes, even at temperatures as high as 850°F. This easy-to-clean professional braiser was crafted from hard anodized aluminum and stainless steel.
No plastic synthetics in coating. 100% PTFE and PFOA free. Made with upcycled materials. Producing this item creates 60% less CO2 emissions than the production of a comparable PTFE-coated piece.
Allow cookware to cool and clean thoroughly after each use. Plunging a hot pan into water can cause irreparable warping. To preserve the non-stick coating, hand-washing in warm, soapy water is recommended. Do not clean with steel wool, nylon scrubbing pads, abrasive cleansers, or bleach.
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Directed by: Robert Siodmak
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I am using opentripplanner for an app development. I want to customize the webapp. It has many different maplayers (its using openlayers). I want to change some mapslayers, but i couldn't find in which java-script file they are creating map and maplayers.
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Whether or not you're pumped for the Super Bowl, chances are you'll find yourself on a bar stool or a house party this Sunday — there are worse ways to spend the evening. But in case you have yet to determine where you're going to hang or what you're going to bring, we've rounded up 10 options for football fun.
Looking for something a little more creative than a pot of chili? Pick up one of the whole animal packages from Frontier. Not only will you have enough ham sandwiches to feed your entire team, you might even have leftovers, to boot. If heading out into all of the chaos is more of your thing, Untitled offers a slightly alternative viewing party than your tradish sports bar. Watch the game on a huge projector screen while enjoying 1920s-inspired game-day eats like oyster dip with house-made salt and vinegar chips and a special punch that is guaranteed to get you to work about an hour late the next day. You heard us say it; heed our warning.
So, click through and start making your plans and placing those catering orders. Lest you end up on your couch with a bag of chips.
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Recipe by J Scholfield
"Great way to serve asparagus, and yummy too."
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1 pound
asparagus, trimmed
1 teaspoon
olive oil
1/4 teaspoon
ground black pepper
2 tablespoons
grated Parmesan cheese
fresh lemon, cut into wedges
We love roasted asparagus. I don't know if the initial steaming (blanching) is really necessary. We like our asparagus on the crisp side though.
In my opinion, steaming the asparagus before roasting it is not only an inconvenient, unnecessary step that uses more pans, but it may even result in overcooking the asparagus once it finally makes it to the 475 degreee oven. I roasted mine in a 400 degree oven alongside the fish I prepared for dinner. Both were done in 15 minutes (as a point of reference my asparagus were on the thicker side) For a seasoning twist I used Penzey's Chicago Steak Seasoning instead of just ground pepper. Easier and five-star excellent if simply roasted in the oven, period.
14 Ratings
I did not bother messing with the steam step. I just layered the asparagus on the baking sheet and followed the rest of the instructions as listed. I did add a sprinkling of salt. I did bake mine just a touch longer--almost 15 minutes. Pretty good. No leftovers--what my family did not eat, I did.
Delicious! Only thing I did was add the lemon juice before baking, because I like my asparagus green. Other than that, this one's a keeper!
So delicious! Did NOT steam the asparagus....just roasted it. Squeezed the fresh lemon over the asparagus after it was roasted and that gave an awesome fresh flavor. My family inhaled this veggie last night and I ws glad I mande 2 bunches because it was gone. Skip the steaming and go right to roasting....you wont regret it. Thanks!
This was an absolute success. I normally have leftovers, not tonight. I used some tips from other people who made this. I baked it at 475 for about 12 minutes and then broiled it for about 4 minutes. I added the lemon juice prior to cooking and it kept that vibrant green color. I added a little salt as well. I did skip the steaming as we prefer a little crunch to our asparagus. This is a wonderful recipe and I will make it again. Thanks for the recipe and thanks for the tips.
I made this recipe two ways - one with the blanching, as written and one without. Really cannot see a reason to blanch. The taste is there, and the Parmesan cheese is a nice touch.
I make this all the time only I add 4pcs minced bacon and 1 tbsp garlic and only a touch of oil to kick this up a notch. You can skip the steaming step all togeher.
* Percent Daily Values are based on a 2,000 calorie diet.
Roasted Parmesan Asparagus
Serving Size: 1/4 of a recipe
Servings Per Recipe: 4
Amount Per Serving
Calories: 44
Calories from Fat: 18
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Reflexite IMO/SOLAS FD1403 (M82) Marine Microprismatic Retroreflective Conspicuity Tape is a tough weather and solvent resistant product designed for rugged outdoor maritime use. It is compliant with U.S. Department of Transportation specification USCG 46 CFR, section 164.018 and International Maritime Organization (IMO) Resolution A.658(16). The approval is for Type I and Type II. IMO/SOLAS (Safety Of Life At Sea) FD1403 (M82) reflective material is composed of cube corner (microprism) retroreflective elements integrally bonded to a flexible, smooth-surfaced tough and weather resistant UV stabilized polymeric film. The prism surfaces are to provide a mirror surface to the prism facets. The resulting film is not more than 0.008" thick, and comes coated with an aggressive pressure sensitive adhesive. Designed to withstand the marine environment, FD1403 survives continuous immersion in seawater, sub-freezing temperatures, and intense exposure to sunlight, guano and harsh weather. Ideal for rigid and flexible applications such as dayboards, buoys and channel markers. High-brightness Reflexite material is visible at distances of more than one kilometer. Rolls ship on a plain white core since cut from log roll material.
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Offers the widest range of application flexibility available. Exhibits excellent processing performance whether manually or automatically applied. Has superior tensile strength, adhesion properties and holding force which ensures consistent, reliable seals. Hot melt adhesive will bond faster to a surface which is referred to as quick-grab or quick-stick. It typically has higher tack (will feel stickier to the touch), but is also softer. It has lower heat resistance, shear resistance, and sometimes UV resistance than an acrylic adhesive. NOTE: it is called hot melt because the adhesive is applied hot by the manufacturer and then hardens as it cools (you do not need to apply heat to the tape yourself).
Properties are similar to that of hot melt rubber, but natural rubber often holds where other adhesives won't (recycled fibers, dust, cold, heat and heavy loads). It provides good overall adhesion and moisture resistance.
Offer excellent performance, especially for applications in temperatures less than 40°F and greater then 120°F. It provides excellent clarity, has high shear strength, is usually more permanent/durable even when exposed to moisture, and it ages well over extended periods in fluorescent and sunlight. Since it remains clear for the life of the application and does not yellow over time it is ideal for applications such as sealing white cartons. While it has good initial adhesion it does take 24-48 hours to cure and to achieve its maximum bond strength (has gradual adhesion buildup). Another difference between hot melt rubber and acrylic adhesive is if you fold tape over making the two adhesive sides touch the acrylic adhesive will remain attached to the carrier (e.g. paper, film) while a hot melt adhesive will stick to itself and pull off of the carrier. It is the best choice for clarity, UV resistance and aging characteristics.
Is great for extreme temperature applications since silicone adhesive can work in continuous operating temperatures from -100°F to 500°F. They also exhibit good chemical resistance, retain electrical properties, and remove cleanly with little or no residue.
Zinc oxide based adhesive formula is a skin-friendly adhesive which is commonly used on sports medicine tapes.
Examples: 1/16 inch = 62.5 mils; 1/32 inch = 31.25 mils
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EnviroTech :: Sustainability
Informex Lines up Industry-changing Green Chemistries
2:51 AM MST | January 31, 2011 | Alex Scott
Informex USA, one of the country's key specialty and fine chemical expos, for the second year running will host a sustainable technology competition at the show. All sustainability award entries are now in and judging has been completed. The competition's results will be announced at the show, in Charlotte, NC, which begins February 7. Judging was based on scope and extent, environmental benefits, and economic feasibility. Fifteen or so entries were considered. This is a similar number of entries that were submitted for consideration at the inaugural...
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Key COSMIC resources
High quality curation by expert postdoctoral scientists
Additional tools to explore COSMIC
Further details on using COSMIC's content
Coding mutation consequence (most severe), as predicted by the VEP
The COSMIC Genome Browser displays all mutation information across all cancers and has been enhanced in v73 to include ENCODE regulatory features and all available SNPs.
Genome browsing by disease is now available via our Cancer Browser.
For more details, please see the datasheet.
Full literature curation across 9 genes are newly included in this release of COSMIC:
SPEN - RNA binding co-regulatory protein.
IKBKB - NF-κB signalling pathway protein.
MYOD1 - nuclear protein, transcription factor.
KDM5C - chromatin modulating tumour suppressor gene.
ACVR1 - type 1 activin receptor.
ESR1 - oestrogen receptor alpha.
CDKN2C - cyclin-dependent kinase inhibitor.
COL2A1 - Collagen, type II, alpha 1 gene.
CACNA1D - L-type voltage-gated calcium channel.
For more details, please see the datasheet.
• Curated Genes; 9 new fully curated genes.
• Cancer Gene Census; 67 gene symbols updated.
• New genomes; From full literature curation of 26 Systematic Screen papers and from ICGC release 18.
• COSMIC Genome Browser; added dbSNP, SNPs and ENCODE regulatory feature tracks, and a new browser for tissue/cancer types.
• Mutation Impact filters; Upgraded to FATHMM-MKL scores.
• Cell Lines Project; 267 Tissue/histology classifications updated.