text:
|Publication number
|Publication type
|Application number
|Publication date
|Dec 14, 2006
|Filing date
|Jun 1, 2006
|Priority date
|Sep 4, 2001
|Also published as
|Publication number
|Edmund Roschak, Loc Phan
|Original Assignee
|Broncus Technologies, Inc.
|Export Citation
|BiBTeX, EndNote, RefMan
|Referenced by (20), Classifications (15), Legal Events (1)
|External Links: USPTO, USPTO Assignment, Espacenet
This application is a non-provisional of U.S. Provisional Application No. 60/686,848, filed Jun. 1, 2005, and is also a continuation-in-part of U.S. patent application Ser. No. 10/895,010, filed on Jul. 19, 2004 which is a continuation-in-part of U.S. patent application Ser. No. 10/235,240, filed on Sep. 4. 2002 which is a non-provisional of U.S. Provisional Application No. 60/317,338, filed on Sep. 4, 2001. 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 hyperinflated 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 restenosis 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, and U.S. patent application Ser. No. _______ entitled DEVICES FOR MAINTAINING PATENCY OF SURGICALLY CREATED CHANNELS IN TISSUE, and filed on Jul. 19, 2004, the entirety of both are 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 modify 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.
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.
It is contemplated that though the invention includes a combination of support member and bioactive substance, it is noted that the structural configurations of several, if not all, of the support members provide unique advantages that lend themselves to use in securing the implant about a wall of an organ. Therefore, it is further contemplated that the structural configurations may also provide inventive embodiments without the bioactive substance.
This application is also related to the following applications 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 grommet or hour-glass shape will be suitable to retain itself on the relatively thin airway wall tissue. In forming this shape, a variation of the implant 200 shrinks in axial length as it secures itself within the channel. Shrinking in axial length may also provide additional benefit as it reduces the length of the implant 200 that extends into the airway. This reduction in length may prevent unwanted tissue damage to the airway wall and/or occlusion of the airway.
In additional variations of the invention, the implant 200 must not only capture relatively thin tissue, but must also maintain a minimum internal diameter to allow sufficient air flow. For example, a fewer number of implants may be used given a sufficiently large diameter. In such cases it is undesirable for the implant 200 to constrict in internal diameter as it forms the non-cylindrical shape. In other variations, the entire implant is expandable, but a portion of the implant 200 expands to a greater amount as compared to a remainder of the implant. Such a configuration allows for the entire implant 200 to expand while still forming a non-cylindrical shape.
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 steel, titanium, 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.
A composition 212, as described herein, is located on the implant. The composition 212 may encapsulate the support member 202, or it may be located on an exterior or interior surface. Alternatively, it may be located between or within the intensities of the support member 202.
The variation of the support member 202 illustrated in
The variation of the implant 200 shown in
The length of the implants of the present invention will depend upon their intended site of implantation. Variations of implants may have lengths ranging from between 2-20 mm. Furthermore, although the figures illustrate the proximal and distal portions of the implant as being symmetric about its center, the implant is not limited to such a configuration.
Furthermore, the implant of the present invention may have any number of extension members on each end device. The number of extension members on each end may range from 2-10. Also, the number of proximal extension members may differ from the number of distal extension members for a particular implant. The extension members may be symmetrical or non-symmetrical about the center section. The proximal and distal extension members may also be arranged in an in-line pattern or an alternating pattern. The extension members or the center section may also contain barbs or other similar configurations to increase adhesion between the implant and the tissue. The extension members may also have openings to permit tissue in-growth for improved retention.
Control Members:
Variations of the implant 200, as seen in shown in
The control members 210 assist the implant 200 in assuming a uniform non-cylindrical expanded shape. For example, as a balloon expands the implant 200 there will be variation in the amounts of expansion of various cells (i.e., where a cell is typically defined by an area surrounded by a number of joined struts—as an example refer to
Typically, one end of the control segment 210 is attached or joined to one location (e.g., a first rib) and the other end of the center-control segment is connected to a second location (e.g., a rib adjacent or opposite to the first rib). However, in alternate variations, the center-control segments may have other constructs. For example, the center-control segments may connect adjacent or non-adjacent center section members. Further, each center-control segment may connect one or more ribs together. The center-control segments may further be doubled up or reinforced with ancillary control segments to provide added control over the expansion of the center section. The ancillary control segments may be different or identical to the primary control segments.
Referring back to
As shown in
The variation of
In any variation of the invention, the control segments, as with other components of the implant, may be added or mounted to the implant or alternatively, they may be integral with the implant. That is, the control segments may be part of the implant rather than separately joined to the implant with adhesives or welding, for example. The control segments may also be mounted exteriorly or interiorly to the members to be linked. Additionally, sections of the implant may be removed to allow areas of the implant to deform more readily. These weakened areas provide another approach to control the final shape of the deployed implant. Details for creating and utilizing weakened sections to control the final shape of the deployed implant may be found in U.S. Pat. No. 09/947,144 filed on Sep. 4, 2001 which is hereby incorporated by reference in its entirety.
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.
Also, the implant described herein may be formed of a plastically deformable material such that the implant is expanded and plastically deforms into a deployed configuration. The implant may be expanded into its expanded state by a variety of devices such as, for example, a balloon catheter.
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. One purpose of the composition is to assist in modifying the healing response as a result of the trauma to lung tissue resulting from creation of the collateral channel. The composition may also serve other purposes as well. For example, the composition may assist in controlling of bacteria, prevent irritation of the tissue near the implant, or may carry additional bio-active substances.
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.
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, polyortho-ester, 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 painting, dip coating, molding, spin-coating, 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 so that inadvertent death of tissue does not occur. 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/balloon catheter too far into the opening into the airway wall. Improper advancing of the implant/balloon could potentially result in a pneumothorax or pneumomediastinum.
To address the above problem, as illustrated in previous figures, the implant 200 may also include a visualization mark 218. The visualization marker 218 is visually apparent during a procedure and gives the medical practitioner an indication when the implant/balloon 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 viewingIt 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 endoscope) 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 expandable implant (such as those described herein and in the cases referenced herein), where the delivery device includes an expandable member having an expandable implant located about the expandable member. Where the implant and the expandable member are of different visually identifiable colors or shades such that the distinction is easy to identify under endoscopic or bronchoscopic viewing.
In one example, as shown in
It should be noted that variations of the invention include coloring the balloon itself, or other expandable member, a color that meets the above criteria.
In another variation, the visualization mark may comprise providing a contrast between the implant and a delivery catheter. In one example the implant appears mostly white and while mounted on a contrasting color inflation balloon. In this example the implant would be placed over a blue deflated balloon catheter. The proximal and distal areas of the implant would be flanked by the deflated blue balloon, 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 balloon 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)ˆ� 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.
Some variations of the invention include an active analog and/or derivative of paclitaxel in addition to the paclitaxel. Such variation may have a ratio of the first amount of paclitaxel to the second amount of the active derivative or analog of paclitaxel comprises of at least 2 to 1, 3 to 1, or other ranges as found necessary to assist in maintaining patency of the implant passageway. The amounts of paclitaxel may be as provided herein or include additional ranges.
Accordingly, a variation of the invention includes an implant with a composition located on the support member and comprising an antiproliferative agent, where the agent comprises a first amount of paclitaxel and a second amount of an active derivative or analog of paclitaxel. One example of such an active derivative or analog of paclitaxel may be 7-epitaxol. It is believed that existence of the active derivative or analog of paclitaxel (e.g., 7-epitaxol) aids in maintaining the patency of the implant passageway.
The process of polymerizing two (2) parts, part A and part B, of Med 6640 silicone, created the 7-epitaxol from the paclitaxel. The epimerization occurs at the number seven (7) carbon from an S enantiomer to an R enantiomer. The conversion takes place when the temperature is raised from 75� C. to 150� C.
It is not exactly known if the production of 7-epitaxol arises from heat alone or whether other reactant components are necessary. The components that are active during this process are: a) paclitaxel; b) heat (150� C.); c) heat (75� C. then 150� C.); d) initiator (Pt�); e) proton radicals of −Pt�, vinyl-silicone; f) xylene; g) dichloromethane; given a certain time parameter.
It may be that the production of 7-epitaxol from paclitaxel only requires heat. It may require that all the components be in the exact order and quantity to produce 7-epitaxol from paclitaxel. Some combinations or some key components and time are all that are required to produce 7-epitaxol from PTX. To understand the exact parameters to produce 7-epitaxol from PTX requires more careful studies.
In one variation of the device where the loading was approximately 6%, it was found that (while the theoretical paclitaxel load per implant was approximately 300 μg) extraction studies of the implant indicated that the actual load of the implant comprised around 250 μg of paclitaxel along with 45 μg of 7-epitaxol. In this case there was 20 μg of drug that was unaccounted. This latter unaccounted amount is generally referred to the bound polymer or bound fraction.
The bound-fraction (i.e., the portion of unaccounted drug discussed above) varies and is not proportional to the percent drug load. Bound-fractions are typical occurrences in matrix-drug-delivery devices. The amount of bound-fraction varies depending upon chemistry of the polymerization reaction, stoichiometry, and the characteristics of the drug.
In another example of the device where the loading was approximately 7%, it was found that, though the theoretical paclitaxel load per implant was approximately 350 μg, extraction studies of the implant indicated that the actual load of the implant comprised around 290 μg of paclitaxel along with 45 μg of 7-epitaxol. In this case the bound fraction was 15 μg.
In another example of the device where the loading was approximately 12%, the theoretical paclitaxel load per implant was approximately 670 μg and extraction studies of the implant indicated that the actual load of the implant comprised around 490 μg of paclitaxel along with 100 μg of 7-epitaxol. In this case the bound fraction was 80 μg.
In yet another example of the device where the loading was approximately 9%, the theoretical paclitaxel load per implant was approximately 400 μg, extraction studies of the implant indicated that the actual load of the implant comprised around 300 μg of paclitaxel along with 50 μg of 7-epitaxol. In this case the bound fraction was 50 μg.
It should be noted that the ratio as well as the total load may be adjusted as the application requires to modify the release characteristics. For example, an implant coated with polymer loaded with relatively high percentage of paclitaxel can have a relatively low total drug load by decreasing the amount of polymer/drug coating.
In variations of the implant, 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.
|Citing Patent
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|Jun 1, 2010
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|Variable resistance pulmonary ventilation bypass valve
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|Device and method for creating a localized pleurodesis and treating a lung through the localized pleurodesis
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|Feb 18, 2009
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|Feb 21, 2008
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|Jan 21, 2014
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|Elongated lung volume reduction devices, methods, and systems
|Jun 28, 2013
|Jun 3, 2014
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|Sep 26, 2011
|Jan 13, 2015
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|Delivery devices with coolable energy emitting assemblies
|Sep 26, 2011
|Apr 14, 2015
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|Delivery devices with coolable energy emitting assemblies
|Jun 28, 2013
|Apr 28, 2015
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|Delivery devices with coolable energy emitting assemblies
|U.S. Classification
|International Classification
|Cooperative Classification
|European Classification
|Aug 22, 2006
Owner name: BRONCUS TECHNOLOGIES, INC., CALIFORNIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:ROSCHAK, EDMUND J.;PHAN, LOC X.;REEL/FRAME:018154/0685;SIGNING DATES FROM 20060802 TO 20060807


text:
Black Cave bivy.
Tom Frost, Royal Robbins with Yvon Chouinard hidden underneath in hammocks at a bivy in the Black Cave during the first ascent of the North America Wall, El Capitan, 1964. Incidentally, this was Yvon's first El Cap Route. Photo taken by Chuck Pratt and courtesy of Tom Frost.
Yvon Chouinard demonstrating the lost art of forging pitons. Here he has the stock heating up in the forge.
Shaping the red hot stock for a Lost Arrow piton.
Getting ready to punch out the eye in the piton. The anvil Yvon is using weighs over 120 pounds. Back when he started making pitons he would roll the anvil down the hillside to the beach in order to make pitons at beach and surfing parties. Afterwards he would carry it back up the hillside.
Grinding off the rough edges.
Reheating the Lost Arrow for the final step, tempering.
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text:
So who will/might be attending the Wolverhampton Concert at Civic Hall?
Let's see how many IncubusHQ members are going!
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There is already an official page for this concert as with all other gigs in the Tour tab. RSVP's are counted there and you get your pre sale information sent if you RSVP 'attending' or 'might attend'. http://incubushq.com/events/incubus-in-concert-wolverhampt Join! It will be added to your events on your profile! x


text:
Hang tight!
Recipe by ROMA
"Curried chicken simmered in coconut milk and tomatoes makes for a mouthwatering hint of the tropics! Goes great with rice and vegetables."
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2 pounds
boneless skinless chicken breasts, cut into 1/2-inch chunks
1 teaspoon
salt and pepper, or to taste
1 1/2 tablespoons
vegetable oil
2 tablespoons
curry powder
onion, thinly sliced
2 cloves
garlic, crushed
1 (14 ounce) can
coconut milk
1 (14.5 ounce) can
stewed, diced tomatoes
1 (8 ounce) can
tomato sauce
3 tablespoons
This recipe is awesome! The only recommendation I would make (my mother was raised in India, so she taught me): the difference between a good curry & a great curry is what my aunt called the broth. The broth is what is made with the spices & the onion. The curry powder (paste is even better) should be cooked in the oil until it is ready - usually about 5 minutes. Then add the onion & spice - cook until the onion is translucent. This will take about 10 minutes, but it makes all the difference in the world. Add more oil as the onion is cooking, if necessary. Then add the tomato (fresh is even better - strained) and cook it for a little while. NOW you're ready to make the curry.
This recipe was a HUGE hit with my family!
I did not care for this. It tasted like canned tomato soup with milk and curry. Leave out the can of tomato sauce! I had to add red curry paste, fish sauce and sweet chili sauce. This won't stay on my recipe list.
2750 Ratings
HELPFUL TIPS AFTER READING ALL THE REVIEWS: UPDATED If you've never had an Indian type cuisine, this is a GREAT one to start with because you can't screw it up! The hardest part is just finding these items at the store if it's your 1st time. Know you have to buy sweetened coconut milk, not the unsweetened kind & "lite coconut milk" for those weight watchers works well too! When I add the stewed tomatoes, I use my spatula and cut them into smaller pieces. Who wants a big chunk & who wants to end up w/nothing? I find cooking it uncovered is your best bet unless you want it simmering FOREVER. Uncovered at a steady med. will still takes 50-60 before the sauce thickens. Any rice goes well with this, so just choose the kind you like. I also only use 2 chicken breasts (1 pound), but keep all the other amounts since this is just for a family of 3. If I used 2lbs, I'd definitely have to use more sauce if cooking uncovered. Note: Expect your house to smell like curry 24hrs after you fix this (in case some of you have company coming over the next day). We have this regularly, so I know!!! ;) This is truly the best!
I didn't listen to the reviews when I decided to make this recipe with all the liquids listed in the ingredients. And I'm glad I did! It thickened up VERY well - but I did let it sit on the stove and simmer for a while (maybe an hour?). I just couldn't justify tossing out the water from the tomatoes, thinking I'd lose all those vitamins... I also only used 1 tsp of oil, light coconut milk, and extra curry. This was GREAT! It totally hit the spot! It's a great healthy recipe if you have veggies on the side (the coconut milk I used only had 6 grams fat per 1/2 cup!).
My husband said this recipe was restaurant quality...I used 1 TBS. of garlic, partially drained the tomatoes, added 2 cubed red potatoes and sprinkled in some red pepper flakes to make it more spicy. I'll make this one again!
Amazing!!!! When I saw how much curry powder I was putting in I have to admit I was a lil worried but the 1st time I make someone else's recipe I follow it to the T before making any changes. This is awesome just the way it is written!! Great flavor!!! My husband loved it and my mom asked for the recipe! Thank you!!!
Excellent every time I make it, at least once a month! Sometimes I use tomato paste if I don't have sauce and I often make it in the crockpot which combines all the flavors just perfectly! Serve with orange slices.
Usually I reduce the salt in recipes, but this dish needs most of the salt called for, and the pepper too. As written, you'll end up with a fairly runny sauce after simmering for 30-40 minutes. However, I simmer this much longer, uncovered and stirring frequently until it is thick and the tomatoes break down and blend into the sauce. (At least an hour depending on how much you let it bubble.) You could instead use less tomatoes, but I really like the recipe the way it's written, just simmered MUCH longer. Goes great with a Thai cucumber salad, zucchini, carrots, and/or cauliflower. I disagree with the other reviewer - unsweetened coconut milk is the way to go. EVERYONE loves this recipe - even those who've never tried curry.
* Percent Daily Values are based on a 2,000 calorie diet.
Curried Coconut Chicken
Serving Size: 1/6 of a recipe
Servings Per Recipe: 6
Amount Per Serving
Calories: 375
Calories from Fat: 188
We have so many top-rated chicken recipes, you'll never run out of dinner ideas again.
Imagine dinner making itself in the slow cooker while you relax or do other things.
Delicious recipes, party ideas, and cooking tips! Get a year of Allrecipes magazine for $7.99!
See how to make quick-and-easy curried chicken.
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What's cooking in Pearland, Texas? A sweet-and-savory fusion dish.


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An Elementary Introduction to Statistical Learning Theory
232 pages
August 2011, ©2011
A joint endeavor from leading researchers in the fields of philosophy and electrical engineering, An Elementary Introduction to Statistical Learning Theory is a comprehensive and accessible primer on the rapidly evolving fields of statistical pattern recognition and statistical learning theory. Explaining these areas at a level and in a way that is not often found in other books on the topic, the authors present the basic theory behind contemporary machine learning and uniquely utilize its foundations as a framework for philosophical thinking about inductive inference.
Promoting the fundamental goal of statistical learning, knowing what is achievable and what is not, this book demonstrates the value of a systematic methodology when used along with the needed techniques for evaluating the performance of a learning system. First, an introduction to machine learning is presented that includes brief discussions of applications such as image recognition, speech recognition, medical diagnostics, and statistical arbitrage. To enhance accessibility, two chapters on relevant aspects of probability theory are provided. Subsequent chapters feature coverage of topics such as the pattern recognition problem, optimal Bayes decision rule, the nearest neighbor rule, kernel rules, neural networks, support vector machines, and boosting.
Appendices throughout the book explore the relationship between the discussed material and related topics from mathematics, philosophy, psychology, and statistics, drawing insightful connections between problems in these areas and statistical learning theory. All chapters conclude with a summary section, a set of practice questions, and a reference sections that supplies historical notes and additional resources for further study.
An Elementary Introduction to Statistical Learning Theory is an excellent book for courses on statistical learning theory, pattern recognition, and machine learning at the upper-undergraduate and graduate levels. It also serves as an introductory reference for researchers and practitioners in the fields of engineering, computer science, philosophy, and cognitive science that would like to further their knowledge of the topic.
Table of Contents
1. Introduction: Classification, Learning, Features, Applications.
1.1 Scope.
1.2 Why Machine Learning?
1.3 Some Applications.
1.4 Measurements, Features, and Feature Vectors.
1.5 The Need for Probability.
1.6 Supervised Learning.
1.7 Summary.
1.8 Appendix: Induction.
1.9 Questions.
1.10 References.
2. Probability.
2.1 Probability of Some Basic Events.
2.2 Probabilities of compound events.
2.3 Conditional probability.
2.4 Drawing without replacement.
2.5 A Classic Birthday Problem.
2.6 Random Variables.
2.7 Expected Value.
2.8 Variance.
2.9 Summary.
2.10 Appendix: Interpretations of Probability.
2.11 Questions.
2.12 References.
3. Probability Densities.
3.1 An Example in Two Dimensions.
3.2 Random Numbers in [0, 1].
3.3 Density Functions.
3.4 Probability Densities in Higher Dimensions.
3.5 Joint and Conditional Densities.
3.6 Expected Value and Variance.
3.7 Laws of Large Numbers.
3.8 Summary.
3.9 Appendix: Measurability.
3.10 Questions.
3.11 References.
4. The Pattern Recognition Problem.
4.1 A Simple Example.
4.2 Decision Rules.
4.3 Success Criterion.
4.4 The Best Classifier: Bayes Decision Rule.
4.5 Continuous Features and Densities.
4.6 Summary.
4.7 Appendix: Uncountably Many.
4.8 Questions.
4.9 References.
5. The Optimal Bayes Decision Rule.
5.1 Bayes Theorem.
5.2 Bayes Decision Rule.
5.3 Optimality and Some Comments.
5.4 An Example.
5.5 Bayes Theorem and Decision Rule With Densities.
5.6 Summary.
5.7 Appendix: Defining Conditional Probability.
5.8 Questions.
5.9 References.
6. Learning from Examples.
6.1 Lack of Knowledge of Distributions.
6.2 Training Data.
6.3 Assumptions on the Training Data.
6.4 A Brute Force Approach to Learning.
6.5 Curse of Dimensionality, Inductive Bias, and No Free Lunch.
6.6 Summary.
6.7 Appendix: What Sort of Learning?
6.8 Questions.
6.9 References.
7. The Nearest Neighbor Rule.
7.1 The Nearest Neighbor Rule.
7.2 Performance of the Nearest Neighbor Rule.
7.3 Intuition and Proof Sketch of Performance.
7.4 Using More Neighbors.
7.5 Summary.
7.6 Appendix: When People Use Nearest Neighbor Reasoning.
7.7 Questions.
7.8 References.
8. Kernel Rules.
8.1 Motivation.
8.2 A Variation on Nearest Neighbor Rules.
8.3 Kernel Rules.
8.4 Universal Consistency of Kernel Rules.
8.5 Potential Functions.
8.6 More General Kernels.
8.7 Summary.
8.8 Appendix: Kernels, Similarity, and Features.
8.9 Questions.
8.10 References.
9. Neural Networks: Perceptrons.
9.1 Multilayer Feed Forward Networks.
9.2 Neural Networks for Learning and Classification.
9.3 Perceptrons.
9.4 Learning Rule for Perceptrons.
9.5 Representational Capabilities of Perceptrons.
9.6 Summary.
9.7 Appendix: Models of Mind.
9.8 Questions.
9.9 References.
10. Multilayer Networks.
10.1 Representation Capabilities of Multilayer Networks.
10.2 Learning and Sigmoidal Outputs.
10.3 Training Error and Weight Space.
10.4 Error Minimization by Gradient Descent.
10.5 Backpropagation.
10.6 Derivation of Backpropagation Equations.
10.7 Summary.
10.8 Appendix: Gradient Descent and Reasoning Toward Reflective Equilibrium.
10.9 Questions.
10.10 References.
11. PAC Learning.
11.1 Class of Decision Rules.
11.2 Best Rule From a Class.
11.3 Probably Approximately Correct Criterion.
11.4 PAC Learning.
11.5 Summary.
11.6 Appendix: Identifying Indiscernibles.
11.7 Questions.
11.8 References.
12. VC Dimension.
12.1 Approximation and Estimation Errors.
12.2 Shattering.
12.3 VC Dimension.
12.4 Learning Result.
12.5 Some Examples.
12.6 Application to Neural Nets.
12.7 Summary.
12.8 Appendix: VC Dimension and Popper Dimension.
12.9 Questions.
12.10 References.
13. Infinite VC Dimension.
13.1 A Hierarchy of Classes and Modified PAC Criterion.
13.2 Misfit Versus Complexity Tradeoff.
13.3 Learning Results.
13.4 Inductive Bias and Simplicity.
13.5 Summary.
13.6 Appendix: Uniform Convergence and Universal Consistency.
13.7 Questions.
13.8 References.
14. The Function Estimation Problem.
14.1 Estimation.
14.2 Success Criterion.
14.3 Best Estimator: Regression Function.
14.4 Learning in Function Estimation.
14.5 Summary.
14.6 Appendix: Regression Toward the Mean.
14.7 Questions.
14.8 References.
15. Learning Function Estimation.
15.1 Review of the Function Estimation/Regression Problem.
15.2 Nearest Neighbor Rules.
15.3 Kernel Methods.
15.4 Neural Networks Learning.
15.5 Estimation with a fixed class of functions.
15.6 Shattering, Pseudo-Dimension, and Learning.
15.7 Conclusion.
15.8 Appendix: Accuracy, Precision, Bias, and Variance in Estimation.
15.9 Questions.
15.10 References.
16. Simplicity.
16.1 Simplicity in Science.
16.2 Ordering Hypotheses.
16.3 Two Examples.
16.4 Simplicity as Simplicity of Representation.
16.5 Pragmatic Theory of Simplicity.
16.6 Simplicity and Global Indeterminacy.
16.7 Summary.
16.8 Appendix: Basic Science and Statistical Learning Theory.
16.9 Questions.
16.10 References.
17. Support Vector Machines.
17.1 Mapping the Feature Vectors.
17.2 Maximizing the Margin.
17.3 Optimization and Support Vectors.
17.4 Implementation and Connection to Kernel Methods.
17.5 Details of the Optimization Problem.
17.6 Summary.
17.7 Appendix: Computation.
17.8 Questions.
17.9 References.
18. Boosting.
18.1 Weak Learning Rules.
18.2 Combining Classifiers.
18.3 Distribution on the Training Examples.
18.4 The AdaBoost Algorithm.
18.5 Performance on Training Data.
18.6 Generalization Performance.
18.7 Summary.
18.8 Appendix: Ensemble Methods.
18.9 Questions.
18.10 References.
Author Information
SANJEEV KULKARNI, PhD, is Professor in the Department of Electrical Engineering at Princeton University, where he is also an affiliated faculty member in the Department of Operations Research and Financial Engineering and the Department of Philosophy. Dr. Kulkarni has published widely on statistical pattern recognition, nonparametric estimation, machine learning, information theory, and other areas. A Fellow of the IEEE, he was awarded Princeton University's President's Award for Distinguished Teaching in 2007.
GILBERT HARMAN, PhD, is James S. McDonnell Distinguished University Professor in the Department of Philosophy at Princeton University. A Fellow of the Cognitive Science Society, he is the author of more than fifty published articles in his areas of research interest, which include ethics, statistical learning theory, psychology of reasoning, and logic.
"The main focus of the book is on the ideas behind basic principles of learning theory and I can strongly recommend the book to anyone who wants to comprehend these ideas." (Mathematical Reviews, 1 January 2013)
"It also serves as an introductory reference for researchers and practitioners in the fields of engineering, computer science, philosophy, and cognitive science that would like to further their knowledge of the topic." (Zentralblatt MATH, 2012)
Buy Both and Save 25%!
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31 October 2012Cabinet Secretary for Culture and External Affairs Fiona Hyslop has launched a new website celebrating international industrial heritage.
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Faith in Action
Giving hope to children
Victims of Philippines extrajudicial killings
United Methodist Baguio Area helps build better future as part of Regional Ecumenical Council in the Cordillera. read more»
Concern grows over rapes in Liberia
United Methodist Human Rights Monitor leads protests
Attacks undermine peace and security, and hinder holistic development of girls and women in Liberia. read more»
'Part of our mission for justice and peace'
Bishop Swenson leading trip to Hiroshima, Nagasaki
World Council of Churches delegation to attend 70th commemoration of atomic bomb attacks. read more»
Getting at roots of injustice
Great Plains Micah Corps interns work for social change
Often the best solution is not the easy solution whether you are weeding a garden or transforming society, says intern. read more»
We the people
A brutal summer for human rights, dignity
People find themselves caught in mix of tragedy, promise, confronting superficial cultural assumptions to defend 'less-than-Christian behavior.' read more»
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Some product exclusions may apply. See product page details for more information. Clearance items are final sale. Price matching does not apply to this or any promotion. Offer is valid until September 13 at 11:59 PM PST. May not be combined with any other offer/discount (unless specified), including invitation credits, promotional gift cards and/or special discount links. Discount applied upon checkout. Log in to your account to see your savings.
You officially have permission to write on the walls—as long as you promise to color inside the lines. This chalkboard calendar features space to schedule the month ahead and serves as a canvas for your artwork, grocery lists, and love notes. Peel and stick the self-adhesive piece as many times as you like; it won't ruin walls and will stick to any flat surface.
Includes 1 decal. Chalk not included. This decal is backed with adhesive that sticks smooth, comes off clean, and can be repositioned time and time again. To apply, simply clean your wall with a damp cloth, let it dry, peel up your art, stick, and smooth.
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While Fairfax County's election results were closely watched on the national stage due to their impact on national politics, many county residents and government officials were much more interested in the outcome of the local bond referendums.
As is typically the case, all four of the bond issues got overwhelming support from voters, each earning 70 percent or more of votes from those that weighed in on that section of the ballot. More than 100,000 voters who participated in the election did not cast votes on the bond questions.
The approvals allow the county to borrow $185 million for parks, libraries, fire and police stations and flood protection for the Huntington community.
While it is a different type of bond than the county normally issues, the Huntington flood protection bond got more support than any other, with nearly 77 percent approval. It will allow the county to borrow $30 million to construct a levee and pump system to provide flood protection to the Huntington community.
The other bonds will support renovations of three libraries, construction of a new library, renovations of 22 courtrooms, rebuilding three fire stations and a host of park projects.
Most voters at the polls support more county investment in infrastructure.
"I am a big proponent of the libraries and the parks," said Clifton resident Rhonda Hulley, who said it was important to her to support those bonds.
However, there are also those fiscally conservative voters like Matt Labudzki, of Clifton, who opposed the borrowing.
"I want fiscal responsibility," he said. "People, including governments, have to learn to live within their means."
Unlike the federal government, Fairfax County is required to produce a balanced budget every year. The county also has a self-imposed cap on borrowing to ensure that its debt service costs remain manageable and the county retains its AAA bond rating.


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Sunday night!
I'm prepared:
Sunday night!
I'm prepared:
Sorry i have never got into it, not mad enough for me.............
Last edited by ROADRUNNER; 03-24-2012 at 12:45 PM.
I'll be watching, awesome show!
- Hall of Fame Safety Rod Woodson on Dan Marino playing in today's NFL:
"...the best quarterback I believe is Dan Marino..."
"If he played with these rules, he'd throw for 100,000 yards."
Twitter - https://twitter.com/ciscoholgate
Now have a few bags of Utz chips, some Talisker, and some Hendrick's Gin for the ladies. Good times.
I'm ready. Also, this is what I'm drinking.
Follow up: Glenmorangie Finealta is sheer badassery.
Harry Crane cracks me up.
Great season so far. That LSD scene last week was great. Roger Sterling is still my favorite character. Love Joan too.
And now his fires have gone out.


text:
Texas Politics
Political Coverage from Austin to Texas on the Potomac in D.C.
Posts filtered on Tag
Some specialty license plates raise questions
Objections by the head of the American Indian Genocide Museum over a specialty license plate recognizing the Buffalo Soldiers raises some interesting questions. African American leaders protested earlier this month when the Texas Department of Motor Vehicles considered a Confederate flag specialty plate considering the iconic image has been hijacked by various hate groups. Steve […] [Read More]


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Activator binding kinetics on Ras and Ras-related GTPases, specifically Ras_act (activated mutant)
The objective of the HTS associated with this secondary assay was to identify small molecule regulators of Ras and Ras-related GTPases (see Summary Report and PubChem AIDs 757, 758, 759, 760, 761, 764). The primary HTS assay was a no-wash fluorescent GTP-binding assay adapted to multiplexed, high-throughput measurements whereby multiple GTPases were simultaneously screened against the MLSCN more ..
Related BioAssays
Related BioAssays
BioActive Compound: 1
Related Experiments
University of New Mexico Assay Overview:
Assay Support: NIH I RO3 MH081231-01
HTS to identify specific small molecule inhibitors of Ras and Ras-related GTPases
PI: Angela Wandinger-Ness, Ph.D.
Co-PI: Larry Sklar, Ph.D.
Assay Development: Zurab Surviladze, Ph.D.
Assay Implementation: Zurab Surviladze, Danuta Wlodek, Terry Foutz, Mark Carter, Anna Waller
Target Team Leader for the Center: Larry Sklar (firstname.lastname@example.com)
Assay Background and Significance:
The objective of the HTS associated with this secondary assay was to identify small molecule regulators of Ras and Ras-related GTPases (see Summary Report and PubChem AIDs 757, 758, 759, 760, 761, 764). The primary HTS assay was a no-wash fluorescent GTP-binding assay adapted to multiplexed, high-throughput measurements whereby multiple GTPases were simultaneously screened against the MLSCN library. The specificity is based on the observation that individual GTPases including wildtype and activated mutants exhibit measurably distinct affinities for Bodipy-FI-GTP. The assay involves the binding of fluorescent GTP to G protein-GST fusion proteins on GSH beads. A set of six G proteins (Rac1 wt, Rab7 wt, Rac1 activated, Ras wt, Rab2 wt, CDC wt) are arrayed under conditions of divalent molecule depletion.
In the assay described here, real-time binding kinetics between GTP and each of the protein targets were characterized in a multiplex assay (Schwartz, et al 2008). The resulting binding of fluorescent GTP after 3 minutes was utilized in determining Bmax and Kd for each target in the presence of 10 microM small molecule activator compound MLS000088004 versus a DMSO control.
Each protein target (4 microM) was bound to glutathione beads overnight at 4 degrees C. Protein on GSH-beads was depleted of nucleotide by incubating with 10 milliM EDTA containing buffer for 20 min at 30 degrees C, washing twice with 0.01% NP-40 containing HPS buffer, then resuspending in the same buffer containing 1 milliM EDTA, 1 milliM DTT and 0.1% BSA. Kinetic assays were performed by incubating 50 microliter of GST-target protein-GSH-bead suspension for 2 min with either DMSO, or 10 microM MLS000088004 and subsequently adding 50 microL of various concentration ice cold BODIPY-GTP. Association of the fluorescent nucleotide was measured using a FacSCAN flow cytometer in the kinetic mode. Data were converted to ASCII format using IDLQuery.
Measured values of bead-bound BODIPY-GTP after 3 minutes of binding are converted to molecular equivalent soluble fluoresceine (MESF) with the aid of calibration beads (Bangs Lab) by the following equation;
kMESF = Slope * MCF + Intercept
where MCF is the Median Channel Fluorescence measurement of bead-bound BODIPY-GTP, kMESF are kiloMESF (1000 * MESF), and Slope and Intercept are the from the linear regression fit of the 5 different levels of calibration beads.
The resulting values of kMESF are graphed versus the different concentrations of BODIPY-GTP in GraphPad Prism and fitted by non-linear regression to one site binding pre the following equation;
kMESF = Bmax * ConcBODIPY-GTP / (Kd + ConcBODIPY-GTP)
where ConcBODIPY-GTP is the concentration of BODIPY-GTP, Bmax is the maximum binding of BODIPY-GTP per bead and Kd is the equilibrium binding constant of BODIPY-GTP to protein on bead.
Keywords: NIH Roadmap, NMMLSC, high throughput flow cytometry, GTPase, multiplex bead-based screening
Only one compound was tested in this assay. Potentially additional compounds will be evaluated.
Result Definitions
** Test Concentration.
Additional Information
Grant Number: NIH I RO3 MH081231-01
Data Table (Concise)


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New Jersey Pay Parity Bill
New Jersey's Governor Chris Christie recently signed the Gender Pay Parity Bill (the "Bill") which impacts New Jersey-based companies that employ fifty or more individuals. Under the Bill, employers must post as well as physically provide a new notice to their employees to inform them of their right to be free from gender-based discrimination in the workplace.
The actual notice has not yet been drafted by the New Jersey Department of Labor ("NJDOL"). Therefore, while technically the Bill goes into effect on November 21, 2012, employers will have thirty days to comply with the notice requirements of the Bill from the date the NJDOL actually issues the required notice.
Employers have to post the notice at their work location. It is prudent to post the notice in the same location as other required posters. In addition to the notice having to be in English and Spanish, the notice must also be provided in any language that is spoken by at least 10% of an employer's workforce (provided that the NJDOL has issued a notice in that language).
All new employees will need to receive a copy of the notice on hire. Furthermore, each year all employees must receive a copy of the notification by December 31st. Finally, employees at any time may request a notice from their employer.
Employers may provide the notification to their employees through:
· e-mail;
· printed material, including pay check insert, flyer or as an attachment to an employee manual or policy book; or
· via an internet or intranet site if the site is for the exclusive use of all employees, can be accessed by all employees and the employer provides notice of the posting to all employees.
Within thirty days of receipt of their notice employees must provide their employer a signed acknowledgement (or electronic verification) that they received this notice.
If you have any questions with respect to the Gender Pay Parity Bill, please do not hesitate to contact our office.


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Screen Measurement Pack (Screen Calipers, Screen Protractor and Screen Compass) was mentioned in his first post almost a year ago. I for one would sure like to see this bundle offered at Bits du Jour again!
We will certainly have the Iconico products up on Bits du Jour again, we did a few over Christmas but we'll have the pack up at some point. I coded the measurement tools and most of what you see on Iconico, some of the apps date back to 2000. Nice to be here too guys.


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