Patent Grant
9533128
This is directed to methods and devices for altering gaseous flow within a lung to improve the expiration cycle of an individual, particularly individuals having chronic obstructive pulmonary disease. The methods and devices create channels in lung tissue and maintain the patency of these surgically created channels in tissue. Maintaining the patency of the channels allows air to pass directly out of the lung tissue which facilitates the exchange of oxygen ultimately into the blood and/or decompresses hyper-inflated lungs.
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.
Both bronchodilator drugs and lung reduction surgery fail to capitalize on the increased collateral ventilation taking place in the diseased lung. There remains a need for a medical procedure that can alleviate some of the problems caused by COPD. There is also a need for a medical procedure that alleviates some of the problems caused by COPD irrespective of whether a portion of the lung, or the entire lung is emphysematous. The production and maintenance of collateral openings through an airway wall allows air to pass directly out of the lung tissue responsible for gas exchange. These collateral openings serve to decompress hyper inflated lungs and/or facilitate an exchange of oxygen into the blood.
It was found that creation of collateral channels in COPD patients allowed expired air to pass out of the lungs and decompressed hyper-inflated lungs. Such 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.
It was found that creating an opening/channel through an airway wall overcomes the shortcomings associated with bronchodilator drugs and lung volume reduction surgery. To further improve the benefit provided by the channel a need further remains to extend the duration of which the channel remains open (e.g., patency of the opening). Surgically creating a hole in tissue triggers a healing cascade. The body's natural healing response sets into motion, amongst other things, cell proliferation which can result in a build-up of scar tissue. This tissue overgrowth 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 avoid partial re-stenosis of the vessel after stent placement. 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 a paclitaxel drug eluting vascular stent into the opening did not yield positive results in maintaining the patency of the opening. The shortcomings were both in the physical structure of the stent along with the failure to control the healing cascade caused by creation of the channel.
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 fibrosus. 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.
In view of the above, a need remains to create channels in airways of COPD patients. A need also remains for methods and devices for creating the channels and placing conduits therein such that the patency of the opening is extended.
The invention includes methods and devices for treating a lung suspected of having chronic obstructive pulmonary disease through the creation of collateral channels. The invention also includes extending the duration during which these channels remain open (e.g., maintaining patency.)
In one variation, the invention includes a method comprising selecting a treatment site in an airway of the lung, creating a hole in an airway wall of the airway; and expanding the hole in the airway wall.
Selecting the treatment site may include visual inspection of the site or inspection for the presence or absence of a blood vessel underneath the surface of the airway wall.
Selection of the site may be performed or aided by non-invasive imaging. Such imaging may include x-ray, ultrasound, Doppler, acoustic, MRI, PET, and computed tomography (CT) scans. Furthermore, a substance may be administered into the lungs to assist in the selection of the treatment site. For example, the substance may comprise a hyperpolarized gas, a thermochromatic dye, a regular dye, and/or a contrast agent.
Variations of the invention include the use of a less-traumatic holemaker for creation of the channel (note that a channel includes a hole that is created and subsequently expanded.) The less traumatic holemaker may include a piercing member (e.g., a needle, a cannula, a blade, a tube, a rod or other similar structure). The less traumatic holemaker may also include devices which minimize the collateral damage to tissue (e.g., low temperature RF devices, pulsating RF, low temperature laser, ultrasound, high pressure water, etc.)
In particular, the devices and methods prevent closure of the channel such that air may flow through the channel and into the airway. Such channels may be made by a variety of methods as discussed in the patents incorporated by reference above. For example, the channel may be made via a surgical incision, a needle, a rotary coring device, etc. Furthermore, the channel may be made by an energy based device, e.g., RF device, laser, etc. However, it has been noted that use of low temperature devices, e.g., mechanical devices, to create the channel result in less trauma to surrounding tissue and thereby minimize the healing response of the tissue. Accordingly, such modes of creating the channel often result in less occlusion of the channel.
The method includes expanding the hole by inserting a conduit into the hole. Furthermore, the method may comprise partially expanding the hole by deploying the conduit in the hole, and then fully expanding the hole by expanding the conduit within the hole.
Preventing closure may be performed using various approaches including, but not limited to, biochemical, electrical, thermal, irradiation, or mechanical approaches (or any combination thereof).
The method may also include delivering a bio-active composition, as described herein, to maintain patency of the channel or conduit. The bio-active composition may be delivered to the airway wall prior to creation of the channel, subsequent to creation of the channel, and/or after insertion and deployment of the conduit. The bio-active composition may also be delivered through a drug eluting process, either through a composition placed on the conduit, or via delivery of a separate eluting substance.
Biochemical approaches include delivery of medicines that inhibit closure of the surgically created channel. The medicines may be delivered locally or systematically. In one variation, a delivery catheter includes a dispense lumen that sends a drug to the target site. Also, bioactive substances may be delivered to the channel tissue using various delivery vehicles such as a conduit. The bioactive substance may be disposed on an exterior surface of the conduit such that it interacts with the channel tissue when the conduit is placed at the injury site. Also, bioactive substances may be delivered to the channel tissue before or after the conduit is positioned in the channel. The bioactive agent may also be delivered to the target site alone. That is, a medicine may be sent to the surgically created channel as the sole mechanism for maintaining the patency of the channel.
Also, systematic delivery of medicines may be carried out through digestion, injection, inhalation, etc. Systematic delivery of medicines may be provided alone or in combination with other techniques described herein. For example, a patient having undergone the procedures described herein may be prescribed steroids and/or COX-2 inhibitors in an attempt to prolong the effects of the treatment.
Any of the conduits discussed herein may also include at least one visualization feature disposed on a portion of the tissue barrier. The visualization feature may be a stripe circumferentially disposed about at least a portion of the center section. The visualization feature serves to aid in placement or deployment of the conduit in a target site.
Another conduit for maintaining the patency of a channel created in tissue comprises a radially expandable center section and extension members as described above. A bioactive substance is disposed on at least a portion of a surface of the conduit. Also, when the conduit is radially expanded it has an overall length and an inner diameter such that a ratio of the overall length to the inner diameter ranges from 1/6 to 2/1. The conduit may also be provided such that this ratio ranges from 1/4 to 1/1 and perhaps, 1/4 to 1/2. A tissue barrier may be disposed on at least a portion of the exterior surface corresponding to the center section. The tissue barrier may be comprised of various materials including but not limited to polymers and elastomers. An example of a material which may be used for the tissue barrier is silicone. Additional matrixes of biodegradable polymer and medicines may be associated with the tissue barrier such that controlled doses of medicines are delivered to the tissue opening.
The invention includes a hole-making catheter for creating and dilating an opening within tissue, the catheter comprising an elongate shaft having a proximal portion and a distal portion, and at least one lumen extending through the proximal end; a balloon having an interior in fluid communication with the lumen, the balloon located on the distal portion of the elongate shaft, the balloon having an uninflated state and an inflated state; a piercing member located at the distal portion of the elongate shaft, the piercing member being extendable and retractable within the elongate shaft; and a depth limiter stop located on the exterior of the distal portion of the elongate shaft, proximal to the balloon and larger in working diameter than the uninflated balloon, which limits the maximum penetration of the catheter into tissue.
The piercing member may include a body portion having a lumen extending therethrough. The lumen of the piercing member may be in fluid communication with a central lumen of the elongate shaft. In some variations of the invention an obturator is used within the device, where the obturator is slidably located within the lumen of the elongate body and piercing member.
The elongate body and/or piercing member may have multiple lumens. For example, they may be constructed from multi-lumen tubing. In some variations, the piercing member is retractable within the elongate shaft.
The balloon member may consist of a distensible balloon or a non-distendsible balloon. For either type of balloon, the working diameter may closely match the outer diameter of the piercing member.
The invention may also include an implant located about the balloon of the device. In use, the piercing member would create a channel within the tissue, the device is then further advanced until the implant is located within the channel. Inflation of the balloon then deploys the implant within the channel thereby improving the patency of the channel.
Implants for the present invention include, but are not limited to, a stent, conduit, grommet, valve, graft, anchor, etc.
It should be noted that since the device must often access airways deep within the lung, the elongate shaft may be comprised of a flexible material. In particular, the elongate shaft may be sufficiently flexible to pass through a fully articulated bronchoscope.
The piercing member of the current invention may also be used to deliver bio-active agents to the site of the collateral channel. As described herein, such agents may increase the duration of patency of the channels and/or implants.
The invention includes a balloon catheter for deploying a device within an opening in tissue, the balloon catheter comprising an elongate shaft having a proximal portion, a distal portion, a proximal end, a distal end; and at least one lumen extending through the proximal end, a balloon having an interior in fluid communication with the lumen, the balloon located on the distal end portion of the elongate shaft, a guide member extending distally from the distal end of the elongate shaft, the guide member comprising a rounded surface at an end opposite to the elongate shaft, where the guide member has sufficient column strength to penetrate the opening in tissue, the guide member further comprising at least one resistance surface a such that when the body enters the opening, the resistance surface exerts resistance against tissue upon removal of the guide member from the opening.
The resistance surface may have an increased diameter greater to provide resistance upon removal from tissue. It may alternatively, or in combination, comprise a rough surface to provide added friction upon removal of the device.
The guide member may be tapered, rounded, partially-spherical, elliptical, prolate, cone-shaped, triangular, or any similar shape. It is contemplated that there may be more than one resistance surface on the guide body. Moreover, the guide body may have a wavy/variable diameter shape providing several resistance surfaces on the areas of increased diameter.
The device may also be used with an implant that may be located about the balloon where upon expansion of the balloon, the implant deploys. The implant may be selected from a stent, conduit, grommet, valve, graft, and anchor.
In another variation of the invention, the balloon catheter may further comprise a dilating member located distally of the balloon. The dilating member may be is located on the distal portion of the shaft between the distal end and the balloon and may comprise a tapered section, a second balloon, or other similar structure.
In some variations of the invention, the dilating member may be retractable within the elongate shaft.
The device may also include a needle assembly moveably located in the instrument lumen, where the needle assembly is advanceable through a hole-making lumen and out of the opening in the rounded surface.
The balloon catheter may be constructed to be sufficient flexibility to advance through a fully articulated bronchoscope.
The balloon catheter may also be configured to deliver bio-active substances (e.g., drugs, medicines, compounds, etc.) to the tissue, either via the elongate tube or the guide member. Furthermore, the device may be adapted to provide suction to clear the target site.
The invention includes a hole-making catheter for creating and dilating an opening within tissue, the catheter comprising; an elongate shaft having a proximal portion and a distal portion, and at least one lumen extending through the proximal end; a nondistensible balloon having an interior in fluid communication with the lumen, the nondistensible balloon located on the distal portion of the elongate shaft; and a piercing member located at the distal portion of the elongate shaft, the piercing member being extendable and retractable within the elongate shaft.
The invention includes an implant delivery system for deploying the implant within a wall of tissue, the system comprising; an elongate shaft having a distal portion, a proximal end, a distal end, at least one lumen extending through the proximal end; a balloon member having an interior in fluid communication with the lumen, the balloon member located on the distal portion of the elongate shaft; a piercing member distally located to the distal end of the elongate shaft within the second lumen, the solid piercing member having a sharpened distal end adapted to penetrate tissue; and an expandable implant located about the balloon member.
The preceding illustrations are examples of the invention described herein. It is contemplated that, where possible, combinations of features/aspects of specific embodiments or combinations of the specific embodiments themselves are within the scope of this disclosure.
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; Ser. No. 10/280,851 filed Oct. 25, 2002; and Ser. No. 10/458,085 filed Jun. 9, 2003. Each of which is incorporated by reference herein.
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 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.
The channels may be maintained by preventing or inhibiting tissue from growing into or otherwise blocking the channel. Chemical, electrical, light, mechanical, or a combination of any two or more of these approaches may be performed to maintain the channel openings. For example, the channel walls may be treated with a bioactive agent which inhibits tissue growth. The bioactive agent may be delivered locally or systematically. Also, the channels may be treated with rf energy, heat, electrical energy, or radiation to inhibit tissue overgrowth. These treatments may be performed once, periodically, or in response to the severity of the channel blockage. For example, the tissue blockage may be periodically removed with a laser or another tissue-removal tool. Also, mechanical devices and instruments may be deployed in the channel to prevent tissue growth from blocking the channel. Mechanical devices include without limitation conduits, valves, sponges, etc. These mechanical devices may be deployed permanently or temporarily. If deployed temporarily, the devices are preferably left in the channel for a sufficient amount of time such that the channel tissue heals coaxially around the device.
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.
Although
As shown in
Additionally, the conduits shown in
It is understood that the conduits discussed herein are not limited to those shown in the figures. Instead, conduits of various configurations may be used as described herein. Such conduits are described in the following patent application Ser. No. 09/908,177 filed Jul. 18, 2001; PCT/US03/12323 filed Apr. 21, 2003; Ser. No. 09/947,144 filed Sep. 4, 2001; Ser. No. 10/235,240 filed Sep. 4, 2002; and Ser. No. 10/458,085 filed Jun. 9, 2003 the entirety of each of which is hereby incorporated by reference.
Conduit States
The conduits described herein may have various states (configurations or profiles) including but not limited to (1.) an undeployed state and (2.) a deployed state.
The undeployed state is the configuration of the conduit when it is not secured in an opening in an airway wall and, in particular, when its extension members (or fingers) are not outwardly deflected to engage the airway wall.
The deployed state is the configuration of the conduit when it is secured in a channel created in an airway wall and, in particular, when its extension members are outwardly bent to engage the airway wall such that the conduit is fixed in the opening. An example of a conduit in its deployed configuration is shown in
Center Section of the Conduit
As shown in
The axial length of the center section or passageway may be relatively short. In
The overall length (L) of the conduit may be distinguished from the length of the center section because the overall length includes the lengths of the extension members. Further, the overall length (L) is dependent on which state the conduit is in. The overall length of the conduit will typically be shorter when it is in a deployed state as shown in
The diameter of the center section, when deployed, thus may be significantly larger than the passageway's axial length (e.g., a 3 mm diameter and an axial length of less than 1 mm). This ratio of the center section length to diameter (D1) may range from about 0:10 to 10:1, 0.1:6 to 2:1 and perhaps from 1:2 to 1:1.
The diameter of the center section, when deployed, may also be nearly equal to the overall length (L) of the conduit 200. This overall length (L) to diameter (D1) ratio may range from 1:10 to 10:1, 1:6 to 2:1, and perhaps from 1:4 to 1:1. However, the invention is not limited to any particular dimensions or ratio unless so indicated in the appended claims. Rather, the conduit should have a center section such that it can maintain the patency of a collateral channel in an airway wall. The dimensions of the center section (and the conduit as a whole) may be chosen based on the tissue dimensions. When the channel is long in its axial length, for example, the length of the center section may likewise be long or identical to the channel's length.
Extension Members of the Conduit
As mentioned above, extending from the ends of the center section 208 are extension members 202A, 202B which, when the conduit is deployed, form angles A1, A2 with a central axis of the passageway. When viewed from the side such as in
The angles A1, A2 may vary and may range from, for example, 30 to 150 degrees, 45 to 135 degrees and perhaps from 30 to 90 degrees. Opposing extension members may thus form angles A1 and A2 of less than 90 degrees when the conduit is deployed in a channel. For example, angles A1 and A2 may range from 30 to 60 degrees when the conduit is deployed.
The conduits of the present invention are effective and may maintain a surgically created opening despite not substantially sandwiching tissue between opposing extension members as described above. Additionally, it is not necessary for the conduits of the present invention to prevent air from flowing along the exterior of the conduit. That is, air may move into (and through) spaces between the exterior of the conduit and the interior wall of the tissue channel. Thus, fluidly sealing the edges of the conduit to prevent side flow or leakage around the conduit is not crucial for the conduits to be effective. However, the conduits of the present invention are not so limited and may reduce or eliminate side flow by, for example, increasing the angles A1 and A2 and adding sealant around the exterior of the conduit.
Moreover, the angle A1 may be different than angle A2. Accordingly, the conduit may include proximal extension members which are parallel (or not parallel) to the distal extension members. Additionally, the angle corresponding to each proximal extension member may be different or identical to that of another proximal extension member. Likewise, the angle corresponding to each distal extension member may be different or identical to that of another distal extension member.
The extension members may have a length between 1 and 20 mm and perhaps, between 2 and 6 mm. Also, with reference to
The number of extension members on each end of the center section may also vary. The number of extension members on each end may range from 2-10 and perhaps, 3-6. Also, the number of proximal extension members may differ from the number of distal extension members for a particular conduit. Moreover, 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 conduit and the tissue. The extension members may also have openings to permit tissue ingrowth for improved retention.
The shape of the extension members may also vary. They may be open-framed and somewhat petal-shaped as shown in
In another variation the conduit is constructed to have a delivery state. The delivery state is the configuration of the conduit when it is being delivered through a working channel of a bronchoscope, endoscope, airway or other delivery tool. The maximum outer diameter of the conduit in its delivery state must therefore be such that it may fit within the delivery tool, instrument, or airway.
In one variation, the conduit is radially expandable such that it may be delivered in a smaller working channel of a scope while maximizing the diameter to which the conduit may expand upon deployment. For example, sizing a conduit for insertion into a bronchoscope having a 2 mm or larger working channel may be desirable. Upon deployment, the conduit may be expanded to have an increased internal diameter (e.g., 3 mm.) However, the invention is not limited to such dimensions. It is contemplated that the conduits 200 may have center sections that are expanded into a larger profile from a reduced profile, or, the center sections may be restrained in a reduced profile, and upon release of the restraint, return to an expanded profile.
Additionally, the conduit need not have a smaller delivery state. In variations where the center section is not able to assume a second smaller delivery profile, a maximum diameter of the first or deployed profile will be sufficiently small such that the conduit may be placed and advanced within an airway or a working channel of a bronchoscope or endoscope. Also, in cases where the conduit is self-expanding, the deployed shape may be identical to the shape of the conduit when the conduit is at rest or when it is completely unrestrained.
Additionally the conduit may be partially expanded in its proximal region in the delivery state, as shown in figure X. The partially expanded portion would still me sized small enough to fit within the working channel of the bronchoscope, but would be significantly larger (e.g., 0.5-2 mm) larger that the distal portion of the conduit. This partial expansion allows for easy placement of the conduit by providing a physical stop for the conduit within the airway wall. After the conduit is placed the entire conduit can be expanded to its intended expanded shape.
The partial expansion state can also be achieved by partially inflating the proximal section of the conduit with a separate balloon on the delivery device. Another possible method is to design the conduit to preferentially expand the proximal section before the distal section, thereby partially expanding the conduit to create the size differential, placing the stent inside the airway wall with the aid of the stop, and then fully expanding the conduit.
Control Members
The conduit 200 shown in
Typically, one end of the center-control segment is attached or joined to the center section at one location (e.g., a first rib) and the other end of the center-control segment is connected to the center section at a second location (e.g., a rib adjacent or opposite to the first rib). However, 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.
As shown in
This also serves to control the deployed shape of the conduit by, for instance, forcing angle A1 to differ from angle A2. Using control segments in this manner can provide for cone-shaped conduits if the various types of control-segments have different lengths. For example, providing longer proximal-control segments than distal-control segments can make angle A1 larger than angle A2. Additionally, cylindrical-shaped conduits may be provided if the center-control segments and the extension-control segments are sized similarly such that angle A1 equals angle A2. Again, the control segments straighten as the conduit expands and the conduit is thus prevented from expanding past a predetermined amount.
The control segments, as with other components of the conduit, may be added or mounted to the center section or alternatively, they may be integral with the center section. That is, the control segments may be part of the conduit rather than separately joined to the conduit 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 conduit may be removed to allow areas of the conduit to deform more readily. These weakened areas provide another approach to control the final shape of the deployed conduit. Details for creating and utilizing weakened sections to control the final shape of the deployed conduit may be found in U.S. patent Ser. No. 09/947,144 filed on Sep. 4, 2001.
Manufacture and Materials
The conduit 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 conduit may be formed from a tube that is slit to form extension members and a center section between the members. One variation of the conduit may be constructed from a metal tube, such as stainless steel, 316L stainless steel, titanium, titanium alloy, nitinol, MP35N (a nickel-cobalt-chromium-molybdenum alloy), etc. Also, the conduit may be formed from a rigid or elastomeric material that is formable into the configurations described herein. Also, the conduit may be formed from a cylinder with the passageway being formed through the conduit. The conduit 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 conduit 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 conduit is a polymeric elastic tube (e.g. a thermoplastic elastomer), the conduit may be extruded and cut to size, injection molded, or otherwise formed.
Additionally, the conduits 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 conduit 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 conduit to assume the deployed configuration. A conduit 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 conduit 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 conduit described herein may be formed of a plastically deformable material such that the conduit is expanded and plastically deforms into a deployed configuration. The conduit may be expanded into its expanded state by a variety of devices such as, for example, a balloon catheter.
The conduit'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 conduit from being ejected or occluded by tissue overgrowth. On the other hand, the surface may be roughened or porous. The conduit may also comprise various coatings and tissue barriers as discussed below.
Tissue Barrier
The tissue barrier may be formed from a material, mesh, sleeve, or coating that is a polymer or an elastomer such as, for example, silicone, fluorosilicone, polyurethane, PET, PTFE, or expanded PTFE. Other biocompatible materials will work, such as a thin foil of metal, etc. The coatings may be applied, for example, by either dip coating, molding, spin-coating, transfer molding or liquid injection molding. Alternatively, the tissue barrier may be a tube of a material and the tube is placed either over and/or within the conduit. The tissue barrier may then be bonded, crimped, heated, melted, shrink fitted or fused to the conduit. The tissue barrier may also be tied to the conduit with a filament of, for example, a suture material.
Still other techniques for attaching the tissue barrier include: solvent swelling applications and extrusion processes; wrapping a sheet of material about the conduit, or placing a tube of the material about the conduit and securing the tube to the conduit. The tissue barrier may be secured on the interior of the conduit by positioning a sheet or tube of material on the inside of the center section and securing the material therein.
The tissue barrier 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 tissue barrier. 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. Given the mesh's radial strength or lack thereof, the use of a reinforcement element serves to prevent the implant from collapsing. Also, as described below, other substances may be applied to the exterior surface of the conduit to control elution of various medicines.
Additionally, the tissue barrier 330 covers only a first region 350 of the extension members and leaves a second region 340 of the extension members uncovered. The second or free region 340 of the extension members 320 is shown as being open-framed. However, the invention is not so limited. The second region of the extension members may be solid and it may include indentations, grooves, and recesses for tissue ingrowth. Also, the extension members may include small holes for tissue ingrowth. For example, the second region of the extension members may have a dense array of small holes. In any event, the conduits described herein may include at least one region or surface which is susceptible to tissue ingrowth or is otherwise adherent to the tissue. Accordingly, tissue ingrowth at the second region 340 of the extension members is facilitated while tissue growth into the passageway 325 is thwarted.
As shown in
Visualization Feature
The conduit shown in
The visualization ring or mark may be a biocompatible polymer and have a color such as white. 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 conduit. 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 tissue barrier. For example, a clear silicone barrier may be coated onto the conduit such that it coaxially covers the extension members and the center section 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 conduit as shown in
Accordingly, the visualization member is made visually apparent for use with, for example, an endoscope. The visualization feature, however, may also be made of other vision-enhancing materials such as radio-opaque metals used in x-ray detection. It is also contemplated that other elements of the conduit can include visualization features such as but not limited to the extension members, tissue barrier, control segments, etc.
In some variations of the invention, it was found that incorporation of a bioactive, as discussed herein, or other substance into the coating caused a coloration effect in the composition layer (e.g., the polymer turns white). This coloration obscures the support member structure in the layer making it difficult to identify the edges and center of the support member or implant. As discussed herein, placement of the implant may depend upon positioning the center of the implant within the opening in tissue. If the support member structure is identifiable, then one is able to visually identify the center of the implant. When the composition colors obscures the support member or renders the implant otherwise opaque, it may become difficult to properly place the device. This may be especially true when the composition layer extends continuously over the support member.
Additionally, the coloration may render the visualization mark difficult to identify especially under direct visualization (e.g., using a scope) In some cases it was undesirable to simply add additional substances on or in the composition layer for marking because such substances could possibly interfere with the implant's ability to deliver the substance as desired. To address these issues, a variation of the invention includes a delivery device for delivering an 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 they 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 is 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.
Bioactive Agents
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.
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 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.
Channel Creation Devices and Methods
As discussed above, the use of low temperature devices, (e.g., mechanical devices, newer generation RF-type devices, etc.) to create the channel may result in less trauma to surrounding tissue and minimize the healing response of the tissue.
As shown in
The piercing member 604 may have a lumen and may be open at a distal end or closed. In those cases where the piercing member 604 is hollow and has an opening at or near the distal end, the surgeon may aspirate the site using the piercing member 604 to determine whether a blood vessel is present and/or penetrated. For example, flashback catheters contain chambers which will fill with blood upon the penetration of a vessel by the distal tip of the catheter. The piercing member may be incorporated to have a flashback chamber to detect the presence of blood flow from a penetrated vessel. Using these approaches, a target site may not be selected until after a hole is made in the airway 100 wall. It should be noted that a piercing member may be of a diameter which results in closure of the puncture site upon removal of the piercing member. Alternatively, the piercing member may be of a sufficient size or construction that the hole remains open upon removal of the piercing member. In any case, the piercing member or another device may be used to mark the site of the opening (e.g., via ink, dye, physical marker, via application of electrical energy, etc.) Furthermore, the invention includes use of both a detecting device as described above in combination with a piercing member. For example, the site may be inspected by the detecting device prior to insertion of a piercing member.
The piercing member lumen may also used to deliver therapeutic fluids to the lungs. For example, in case of bleeding after channel creation the physician may apply epinephrine or saline the lungs. Alternatively the physician may use the piercing member to apply epinephrine to the airway wall prior to creation of the channel, to prevent bleeding. This may be done by injecting directly into the airway wall at or about the site of passage creation; singly or in a surrounding pattern of multiple applications. The physician may also use the piercing member lumen to apply any of the bioactive agents discussed herein, before or after passage creation.
Because it may be desirable to reach remote airways within the lung, it may be necessary to fully articulate the scope 404 to access and inspect a desirable site. Therefore, to inspect the site and create an opening, it may be desirable to maintain the scope 404 in a fixed position and simply advance/retract various components of the scope or devices in the scope. Accordingly, a piercing member may be selected to have a length that will sufficiently pass through the airway wall, while being small enough that it will also pass through a fully articulated bronchoscope. Furthermore, the piercing member may have sections of varying stiffness where a distal portion, (that is sufficient stiff to penetrate the tissue) may be of a length such that it is able to advance through a fully articulated bronchoscope. For example, the piercing member may comprised of a sharpened cannula which has a length from between 2 mm to 30 mm. The diameter may range between 16 Ga to 25 Ga or larger. The cannula may be affixed to a catheter having a relatively flexible proximal portion. In any case, the length of the piecing member 604 may vary as needed.
The piercing member is not limited to a cannula, it may be of solid construction, such as a sharpened rod or wire. Additionally the piercing member may be adapted with an elongate member, such as a wire, rod, or tube, which extends throughout the device. The purpose of the elongate member is to provide column strength to the piercing member and necessary bending resistance to the catheter, because it has been found that the device must have high column strength to effectively pierce the airway wall, otherwise the device will deflect and not create a passageway. The elongate member may be utilized to expose and retract the piercing member within the catheter, as the elongate member may extend throughout the device to a user interface. The elongate member and piercing member may also be constructed from one piece of material, thereby making them one part. Alternatively the elongate member may be a separate part welded, bonded, mechanically attached, or a combination thereof, to the piercing member.
However, it is understood, that the current invention is not limited to any particular length of the piercing member. Furthermore, the piercing member may be comprised of a resilient polymer, a polymer with a reinforced structure (e.g., a braid, coil, etc.), a super-elastic alloy, a metallic material with sufficient resilience, etc, such that it may navigate through a fully articulated bronchoscope yet return to its original profile upon exiting the working channel of the scope.
In some variations of the invention, the piercing member of the device may be retractable within a lumen of an elongate shaft so as to prevent damage to the bronchoscope or to tissue as the device advances to the target site. Additionally the piercing member may be retracted after the initial piercing of the airway wall, and blunt trauma may be used to further push the remaining portion of the catheter into the airway wall. This technique may help avoid additional bleeding and pneumothoraxes from an exposed piercing member. The catheter may be advanced to tortuous locations, therefore the device may incorporate low friction materials to make it easier to reach the treatment site. The materials may be selected from a group of low friction polymers, for example PTFE. Low friction materials may also be applied as a coating onto the pierced member or elongate member, for example PTFE or titanium nitride. Reducing the contact surface area between the members may also help to reduce friction. Adding or removing material from the surfaces of members is one way to reduce contact surface area. For example attaching a closed coiled spring around the piercing member or elongate member, effectively reduces the surface area contacted between the elongate member and lumen because only the peaks of the coils contact the lumen.
In additional variations of the invention, as shown in
The piercing member 604 may also be used to deliver bioactive substances (as described herein) to the site of the opening. In such a case, the piercing member 604 may deliver the bioactive substance during creation of the opening (e.g., see
It is also contemplated that variations of the invention include a piercing member which is affixed to the catheter. Alternatively, the piercing member could have a flexible body that extends through the catheter to a proximal hub which is able to be coupled to a vacuum source, a source of medication, etc. Furthermore, either the piercing member and/or balloon catheter may be “pre-loaded” with a bioactive substance. Such a feature allows improves the precision of amount of substance delivered to the desired site.
As mentioned above, the piercing member 604 may be of a sufficient size or construction that the hole remains open upon removal of the piercing member. Once variation of this as shown in
The makeup of airway tissue may require a considerable amount of force to create a channel with the piercing device. Therefore, it will generally be easier to create a channel if the device has sufficient column strength to avoid bending of the device when applying a force at the proximal end of the device.
Additional variations of the invention may incorporate a nondistensible balloon to overcome the toughness of the airway tissue. Nondistensible balloons are generally made up of relatively inelastic materials consisting of PET, nylons, polyurethanes, polyolefins, PVC, and other crosslinked polymers. The makeup of airway tissue may be very tough and resist radial expansions. Therefore it will be generally easier to expand the channel in the airway wall using high pressure nondistensible balloons (>6 atm), which generally inflate in a uniform shape.
Nondistensible balloons will occupy a greater mass than distensible balloons because they in an inelastic predetermined form. Too much balloon mass will have too large of a working diameter, which in turn will hinder entry into a channel. Working diameter is the smallest effective diameter opening the uninflated nondistensible balloon can be inserted into. Therefore it is desirable to have the uninflated nondistensible balloon to have a working diameter close to the diameter of the piercing device 604. This can be attained by using a thin walled balloon, using a balloon with a small distal profile, by using a balloon with a distal end which is close in actual diameter to the diameter of the piercing member, or by using a balloon which folds into a low profile state, or a combination of these.
As shown in
Variations of the invention include a depth limiting feature that may prevent inadvertent advancement of the device when creating the channel. One example of this may be a circular tube 654 placed over the device and set at a fixed distance (e.g. 10 mm) from the distal tip of the piercing member, proximal to the balloon, as shown in
As shown in
The collar 650 protects the bronchoscope by preventing deflection of the distal tip. Deflection can take place when there is a significant amount of gap between the inner sheath 622 and the distal tip of the piercing member in the retracted mode. When the device is being maneuvered through a bronchoscope in a torturous configuration, the lumen 656 can deflect while the stiffer piercing member will not, and thus the piercing member may pierce through the deflected lumen 656 and subsequently into the bronchoscope. By setting a small gap (e.g. <1 mm) this deflection may be eliminated, and the scope protected.
The collar 650 also allows the piercing member to be reliably extended. It was found that when a similar feature was placed at the proximal section of the device the piercing member could not reliably be extended to a set distance beyond the distal tip. This is because when in a torturous configuration the outer sheath 620 of the device may have a tendency to stretch or compress. As a result the tubing may stretch to such a degree that when the piercing member is fully extended it still may not fully extend past the distal tip of the lumen 656. By locating the collar 650 in the distal portion of the lumen 656 (e.g. less than 2 inches from the distal tip) the stretching or compression is minimized or eliminated.
Conduit Deployment Devices and Methods
It should be noted that deployment of conduits is not limited to that shown in
In one additional variation of the invention, as shown in
In use, the conduit 200 is deployed with the distal side towards the parenchymal tissue 460 while the proximal side remains adjacent or in the airway 450. Of course, where the proximal and distal extension members are identical, the conduit may be deployed with either side towards the parenchymal tissue.
In any case, after creation of the channel 112 the surgeon may advance a balloon catheter 630 containing a conduit 200 towards the site of the opening 112. The variation of the balloon catheter 630 depicted in the figure also includes a guide body 632. Because the opening 112 may be difficult to locate, the guide body 632 may serve various functions to assist in locating the opening 112 and placing the conduit 200. For example, as shown in
As shown in
The balloon catheters 630 of the present invention may include a dilating member between the guide body 632 and balloon 614. In the variation shown in
Any of the balloons described herein may be distensible balloons (e.g., they assume a predetermined shape upon expansion) or elastic balloons (e.g., simply expand). Use of a distensible balloon permits control in dilating the opening 112 or placement of the conduit.
All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. To the extent there is a conflict in a meaning of a term, or otherwise, the present application will control. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims. It is also contemplated that combinations of the above described embodiments/variations or combinations of the specific aspects of the above described embodiments/variations 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)^½ 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 in addition polymerization by platinum catalyst.
The composition for the example may be as follow: polymer part: polydimethylsiloxane, vinyldimethyl terminated, any viscosity; and/or polydimethylsiloxane, vinylmonomethyl terminated, any viscosity. The cross-linker part: polydimethylsiloxane, any viscosity; and or polymonomethylsiloxane, any viscosity. Platinum catalyst part and/or cross-linker part: platinum; and/or platinum-divinyltetramethyldisiloxane complex in xylene, 2-3% Pt; and/or platinum-divinyltetramethyldisiloxane complex in vinyl terminated polydimethylsiloxane, 2-3% Pt; and/or platinum-divinyltetramethyldisiloxane complex in vinyl terminated polydimethylsiloxane, ˜1% Pt; platinum-Cyclovinylmethylsiloxane complex, 2-3% Pt in cyclic vinyl methyl siloxane.
These components may be combined in different ratios to make the polymer. The hydrocarbon side chain off the silicone back bone makes this polymer system unique and may result in a “zero-order”-like release profile. The amount of vinyl siloxane cross-linker may determine the rate of the drug release and diffusivity of the polymer to the drug. There are other types of polydimethylsiloxanes such as: trimethylsiloxy terminated polydimethylsiloxane in various viscosities, (48-96%) dimethyl (4-52%) diphenylsiloxane copolymer in various viscosities, dimethylsiloxane-ethylene oxide copolymer, dimethyl diphenylsiloxane copolymer, polymethylhydrosiloxane, trimethylsilyl terminated at various viscosities, (30-55%) methyldro-(45-70%) dimethylsiloxane copolymer at various viscosities, polymethylphenylsiloxane, polydimethylsiloxane silanol terminated at various viscosities, polydimethylsiloxane aminopropyldimethyl terminated at various viscosities. For paclitaxel a release profile was found to be acceptable with a polymer system consisting of polydimethylsiloxane vinyl terminated at various viscosity and a range of platinum-mono, di, tri and/or tetramethyldisiloxane complex.
This application is a continuation of U.S. patent application Ser. No. 11/335,263 filed Jan. 18, 2006, which is a continuation of International Application Number PCT/US2004/023304 filed Jul. 19, 2004 which claims the benefit under 35 U.S.C. §119(e) of Provisional Application No. 60/488,332 filed Jul. 18, 2003, the contents of each of which are incorporated by reference herein in their entirety.
| Number | Name | Date | Kind |
|---|---|---|---|
| 2127903 | Bowen | Aug 1938 | A |
| 3174851 | Buehler et al. | Mar 1965 | A |
| 3351463 | Rozner et al. | Nov 1967 | A |
| 3433226 | Boyd | Mar 1969 | A |
| 3490457 | Petersen | Jan 1970 | A |
| 3565062 | Kuris | Feb 1971 | A |
| 3617060 | Lezzi | Nov 1971 | A |
| 3707151 | Jackson | Dec 1972 | A |
| 3753700 | Harrison et al. | Aug 1973 | A |
| 3779234 | Eggleton et al. | Dec 1973 | A |
| 3823717 | Pohlman et al. | Jul 1974 | A |
| 3828790 | Curtiss et al. | Aug 1974 | A |
| 3874388 | King et al. | Apr 1975 | A |
| 3889688 | Eamkaow | Jun 1975 | A |
| 3942530 | Northeved | Mar 1976 | A |
| 4249539 | Vilkomerson et al. | Feb 1981 | A |
| 4249541 | Pratt | Feb 1981 | A |
| 4319580 | Colley et al. | Mar 1982 | A |
| 4324235 | Beran | Apr 1982 | A |
| 4327739 | Chmiel et al. | May 1982 | A |
| 4332254 | Lundquist | Jun 1982 | A |
| 4355426 | MacGregor | Oct 1982 | A |
| 4407294 | Vilkomerson | Oct 1983 | A |
| 4431006 | Trimmer et al. | Feb 1984 | A |
| 4469142 | Harwood | Sep 1984 | A |
| 4493320 | Treat | Jan 1985 | A |
| 4503569 | Dotter | Mar 1985 | A |
| 4534761 | Raible | Aug 1985 | A |
| 4538606 | Whited | Sep 1985 | A |
| 4538618 | Rosenberg et al. | Sep 1985 | A |
| 4582067 | Silverstein et al. | Apr 1986 | A |
| 4583969 | Mortensen | Apr 1986 | A |
| 4622968 | Persson | Nov 1986 | A |
| 4655771 | Wallsten | Apr 1987 | A |
| 4658817 | Hardy | Apr 1987 | A |
| 4674498 | Stasz | Jun 1987 | A |
| 4676782 | Yamamoto et al. | Jun 1987 | A |
| 4682596 | Bales et al. | Jul 1987 | A |
| 4687482 | Hanson | Aug 1987 | A |
| 4706689 | Man | Nov 1987 | A |
| 4750902 | Wuchinich et al. | Jun 1988 | A |
| 4753236 | Healey | Jun 1988 | A |
| 4757821 | Snyder | Jul 1988 | A |
| 4757822 | Di Giuliomaria et al. | Jul 1988 | A |
| 4767627 | Caldwell et al. | Aug 1988 | A |
| 4769031 | McGough et al. | Sep 1988 | A |
| 4770185 | Silverstein et al. | Sep 1988 | A |
| 4771788 | Millar | Sep 1988 | A |
| 4773413 | Hussein et al. | Sep 1988 | A |
| 4781676 | Schweighardt et al. | Nov 1988 | A |
| 4785402 | Matsuo et al. | Nov 1988 | A |
| 4795465 | Marten | Jan 1989 | A |
| 4802476 | Noerenberg et al. | Feb 1989 | A |
| 4807634 | Enjoji et al. | Feb 1989 | A |
| 4808153 | Parisi | Feb 1989 | A |
| 4834102 | Schwarzchild et al. | May 1989 | A |
| 4855563 | Beresnev et al. | Aug 1989 | A |
| 4862874 | Kellner | Sep 1989 | A |
| 4869268 | Yoon | Sep 1989 | A |
| 4870953 | Don Micheal et al. | Oct 1989 | A |
| 4887606 | Yock et al. | Dec 1989 | A |
| 4892098 | Sauer | Jan 1990 | A |
| 4892099 | Ohkawa et al. | Jan 1990 | A |
| 4899757 | Pope, Jr. et al. | Feb 1990 | A |
| 4917097 | Proudian et al. | Apr 1990 | A |
| 4920954 | Alliger et al. | May 1990 | A |
| 4924863 | Sterzer | May 1990 | A |
| 4930525 | Palestrant | Jun 1990 | A |
| 4936281 | Stasz | Jun 1990 | A |
| 4955377 | Lennox et al. | Sep 1990 | A |
| 4957508 | Kaneko et al. | Sep 1990 | A |
| 4966162 | Wang | Oct 1990 | A |
| 4967753 | Haase et al. | Nov 1990 | A |
| 4973301 | Nissenkorn | Nov 1990 | A |
| 4976690 | Solar et al. | Dec 1990 | A |
| 4977898 | Schwarzschild et al. | Dec 1990 | A |
| 5002058 | Martinelli | Mar 1991 | A |
| 5030201 | Palestrant | Jul 1991 | A |
| 5042981 | Gross | Aug 1991 | A |
| 5047026 | Rydell | Sep 1991 | A |
| 5054483 | Marten et al. | Oct 1991 | A |
| 5061275 | Wallsten et al. | Oct 1991 | A |
| 5064435 | Porter | Nov 1991 | A |
| 5069664 | Guess et al. | Dec 1991 | A |
| 5081993 | Kitney et al. | Jan 1992 | A |
| 5100423 | Fearnot | Mar 1992 | A |
| 5102417 | Palmaz | Apr 1992 | A |
| 5105816 | Shimura et al. | Apr 1992 | A |
| 5105817 | Uchibori et al. | Apr 1992 | A |
| 5123917 | Lee | Jun 1992 | A |
| 5125926 | Rudko et al. | Jun 1992 | A |
| 5127917 | Niederhauser et al. | Jul 1992 | A |
| 5131394 | Gehlbach | Jul 1992 | A |
| 5145684 | Liversidge et al. | Sep 1992 | A |
| 5148809 | Biegeleisen-Knight et al. | Sep 1992 | A |
| 5155435 | Kaufman et al. | Oct 1992 | A |
| 5170793 | Takano et al. | Dec 1992 | A |
| 5178635 | Gwon et al. | Jan 1993 | A |
| 5190528 | Fonger et al. | Mar 1993 | A |
| 5201316 | Pomeranz et al. | Apr 1993 | A |
| 5201741 | Dulebohn | Apr 1993 | A |
| 5209721 | Wilk | May 1993 | A |
| 5220924 | Frazin | Jun 1993 | A |
| 5226421 | Frisbie et al. | Jul 1993 | A |
| 5234447 | Kaster et al. | Aug 1993 | A |
| 5238027 | Lee | Aug 1993 | A |
| 5246011 | Caillouette | Sep 1993 | A |
| 5246014 | Williams et al. | Sep 1993 | A |
| 5254112 | Sinofsky et al. | Oct 1993 | A |
| 5257990 | Nash | Nov 1993 | A |
| 5259385 | Miller et al. | Nov 1993 | A |
| 5261409 | Dardel | Nov 1993 | A |
| 5263992 | Guire | Nov 1993 | A |
| 5269326 | Verrier | Dec 1993 | A |
| 5273529 | Idowu | Dec 1993 | A |
| 5275166 | Vaitekunas et al. | Jan 1994 | A |
| 5282799 | Rydell | Feb 1994 | A |
| 5282824 | Gianturco | Feb 1994 | A |
| 5287861 | Wilk | Feb 1994 | A |
| 5295484 | Marcus et al. | Mar 1994 | A |
| 5299578 | Rotteveel et al. | Apr 1994 | A |
| 5309915 | Ember | May 1994 | A |
| 5311871 | Yock | May 1994 | A |
| 5313950 | Ishikawa et al. | May 1994 | A |
| 5316001 | Ferek-Petric et al. | May 1994 | A |
| 5318564 | Eggers | Jun 1994 | A |
| 5320106 | Tanaka | Jun 1994 | A |
| 5330500 | Song | Jul 1994 | A |
| 5334146 | Ozasa | Aug 1994 | A |
| 5334183 | Wuchinich | Aug 1994 | A |
| 5334210 | Gianturco | Aug 1994 | A |
| 5339289 | Erickson | Aug 1994 | A |
| 5344420 | Hilal et al. | Sep 1994 | A |
| 5351693 | Taimisto et al. | Oct 1994 | A |
| 5363852 | Sharkawy | Nov 1994 | A |
| 5363853 | Lieber et al. | Nov 1994 | A |
| 5366504 | Andersen et al. | Nov 1994 | A |
| 5368035 | Hamm et al. | Nov 1994 | A |
| 5372138 | Crowley et al. | Dec 1994 | A |
| 5375602 | Lancee et al. | Dec 1994 | A |
| 5377682 | Ueno et al. | Jan 1995 | A |
| 5380316 | Aita et al. | Jan 1995 | A |
| 5381795 | Nordgren et al. | Jan 1995 | A |
| 5383460 | Jang et al. | Jan 1995 | A |
| 5383887 | Nadal | Jan 1995 | A |
| 5385148 | Lesh et al. | Jan 1995 | A |
| 5389096 | Aita et al. | Feb 1995 | A |
| 5402792 | Kimura | Apr 1995 | A |
| 5409012 | Sahatjian | Apr 1995 | A |
| 5409019 | Wilk | Apr 1995 | A |
| 5411466 | Hess | May 1995 | A |
| 5413601 | Keshelava | May 1995 | A |
| 5417697 | Wilk et al. | May 1995 | A |
| 5421955 | Lau | Jun 1995 | A |
| 5425739 | Jessen | Jun 1995 | A |
| 5427107 | Milo et al. | Jun 1995 | A |
| 5429144 | Wilk | Jul 1995 | A |
| 5435314 | Dias | Jul 1995 | A |
| 5443498 | Fontaine | Aug 1995 | A |
| 5443843 | Curatolo et al. | Aug 1995 | A |
| 5452733 | Sterman et al. | Sep 1995 | A |
| 5454373 | Koger et al. | Oct 1995 | A |
| 5454809 | Janssen | Oct 1995 | A |
| 5456258 | Kondo et al. | Oct 1995 | A |
| 5458120 | Lorraine | Oct 1995 | A |
| 5464016 | Nicholas et al. | Nov 1995 | A |
| 5465726 | Dickinson et al. | Nov 1995 | A |
| 5466242 | Mori | Nov 1995 | A |
| 5470308 | Edwards et al. | Nov 1995 | A |
| 5474075 | Goldberg et al. | Dec 1995 | A |
| 5484416 | Gittings | Jan 1996 | A |
| 5485841 | Watkin et al. | Jan 1996 | A |
| 5500012 | Brucker et al. | Mar 1996 | A |
| 5505088 | Chandraratna et al. | Apr 1996 | A |
| 5509900 | Kirkman | Apr 1996 | A |
| 5514154 | Lau et al. | May 1996 | A |
| 5520684 | Imran | May 1996 | A |
| 5522822 | Phelps et al. | Jun 1996 | A |
| 5524630 | Crowley | Jun 1996 | A |
| 5527292 | Adams et al. | Jun 1996 | A |
| 5527324 | Krantz et al. | Jun 1996 | A |
| 5540713 | Schnepp-Pesch et al. | Jul 1996 | A |
| 5545210 | Hess et al. | Aug 1996 | A |
| 5554118 | Jang | Sep 1996 | A |
| 5554152 | Aita et al. | Sep 1996 | A |
| 5555886 | Weng et al. | Sep 1996 | A |
| 5562922 | Lambert | Oct 1996 | A |
| 5564434 | Halperin et al. | Oct 1996 | A |
| 5571086 | Kaplan et al. | Nov 1996 | A |
| 5571180 | Blom | Nov 1996 | A |
| 5573531 | Gregory | Nov 1996 | A |
| 5575815 | Slepian et al. | Nov 1996 | A |
| 5575818 | Pinchuk | Nov 1996 | A |
| 5588432 | Crowley | Dec 1996 | A |
| 5593417 | Rhodes | Jan 1997 | A |
| 5593442 | Klein | Jan 1997 | A |
| 5596989 | Morita | Jan 1997 | A |
| 5607444 | Lam | Mar 1997 | A |
| 5615679 | Ri et al. | Apr 1997 | A |
| 5616608 | Kinsella et al. | Apr 1997 | A |
| 5618301 | Hauenstein et al. | Apr 1997 | A |
| 5629678 | Gargano et al. | May 1997 | A |
| 5629687 | Sutton et al. | May 1997 | A |
| 5630837 | Crowley | May 1997 | A |
| D380266 | Boatman et al. | Jun 1997 | S |
| 5638819 | Manwaring et al. | Jun 1997 | A |
| 5645559 | Hachtman et al. | Jul 1997 | A |
| 5647871 | Levine et al. | Jul 1997 | A |
| 5653746 | Schmitt | Aug 1997 | A |
| 5655548 | Nelson et al. | Aug 1997 | A |
| 5658279 | Nardella et al. | Aug 1997 | A |
| 5658280 | Issa | Aug 1997 | A |
| 5672172 | Zupkas | Sep 1997 | A |
| 5674242 | Phan et al. | Oct 1997 | A |
| 5674277 | Freitag | Oct 1997 | A |
| 5674298 | Levy et al. | Oct 1997 | A |
| 5678555 | O'Connell | Oct 1997 | A |
| 5682880 | Brain | Nov 1997 | A |
| 5693085 | Buirge et al. | Dec 1997 | A |
| 5704361 | Seward et al. | Jan 1998 | A |
| 5713949 | Jayaraman | Feb 1998 | A |
| 5716393 | Lindenberg et al. | Feb 1998 | A |
| 5718701 | Shai et al. | Feb 1998 | A |
| 5720735 | Dorros | Feb 1998 | A |
| 5725547 | Chuter | Mar 1998 | A |
| 5725572 | Lam et al. | Mar 1998 | A |
| 5733301 | Forman | Mar 1998 | A |
| 5736642 | Yost et al. | Apr 1998 | A |
| 5741234 | Aboul-Hosn | Apr 1998 | A |
| 5741333 | Frid | Apr 1998 | A |
| 5746767 | Smith | May 1998 | A |
| 5752518 | McGee et al. | May 1998 | A |
| 5755769 | Richard et al. | May 1998 | A |
| 5755778 | Kleshinski | May 1998 | A |
| 5759174 | Fischell et al. | Jun 1998 | A |
| 5759769 | Sia et al. | Jun 1998 | A |
| 5762638 | Shikani et al. | Jun 1998 | A |
| 5779642 | Nightengale | Jul 1998 | A |
| 5782762 | Vining | Jul 1998 | A |
| 5792119 | Marx | Aug 1998 | A |
| 5795325 | Valley et al. | Aug 1998 | A |
| 5807261 | Benaron et al. | Sep 1998 | A |
| 5810008 | Dekel et al. | Sep 1998 | A |
| 5810836 | Hussein et al. | Sep 1998 | A |
| 5819723 | Joseph | Oct 1998 | A |
| 5824046 | Smith et al. | Oct 1998 | A |
| 5824048 | Tuch | Oct 1998 | A |
| 5830191 | Hildwein et al. | Nov 1998 | A |
| 5830222 | Makower | Nov 1998 | A |
| 5840431 | Kall | Nov 1998 | A |
| 5843079 | Suslov | Dec 1998 | A |
| 5843158 | Lenker et al. | Dec 1998 | A |
| 5843175 | Frantzen | Dec 1998 | A |
| 5846205 | Curley et al. | Dec 1998 | A |
| 5849037 | Frid | Dec 1998 | A |
| 5855597 | Jayaraman | Jan 1999 | A |
| 5855598 | Pinchuk | Jan 1999 | A |
| 5860920 | McGee et al. | Jan 1999 | A |
| 5860951 | Eggers et al. | Jan 1999 | A |
| 5868763 | Spence et al. | Feb 1999 | A |
| 5868777 | Lam | Feb 1999 | A |
| 5873904 | Ragheb et al. | Feb 1999 | A |
| 5876345 | Eaton et al. | Mar 1999 | A |
| 5876434 | Flomenblit et al. | Mar 1999 | A |
| 5876445 | Andersen et al. | Mar 1999 | A |
| 5876448 | Thompson et al. | Mar 1999 | A |
| 5885219 | Nightengale | Mar 1999 | A |
| 5906587 | Zimmon | May 1999 | A |
| 5906621 | Secrest et al. | May 1999 | A |
| 5916158 | Webster, Jr. | Jun 1999 | A |
| 5919191 | Lennox et al. | Jul 1999 | A |
| 5922019 | Hankh et al. | Jul 1999 | A |
| 5935135 | Bramfitt et al. | Aug 1999 | A |
| 5938697 | Killion et al. | Aug 1999 | A |
| 5951567 | Javier, Jr. et al. | Sep 1999 | A |
| 5954636 | Schwartz et al. | Sep 1999 | A |
| 5954649 | Chia et al. | Sep 1999 | A |
| 5957849 | Munro | Sep 1999 | A |
| 5957919 | Laufer | Sep 1999 | A |
| 5957949 | Leonhardt et al. | Sep 1999 | A |
| 5957974 | Thompson et al. | Sep 1999 | A |
| 5967990 | Thierman et al. | Oct 1999 | A |
| 5968053 | Revelas | Oct 1999 | A |
| 5968070 | Bley et al. | Oct 1999 | A |
| 5971767 | Kaufman et al. | Oct 1999 | A |
| 5971980 | Sherman | Oct 1999 | A |
| 5972017 | Berg et al. | Oct 1999 | A |
| 5976178 | Goldsteen et al. | Nov 1999 | A |
| 5984871 | TenHoff et al. | Nov 1999 | A |
| 5989276 | Houser et al. | Nov 1999 | A |
| 5993484 | Shmulewitz | Nov 1999 | A |
| 5997547 | Nakao et al. | Dec 1999 | A |
| 6001124 | Bachinski | Dec 1999 | A |
| 6002955 | Willems et al. | Dec 1999 | A |
| 6003517 | Sheffield et al. | Dec 1999 | A |
| 6004269 | Crowley et al. | Dec 1999 | A |
| 6004273 | Sakamoto et al. | Dec 1999 | A |
| 6004319 | Goble et al. | Dec 1999 | A |
| 6007546 | Snow et al. | Dec 1999 | A |
| 6007574 | Pulnev et al. | Dec 1999 | A |
| 6010529 | Herweck et al. | Jan 2000 | A |
| 6011995 | Guglielmi et al. | Jan 2000 | A |
| 6013033 | Berger et al. | Jan 2000 | A |
| 6013093 | Nott et al. | Jan 2000 | A |
| 6013854 | Moriuchi | Jan 2000 | A |
| 6015405 | Schwartz et al. | Jan 2000 | A |
| 6015415 | Avelianet | Jan 2000 | A |
| 6019787 | Richard et al. | Feb 2000 | A |
| 6019789 | Dinh et al. | Feb 2000 | A |
| 6022371 | Killion | Feb 2000 | A |
| 6024703 | Zanelli et al. | Feb 2000 | A |
| 6024756 | Huebsch et al. | Feb 2000 | A |
| 6030392 | Dakov | Feb 2000 | A |
| 6032674 | Eggers et al. | Mar 2000 | A |
| 6036702 | Bachinski et al. | Mar 2000 | A |
| 6045511 | Ott et al. | Apr 2000 | A |
| 6045532 | Eggers et al. | Apr 2000 | A |
| 6048362 | Berg | Apr 2000 | A |
| 6053940 | Wijay | Apr 2000 | A |
| 6053941 | Lindenberg et al. | Apr 2000 | A |
| 6059731 | Seward et al. | May 2000 | A |
| 6059811 | Pinchasik et al. | May 2000 | A |
| 6063111 | Hieshima et al. | May 2000 | A |
| 6064902 | Haissaguerre et al. | May 2000 | A |
| 6066169 | McGuinness | May 2000 | A |
| 6068638 | Makower | May 2000 | A |
| 6070094 | Swanson et al. | May 2000 | A |
| 6074349 | Crowley | Jun 2000 | A |
| 6074362 | Jang et al. | Jun 2000 | A |
| 6074416 | Berg et al. | Jun 2000 | A |
| 6080109 | Baker et al. | Jun 2000 | A |
| 6083162 | Vining | Jul 2000 | A |
| 6093195 | Ouchi | Jul 2000 | A |
| 6096053 | Bates | Aug 2000 | A |
| 6099563 | Zhong | Aug 2000 | A |
| 6102887 | Altman | Aug 2000 | A |
| 6112123 | Kelleher et al. | Aug 2000 | A |
| 6113612 | Swanson et al. | Sep 2000 | A |
| 6117101 | Diederich et al. | Sep 2000 | A |
| 6120432 | Sullivan et al. | Sep 2000 | A |
| 6120534 | Ruiz | Sep 2000 | A |
| 6120803 | Wong et al. | Sep 2000 | A |
| 6124523 | Banas et al. | Sep 2000 | A |
| 6129726 | Edwards et al. | Oct 2000 | A |
| 6135997 | Laufer et al. | Oct 2000 | A |
| 6143019 | Motamedi et al. | Nov 2000 | A |
| 6152937 | Peterson et al. | Nov 2000 | A |
| 6152945 | Bachinski et al. | Nov 2000 | A |
| 6159225 | Makower | Dec 2000 | A |
| 6162245 | Jayaraman | Dec 2000 | A |
| 6165127 | Crowley | Dec 2000 | A |
| 6174323 | Biggs et al. | Jan 2001 | B1 |
| 6176872 | Miksza | Jan 2001 | B1 |
| 6181348 | Geiger | Jan 2001 | B1 |
| 6183444 | Glines et al. | Feb 2001 | B1 |
| 6186942 | Sullivan et al. | Feb 2001 | B1 |
| 6188355 | Gilboa | Feb 2001 | B1 |
| 6190353 | Makower et al. | Feb 2001 | B1 |
| 6197042 | Ginn et al. | Mar 2001 | B1 |
| 6200313 | Abe et al. | Mar 2001 | B1 |
| 6200564 | Lamont et al. | Mar 2001 | B1 |
| 6206831 | Suorsa et al. | Mar 2001 | B1 |
| 6226543 | Gilboa et al. | May 2001 | B1 |
| 6231587 | Makower | May 2001 | B1 |
| 6235024 | Tu | May 2001 | B1 |
| 6235054 | Berg et al. | May 2001 | B1 |
| 6239705 | Glen | May 2001 | B1 |
| 6241742 | Spence et al. | Jun 2001 | B1 |
| 6241746 | Bosma et al. | Jun 2001 | B1 |
| 6245020 | Moore et al. | Jun 2001 | B1 |
| 6245057 | Sieben et al. | Jun 2001 | B1 |
| 6245102 | Jayaraman | Jun 2001 | B1 |
| 6246784 | Summers et al. | Jun 2001 | B1 |
| 6254632 | Wu et al. | Jul 2001 | B1 |
| 6258100 | Alferness et al. | Jul 2001 | B1 |
| 6258115 | Dubrul | Jul 2001 | B1 |
| 6261601 | Talwar et al. | Jul 2001 | B1 |
| 6264690 | Von Oepen | Jul 2001 | B1 |
| 6270515 | Linden et al. | Aug 2001 | B1 |
| 6270524 | Kim | Aug 2001 | B1 |
| 6272366 | Vining | Aug 2001 | B1 |
| 6273907 | Laufer | Aug 2001 | B1 |
| 6280457 | Wallace et al. | Aug 2001 | B1 |
| 6283951 | Flaherty et al. | Sep 2001 | B1 |
| 6283983 | Makower et al. | Sep 2001 | B1 |
| 6283988 | Laufer et al. | Sep 2001 | B1 |
| 6287290 | Perkins et al. | Sep 2001 | B1 |
| 6290728 | Phelps et al. | Sep 2001 | B1 |
| 6292494 | Baker et al. | Sep 2001 | B1 |
| 6293951 | Alferness et al. | Sep 2001 | B1 |
| 6299604 | Ragheb et al. | Oct 2001 | B1 |
| 6299635 | Frantzen | Oct 2001 | B1 |
| 6306096 | Seward et al. | Oct 2001 | B1 |
| 6306097 | Park et al. | Oct 2001 | B1 |
| 6309375 | Glines et al. | Oct 2001 | B1 |
| 6309415 | Pulnev et al. | Oct 2001 | B1 |
| 6309416 | Swanson et al. | Oct 2001 | B1 |
| 6325825 | Kula et al. | Dec 2001 | B1 |
| 6328689 | Gonzalez et al. | Dec 2001 | B1 |
| 6331116 | Kaufman et al. | Dec 2001 | B1 |
| 6334869 | Leonhardt et al. | Jan 2002 | B1 |
| 6335029 | Kamath et al. | Jan 2002 | B1 |
| 6336933 | Parodi | Jan 2002 | B1 |
| 6342591 | Zamora et al. | Jan 2002 | B1 |
| 6343936 | Kaufman et al. | Feb 2002 | B1 |
| 6344053 | Boneau | Feb 2002 | B1 |
| 6346940 | Fukunaga | Feb 2002 | B1 |
| 6355057 | DeMarais et al. | Mar 2002 | B1 |
| 6371964 | Vargas et al. | Apr 2002 | B1 |
| 6379382 | Yang | Apr 2002 | B1 |
| 6380732 | Gilboa | Apr 2002 | B1 |
| 6391036 | Berg et al. | May 2002 | B1 |
| 6394093 | Lethi | May 2002 | B1 |
| 6394956 | Chandrasekaran et al. | May 2002 | B1 |
| 6409686 | Guthrie et al. | Jun 2002 | B1 |
| 6411852 | Danek et al. | Jun 2002 | B1 |
| 6440163 | Swanson et al. | Aug 2002 | B1 |
| 6451048 | Berg et al. | Sep 2002 | B1 |
| 6458153 | Bailey et al. | Oct 2002 | B1 |
| 6466687 | Uppaluri et al. | Oct 2002 | B1 |
| 6488673 | Laufer et al. | Dec 2002 | B1 |
| 6490474 | Willis et al. | Dec 2002 | B1 |
| 6493589 | Medhkour et al. | Dec 2002 | B1 |
| 6505065 | Yanof et al. | Jan 2003 | B1 |
| 6506408 | Palasis | Jan 2003 | B1 |
| 6508822 | Peterson et al. | Jan 2003 | B1 |
| 6511491 | Grudem et al. | Jan 2003 | B2 |
| 6514249 | Maguire et al. | Feb 2003 | B1 |
| 6514290 | Loomas | Feb 2003 | B1 |
| 6516213 | Nevo | Feb 2003 | B1 |
| 6528301 | Breme et al. | Mar 2003 | B1 |
| 6533812 | Swanson et al. | Mar 2003 | B2 |
| 6551302 | Rosinko et al. | Apr 2003 | B1 |
| 6554848 | Boylan et al. | Apr 2003 | B2 |
| 6556696 | Summers et al. | Apr 2003 | B1 |
| 6558333 | Gilboa et al. | May 2003 | B2 |
| 6574498 | Gilboa | Jun 2003 | B1 |
| 6575969 | Rittman et al. | Jun 2003 | B1 |
| 6585655 | Crowley | Jul 2003 | B2 |
| 6593884 | Gilboa et al. | Jul 2003 | B1 |
| 6599303 | Peterson et al. | Jul 2003 | B1 |
| 6599311 | Biggs et al. | Jul 2003 | B1 |
| 6602263 | Swanson et al. | Aug 2003 | B1 |
| 6615155 | Gilboa | Sep 2003 | B2 |
| 6616675 | Evard et al. | Sep 2003 | B1 |
| 6620176 | Peterson et al. | Sep 2003 | B1 |
| 6623437 | Hinchliffe et al. | Sep 2003 | B2 |
| 6629951 | Laufer et al. | Oct 2003 | B2 |
| 6634363 | Danek et al. | Oct 2003 | B1 |
| 6635279 | Kolter et al. | Oct 2003 | B2 |
| 6635281 | Wong et al. | Oct 2003 | B2 |
| 6652577 | Gianotti | Nov 2003 | B2 |
| 6652582 | Stinson | Nov 2003 | B1 |
| 6660015 | Berg et al. | Dec 2003 | B1 |
| 6663662 | Pacetti et al. | Dec 2003 | B2 |
| 6667051 | Gregory | Dec 2003 | B1 |
| 6673084 | Peterson et al. | Jan 2004 | B1 |
| 6689803 | Hunter | Feb 2004 | B2 |
| 6692494 | Cooper et al. | Feb 2004 | B1 |
| 6694163 | Vining | Feb 2004 | B1 |
| 6699256 | Logan et al. | Mar 2004 | B1 |
| 6702780 | Gilboa et al. | Mar 2004 | B1 |
| 6702829 | Bachinski et al. | Mar 2004 | B2 |
| 6711429 | Gilboa et al. | Mar 2004 | B1 |
| 6712804 | Roue et al. | Mar 2004 | B2 |
| 6712812 | Roschak et al. | Mar 2004 | B2 |
| 6712845 | Hossainy | Mar 2004 | B2 |
| 6719698 | Manor et al. | Apr 2004 | B2 |
| 6719781 | Kim | Apr 2004 | B1 |
| 6730064 | Ragheb et al. | May 2004 | B2 |
| 6730349 | Schwarz et al. | May 2004 | B2 |
| 6749576 | Bauer | Jun 2004 | B2 |
| 6749606 | Keast et al. | Jun 2004 | B2 |
| 6770070 | Balbierz | Aug 2004 | B1 |
| 6785410 | Vining et al. | Aug 2004 | B2 |
| 6790228 | Hossainy et al. | Sep 2004 | B2 |
| 6819785 | Vining et al. | Nov 2004 | B1 |
| 6829379 | Knoplioch et al. | Dec 2004 | B1 |
| 6833814 | Gilboa et al. | Dec 2004 | B2 |
| 6852111 | Lieber | Feb 2005 | B1 |
| 6866674 | Galdonik et al. | Mar 2005 | B2 |
| 6869443 | Buscemi et al. | Mar 2005 | B2 |
| 6872183 | Sampson et al. | Mar 2005 | B2 |
| 6886558 | Tanaka | May 2005 | B2 |
| 6890583 | Chudzik et al. | May 2005 | B2 |
| 6899731 | Li et al. | May 2005 | B2 |
| 6909913 | Vining | Jun 2005 | B2 |
| 6918869 | Shaw et al. | Jul 2005 | B2 |
| 6918927 | Bates et al. | Jul 2005 | B2 |
| 6920882 | Berg et al. | Jul 2005 | B2 |
| 6929637 | Gonzalez et al. | Aug 2005 | B2 |
| 6941950 | Wilson et al. | Sep 2005 | B2 |
| 6960219 | Grudem et al. | Nov 2005 | B2 |
| 6961600 | Kohl et al. | Nov 2005 | B2 |
| 6970733 | Willis et al. | Nov 2005 | B2 |
| 6994713 | Berg et al. | Feb 2006 | B2 |
| 6996430 | Gilboa et al. | Feb 2006 | B1 |
| 6997189 | Biggs et al. | Feb 2006 | B2 |
| 7011094 | Rapacki et al. | Mar 2006 | B2 |
| 7014654 | Welsh et al. | Mar 2006 | B2 |
| 7022088 | Keast et al. | Apr 2006 | B2 |
| 7052501 | McGuckin | May 2006 | B2 |
| 7086398 | Tanaka | Aug 2006 | B2 |
| 7149564 | Vining et al. | Dec 2006 | B2 |
| 7175644 | Cooper et al. | Feb 2007 | B2 |
| 7179220 | Kukuk | Feb 2007 | B2 |
| 7191101 | Knoplioch et al. | Mar 2007 | B2 |
| 7226442 | Sheppard, Jr. et al. | Jun 2007 | B2 |
| 7232409 | Hale et al. | Jun 2007 | B2 |
| 7236620 | Gurcan | Jun 2007 | B1 |
| 7260250 | Summers et al. | Aug 2007 | B2 |
| 7356367 | Liang et al. | Apr 2008 | B2 |
| 7422563 | Roshak et al. | Sep 2008 | B2 |
| 7481775 | Weiker et al. | Jan 2009 | B2 |
| 7483755 | Ingle et al. | Jan 2009 | B2 |
| 7517320 | Wibowo et al. | Apr 2009 | B2 |
| 7815590 | Cooper | Oct 2010 | B2 |
| 7963925 | Schecter | Jun 2011 | B1 |
| 7985187 | Wibowo et al. | Jul 2011 | B2 |
| 8235908 | Roschak et al. | Aug 2012 | B2 |
| 8337516 | Escudero et al. | Dec 2012 | B2 |
| 8409167 | Roshak | Apr 2013 | B2 |
| 8784400 | Roschak | Jul 2014 | B2 |
| 20010007940 | Tu et al. | Jul 2001 | A1 |
| 20010021872 | Bailey et al. | Sep 2001 | A1 |
| 20010026666 | Ferrera et al. | Oct 2001 | A1 |
| 20010027339 | Boatman et al. | Oct 2001 | A1 |
| 20010027341 | Gianotti | Oct 2001 | A1 |
| 20010044576 | Vining | Nov 2001 | A1 |
| 20010044650 | Simso et al. | Nov 2001 | A1 |
| 20010047180 | Grudem et al. | Nov 2001 | A1 |
| 20010052344 | Doshi | Dec 2001 | A1 |
| 20020002401 | McGuckin et al. | Jan 2002 | A1 |
| 20020022833 | Maguire et al. | Feb 2002 | A1 |
| 20020028006 | Novak et al. | Mar 2002 | A1 |
| 20020028008 | Fan et al. | Mar 2002 | A1 |
| 20020032477 | Helmus et al. | Mar 2002 | A1 |
| 20020042564 | Cooper et al. | Apr 2002 | A1 |
| 20020042622 | Vargas et al. | Apr 2002 | A1 |
| 20020049370 | Laufer et al. | Apr 2002 | A1 |
| 20020055772 | McGuckin et al. | May 2002 | A1 |
| 20020071902 | Ding et al. | Jun 2002 | A1 |
| 20020087153 | Roschak et al. | Jul 2002 | A1 |
| 20020091433 | Ding et al. | Jul 2002 | A1 |
| 20020111619 | Keast et al. | Aug 2002 | A1 |
| 20020111620 | Cooper et al. | Aug 2002 | A1 |
| 20020119178 | Levesque et al. | Aug 2002 | A1 |
| 20020123786 | Gittings et al. | Sep 2002 | A1 |
| 20020128647 | Roschak et al. | Sep 2002 | A1 |
| 20020131625 | Vining et al. | Sep 2002 | A1 |
| 20020133057 | Kukuk | Sep 2002 | A1 |
| 20020138074 | Keast et al. | Sep 2002 | A1 |
| 20020147462 | Mair | Oct 2002 | A1 |
| 20020161321 | Sweezer et al. | Oct 2002 | A1 |
| 20020161377 | Rabkin | Oct 2002 | A1 |
| 20030017150 | Torphy | Jan 2003 | A1 |
| 20030070676 | Cooper et al. | Apr 2003 | A1 |
| 20030120292 | Park et al. | Jun 2003 | A1 |
| 20030130575 | Desai | Jul 2003 | A1 |
| 20030130657 | Tom et al. | Jul 2003 | A1 |
| 20030153971 | Chandrasekaran | Aug 2003 | A1 |
| 20030204138 | Choi | Oct 2003 | A1 |
| 20030216806 | Togawa et al. | Nov 2003 | A1 |
| 20040055606 | Hendricksen et al. | Mar 2004 | A1 |
| 20040060563 | Rapacki et al. | Apr 2004 | A1 |
| 20040073155 | Laufer et al. | Apr 2004 | A1 |
| 20040073201 | Cooper et al. | Apr 2004 | A1 |
| 20040073284 | Bates et al. | Apr 2004 | A1 |
| 20040078054 | Biggs et al. | Apr 2004 | A1 |
| 20040093070 | Hojeibane et al. | May 2004 | A1 |
| 20040211434 | Loomas et al. | Oct 2004 | A1 |
| 20040220496 | Gonzalez | Nov 2004 | A1 |
| 20040220556 | Cooper et al. | Nov 2004 | A1 |
| 20040261203 | Dworzan | Dec 2004 | A1 |
| 20050016530 | McCutcheon et al. | Jan 2005 | A1 |
| 20050043751 | Phan et al. | Feb 2005 | A1 |
| 20050043752 | Phan et al. | Feb 2005 | A1 |
| 20050049615 | Cooper et al. | Mar 2005 | A1 |
| 20050056292 | Cooper | Mar 2005 | A1 |
| 20050060041 | Phan et al. | Mar 2005 | A1 |
| 20050060042 | Phan et al. | Mar 2005 | A1 |
| 20050060044 | Roschak et al. | Mar 2005 | A1 |
| 20050085801 | Cooper et al. | Apr 2005 | A1 |
| 20050096529 | Cooper et al. | May 2005 | A1 |
| 20050107679 | Geiger et al. | May 2005 | A1 |
| 20050107783 | Tom et al. | May 2005 | A1 |
| 20050135662 | Vining et al. | Jun 2005 | A1 |
| 20050137518 | Biggs et al. | Jun 2005 | A1 |
| 20050137611 | Escudero et al. | Jun 2005 | A1 |
| 20050137712 | Biggs et al. | Jun 2005 | A1 |
| 20050137715 | Phan et al. | Jun 2005 | A1 |
| 20050147284 | Vining et al. | Jul 2005 | A1 |
| 20050165342 | Odland | Jul 2005 | A1 |
| 20050171527 | Bhola | Aug 2005 | A1 |
| 20050177144 | Phan et al. | Aug 2005 | A1 |
| 20050182295 | Soper et al. | Aug 2005 | A1 |
| 20050182475 | Jen et al. | Aug 2005 | A1 |
| 20050192526 | Biggs et al. | Sep 2005 | A1 |
| 20050228268 | Cole | Oct 2005 | A1 |
| 20050251202 | Ewers et al. | Nov 2005 | A1 |
| 20050261550 | Akimoto et al. | Nov 2005 | A1 |
| 20050288549 | Mathis | Dec 2005 | A1 |
| 20060023966 | Vining | Feb 2006 | A1 |
| 20060142672 | Keast et al. | Jun 2006 | A1 |
| 20060183973 | Kamrava | Aug 2006 | A1 |
| 20060254600 | Danek et al. | Nov 2006 | A1 |
| 20060276807 | Keast et al. | Dec 2006 | A1 |
| 20060280772 | Roschak et al. | Dec 2006 | A1 |
| 20060280773 | Roschak et al. | Dec 2006 | A1 |
| 20070010438 | Mayo et al. | Jan 2007 | A1 |
| 20070016072 | Grunwald et al. | Jan 2007 | A1 |
| 20070092864 | Reinhardt et al. | Apr 2007 | A1 |
| 20070123922 | Cooper et al. | May 2007 | A1 |
| 20070250070 | Nobis et al. | Oct 2007 | A1 |
| 20070255304 | Roschak et al. | Nov 2007 | A1 |
| 20080009760 | Wibowo et al. | Jan 2008 | A1 |
| 20080027273 | Gutterman | Jan 2008 | A1 |
| 20080039715 | Wilson et al. | Feb 2008 | A1 |
| 20080086107 | Roschak | Apr 2008 | A1 |
| 20080097139 | Clerc et al. | Apr 2008 | A1 |
| 20080213337 | Hermansson et al. | Sep 2008 | A1 |
| 20080302359 | Loomas et al. | Dec 2008 | A1 |
| 20080312543 | Laufer et al. | Dec 2008 | A1 |
| 20090054805 | Boyle, Jr. | Feb 2009 | A1 |
| 20090076491 | Roschak et al. | Mar 2009 | A1 |
| 20090124883 | Wibowo et al. | May 2009 | A1 |
| 20090131765 | Roschak et al. | May 2009 | A1 |
| 20090143678 | Keast et al. | Jun 2009 | A1 |
| 20090163949 | Rolnick et al. | Jun 2009 | A1 |
| 20090204005 | Keast et al. | Aug 2009 | A1 |
| 20090275840 | Roschak et al. | Nov 2009 | A1 |
| 20090287087 | Gwerder et al. | Nov 2009 | A1 |
| 20090318904 | Cooper et al. | Dec 2009 | A9 |
| 20100041949 | Tolkowsky | Feb 2010 | A1 |
| 20100268316 | Brenneman et al. | Oct 2010 | A1 |
| 20100305463 | Macklem et al. | Dec 2010 | A1 |
| 20100312141 | Keast et al. | Dec 2010 | A1 |
| 20110082456 | Welt et al. | Apr 2011 | A1 |
| 20110146673 | Keast et al. | Jun 2011 | A1 |
| 20110146674 | Roschak | Jun 2011 | A1 |
| 20110251592 | Biggs et al. | Oct 2011 | A1 |
| 20110306997 | Roshak et al. | Dec 2011 | A9 |
| 20120085346 | Roschak | Apr 2012 | A9 |
| 20120089116 | Roschak | Apr 2012 | A9 |
| 20120123264 | Keast et al. | May 2012 | A9 |
| 20120221013 | Hawkins et al. | Aug 2012 | A1 |
| 20120232523 | Roschak | Sep 2012 | A1 |
| 20120289776 | Keast et al. | Nov 2012 | A1 |
| 20120289815 | Keast et al. | Nov 2012 | A1 |
| 20130041373 | Laufer | Feb 2013 | A1 |
| 20130046198 | Roshak et al. | Feb 2013 | A1 |
| 20130046296 | Laufer | Feb 2013 | A1 |
| 20130123638 | Tom et al. | May 2013 | A1 |
| Number | Date | Country |
|---|---|---|
| 0316789 | May 1989 | EP |
| 0347098 | Dec 1989 | EP |
| 0443256 | Aug 1991 | EP |
| 1151729 | Nov 2001 | EP |
| 1400204 | Mar 2004 | EP |
| 1436022 | Jul 2004 | EP |
| 1485033 | Dec 2004 | EP |
| 1485035 | Dec 2004 | EP |
| 1509168 | Mar 2005 | EP |
| 1648283 | Apr 2006 | EP |
| 1648284 | Apr 2006 | EP |
| 1786499 | May 2007 | EP |
| 1802365 | Jul 2007 | EP |
| 2000-107178 | Apr 2000 | JP |
| 2001-104315 | Apr 2001 | JP |
| WO 8705739 | Sep 1987 | WO |
| WO 8906515 | Jul 1989 | WO |
| WO 9001300 | Feb 1990 | WO |
| WO 9108706 | Jun 1991 | WO |
| WO 9502361 | Jan 1995 | WO |
| WO 9639914 | Dec 1996 | WO |
| WO 9717014 | May 1997 | WO |
| WO 9717105 | May 1997 | WO |
| WO 9816161 | Apr 1998 | WO |
| WO 9828035 | Jul 1998 | WO |
| WO 9848706 | Nov 1998 | WO |
| WO 9901076 | Jan 1999 | WO |
| WO 9911182 | Mar 1999 | WO |
| WO 9925419 | May 1999 | WO |
| WO 9938454 | Aug 1999 | WO |
| WO 9960953 | Dec 1999 | WO |
| WO 0027313 | May 2000 | WO |
| WO 0045742 | Aug 2000 | WO |
| WO 0067825 | Nov 2000 | WO |
| WO 0072908 | Dec 2000 | WO |
| WO 0074579 | Dec 2000 | WO |
| WO 0113839 | Mar 2001 | WO |
| WO 0128433 | Apr 2001 | WO |
| WO 0132088 | May 2001 | WO |
| WO 0139672 | Jun 2001 | WO |
| WO 0149213 | Jul 2001 | WO |
| WO 0154585 | Aug 2001 | WO |
| WO 0170117 | Sep 2001 | WO |
| WO 0174274 | Oct 2001 | WO |
| WO 0189366 | Nov 2001 | WO |
| WO 0200278 | Jan 2002 | WO |
| WO 02064045 | Aug 2002 | WO |
| WO 02064190 | Aug 2002 | WO |
| WO 02069823 | Sep 2002 | WO |
| WO 03071924 | Sep 2003 | WO |
| WO 03073358 | Sep 2003 | WO |
| WO 03088820 | Oct 2003 | WO |
| WO 03097153 | Nov 2003 | WO |
| WO 03103479 | Dec 2003 | WO |
| WO 2005006963 | Jan 2005 | WO |
| WO 2005006964 | Jan 2005 | WO |
| WO 2006014731 | Feb 2006 | WO |
| WO 2006014732 | Feb 2006 | WO |
| WO 2006130821 | Dec 2006 | WO |
| WO 2006130873 | Dec 2006 | WO |
| WO 2007033379 | Mar 2007 | WO |
| WO 2007062406 | May 2007 | WO |
| Entry |
|---|
| Choong, C., et al., “Feasibility and safety of airway bypass stent placement and influence of topical mitomycin C on stent patency,” J. Thorac. Cardiovasc Surg., 129:632-638, 2005. |
| Choong, C., et al., “Prolongaton of patency of airway bypass stents with use of drug-eluting stents,” J. Thorac. Cardiovasc. Surg., 131: 60-64, 2006. |
| Cordis Johnson & Johnson Gateway LLC: Bx Velocity Stent. Viewed at: http://www.jnjgateway.com/home.jhtm?loc=USENG&page=viewContent&contentId=fc0de00100001015&parentId=fcde00100001015&specialty=Circulatory—Disease—Management&category=Cardiac—Diagnosis—Interventions&subcategory=Stents—Balloon—Expandable Viewed on Sep. 5, 2002, 4 pages. (please note p. 4 of 4 is blank). |
| Fessler, H., “Collateral Ventilation, the Bane of Bronchoscopic Volume Reduction,” Am J. Respir Crit. Care Med. (editorial), 171:423-425, 2005. |
| Flenley, D., et al., “Factors Affecting Gas Exchange by Collateral Ventilation in the Dog,” Respiration Physiology, 15:52-69, 1972. |
| Hogg, W., et al., “Gas Diffusion Across Collateral Channels,” Journal of Applied Physiology, 33(5):568-575. |
| Lausberg, H., et al., “Bronchial fenestraton improves expiratory flow in emphysematous human lungs,” Ann. Thorac. Surg., 75:393-398, 2003. |
| Macklem, P., “Collateral ventilation,” N. Engl. J. Med., 298(1):49-50, 1978. |
| Menkes, H., et al., “Influence of Surface Forces on Collateral Ventilation,” Journal of Applied Physiology, 31(4):544-549, 1971. |
| Panettieri, R., “Chronic Obstructive Pulmonary Disease,” Lippincott's Pathophysiology Series: Pulmonary Pathophysiology, pp. 93-107, Grippi, M., et al., eds., J.B. Lippincott Company, Philadelphia, PA, 1995. |
| Pulmonary and Critical Care Medicine. Interventional Bronchoscopy with Stent Implant: Stents. Viewed at: http://view.vcu.edu/pulm-ccm/stents.htm Viewed on Aug. 26, 2002. 2 pages. |
| Rendina, E., et al., “Feasibility and safety of the airway bypass procedure for patients with emphysema,” J. Thorac. Cardiovasc. Surg., 125:1294-1299, 2003. |
| Terry, P., et al., “Collateral Ventilation in Man,” The New England Journal of Medicine, 298(1):10-15, 1978. |
| Wagner, E., et al., “Direct Assessment of Small Airways Reactivity in Human Subjects,” Am. J. Respir. Crit. Care Med., 157:447-452, 1998. |
| Woolcock, A., et al., “Mechanical Factors Influencing Collateral Ventilation in Human, Dog and Pig Lungs,” Journal of Applied Physiology, 30(1):99-115, 1971. |
| Morrell et al, “Collateral ventilation and gas exchange in emphysema”, Am J Respir Crit Care Med; (3); Sep. 1994: pp. 635-641. |
| Number | Date | Country | |
|---|---|---|---|
| 20130123826 A1 | May 2013 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60488332 | Jul 2003 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 11335263 | Jan 2006 | US |
| Child | 13664862 | US | |
| Parent | PCT/US2004/023304 | Jul 2004 | US |
| Child | 11335263 | US |
