Patent Application
20240001086
The present invention generally relates to the field of treatment of the pulmonary diseases through the delivery of an agent to an airway of a patient.
Pulmonary diseases may cause a wide range of problems that adversely affect performance of the lungs. Pulmonary diseases, such as asthma and chronic obstructive pulmonary disease (“COPD”), may lead to increased airflow resistance in the lungs. Mortality, health-related costs, and the size of the population having adverse effects due to pulmonary diseases are all substantial. These diseases often adversely affect quality of life. Symptoms are varied but often include cough; breathlessness; and wheeze. In COPD, for example, breathlessness may be noticed when performing somewhat strenuous activities, such as running, jogging, brisk walking, etc. As the disease progresses, breathlessness may be noticed when performing non-strenuous activities, such as walking. Over time, symptoms of COPD may occur with less and less effort until they are present all of the time, thereby severely limiting a person's ability to accomplish normal tasks.
Pulmonary diseases are often characterized by airway obstruction associated with blockage of an airway lumen, thickening of an airway wall, alteration of structures within or around the airway wall, or combinations thereof. Airway obstruction can significantly decrease the amount of gas exchanged in the lungs, resulting in breathlessness. Blockage of an airway lumen can be caused by excessive intraluminal mucus or edema fluid, or both. Thickening of the airway wall may be attributable to excessive contraction of the airway smooth muscle, airway smooth muscle hypertrophy, mucous glands hypertrophy, inflammation, edema, or combinations thereof. Alteration of structures around the airway, such as destruction of the lung tissue itself, can lead to a loss of radial traction on the airway wall and subsequent narrowing of the airway.
A variety of solutions have been proposed for addressing pulmonary disorders, including COPD. One conventional treatment for COPD includes delivering the pharmaceutical drug tiotropium to the lungs via an inhaler. Typically, a patient places tiotropium capsules in a specially designed inhaler, and then breathes in dry powder contained in the capsules through the inhaler. This treatment must be administered on a recurring, sometimes daily, basis and its efficacy can be highly dependent on patient compliance.
Another conventional treatment includes maneuvering a catheter with an electrode to an affected area of the lungs and delivering thermal radiofrequency energy directly to the airway wall to directly heat the tissue and thereby reduce airway smooth muscle mass. This treatment, known as bronchial thermoplasty, requires patients to be treated over multiple sessions with each session targeting a different area of the lungs. Possible side-effects over the course of the treatments include asthma attacks, wheezing, chest discomfort, chest pain, partial collapse of the lungs, lower airway bleeding, anxiety, headaches, and nausea.
Several particularly effective treatments for pulmonary disorders are described in, for example, U.S. Pat. No. 8,088,127, titled, “Systems, Assemblies, and Methods for Treating a Bronchial Tree,” and U.S. Patent Application Publication No. 2011/0152855, titled, “Delivery Devices With Coolable Energy Emitting Assemblies.” In one example treatment described in these documents, a pulmonary treatment system delivers energy to damage a nerve trunk extending along a first airway of a patient, which thereby reduces airway resistance in a second airway distal to the first airway. This treatment provides numerous advantages over other, conventionally available treatments, including being far less invasive and requiring far fewer treatments.
It has been recognized that delivering an agent to an airway wall of a patient at a treatment location can affect nerves extending along the airway, thereby reducing airway obstruction in airways distal to the treatment location.
In one aspect, a medication delivery device for treatment of a pulmonary disorder in a patient includes an elongate member, an inflatable balloon coupled to a distal end of the elongate member, and an agent delivery portion coupled to an external surface of the inflatable balloon, the agent delivery portion including an agent that disrupts nerve activity, such as pulmonary nerve activity. In an embodiment, the inflatable balloon is configured to engage a wall of the airway when the balloon is in an inflated condition. The agent delivery portion is configured to be released from the external surface of the balloon, and absorbed into airway tissue to disrupt the nerve activity, and more particularly pulmonary nerve activity.
In some embodiments, the agent is intended to have a permanent effect on the nerves. In this case, the agent can be selected from a group of ribosome-inactivating proteins including ricin, abrin, and saporin. The agent can be selected from a group of agents consisting of phenol (3%), ropivacaine (also referred to as rINN, a local anesthetic that been shown to ablate nerve axons), sodium tetradecyl sulfate (STS) (1%-3%), polidocanol, ethanol (99.5%), sugar (hypertonic [50%] dextrose solution), ethanolamine oleate (5%), sodium morrhuate (5%), arsenic, nitric oxide, and glutonate.
In other examples, the agent is intended to have only a short term effect on the nerves. Such effects can be realized, for example, only while the agent delivery device, such as a drug eluting stent, is in place. In this case, the agent can be selected from a group consisting of lidocain, bupivacaine, mepivacaine, procainamide, mexiletine, tocainide, tetrodotoxin, tetraethylammonium, and chlorotoxin.
The balloon can be expandable to a size sufficient to bring an entire exposed surface of the agent delivery portion into direct contact with a body lumen at least 6 mm in diameter.
The exposed surface of the agent delivery portion can be a band that extends at least partially around a circumference of the balloon. The band can extend completely around the circumference of the balloon.
The agent delivery portion can be movable relative to the balloon. The agent delivery portion can be a ring that floats freely relative to the balloon.
The agent delivery portion can be a layer that directly coats a portion of the external surface of the balloon.
The balloon can be sized for treatment of a main stem bronchus or a lobar bronchus of an adult human between the ages of 21 and 58.
In another aspect, a medication delivery device for treatment of a pulmonary disorder in a patient includes an expandable member that includes a collapsed configuration for delivery to a treatment location in an airway of the patient and an expanded, treatment configuration in which an outside perimeter of the expandable member contacts an interior surface of the airway of the patient at the treatment location; and a medication delivery portion coupled to an exterior surface of the expandable member. The medication delivery portion can extend in a circumferential direction around the expandable member. The medication delivery portion can be sized to fit at least partially between two adjacent cartilage rings of the airway when the expandable member is in the expanded, treatment configuration. The medication delivery portion can include a medication that affects nerves that run along the airway so as to relieve airway obstruction in at least one airway distal to the treatment location.
In an embodiment, the medication can be configured to be released from the medication delivery portion when the expandable member is in the treatment configuration. In another embodiment, the medication can be configured to be released from the medication delivery portion when the expandable member is an air-filled environment. The medication in either embodiment can be configured to be absorbed by airway tissue to disrupt activity in the nerves.
The expandable member can be a basket that is configured for temporary deployment in the airway during treatment of the airway followed by withdrawal from the airway.
The expandable member can be a balloon. The medication delivery portion includes a raised portion of the balloon that includes a profile shaped to facilitate seating between the two adjacent cartilage rings. The medication delivery portion can be movable relative to the balloon to facilitate to facilitate seating between the two adjacent cartilage rings. The medication delivery portion can include a plurality of needles that extend radially outward from a surface of the balloon when the balloon is in the expanded, treatment configuration. The plurality of needles can be coated with the medication. The plurality of needles can be arranged around the circumference of the expandable member to preferentially target nerves located on a posterior side of the patient.
The expandable member can be a stent. The stent can be configured for permanent placement in the airway. The stent can be configured for temporary placement in the airway. The medication delivery portion can include a coating on struts of the stent. The medication delivery portion can include a covering that extends over struts of the stent. The medication delivery portion can include a raised portion that includes a profile shaped to facilitate engagement between the two adjacent cartilage rings. The raised portion can be movable relative to the stent to facilitate to facilitate seating between the two adjacent cartilage rings. The stent can include tapers on opposite ends that facilitate placement and retention in the airway of the patient.
The medication delivery device can further include a plurality of marking elements arranged on either side of the medication delivery portion to facilitate placement between the adjacent cartilage rings.
The agent can be selected from a group of ribosome-inactivating proteins including ricin, abrin, and saporin. The agent can be selected from a group of agents consisting of phenol (3%), ropivacaine (also referred to as rINN, a local anesthetic that been shown to ablate nerve axons), sodium tetradecyl sulfate (STS) (1%-3%), polidocanol, ethanol (99.5%), sugar (hypertonic [50%] dextrose solution), ethanolamine oleate (5%), sodium morrhuate (5%), arsenic, nitric oxide, and glutonate. The agent can be selected from a group consisting of lidocain, bupivacaine, mepivacaine, procainamide, mexiletine, tocainide, tetrodotoxin, tetraethylammonium, and chlorotoxin.
The expandable member can be sized for treatment of a main stem bronchus or a lobar bronchus of an adult human between the ages of 21 and 58.
In another aspect, a medication delivery system for treatment of a pulmonary disorder in a patient can include an elongate delivery device, and a medication delivery treatment device. The delivery device can include a lumen with an inside diameter ranging from 1.0 mm to 6.0 mm. The medication delivery treatment device includes an expandable member that includes a collapsed configuration for delivery through the lumen of the elongate delivery device to a treatment location in an airway of the patient and an expanded, treatment configuration in which an outside perimeter of the expandable member contacts an interior surface of the airway of the patient at the treatment location; and a medication delivery portion coupled to an exterior surface of the expandable member. The medication delivery portion includes a medication that affects nerves that run along the airway so as to relieve airway obstruction in at least one airway distal to the treatment location.
The elongate delivery device can be a flexible bronchoscope.
The expandable member can be an inflatable balloon. The expandable member can be a stent.
The medication delivery system can further include an elongate sheath including an outside diameter that is less than the inside diameter of the lumen of the flexible bronchoscope and an inside diameter that is greater than an outside diameter of the stent in the collapsed configuration.
The medication delivery system can further include a balloon dimensioned to expand the stent from the collapsed configuration to the expanded configuration.
The medication delivery system can further include a plurality of needles coupled to the medication delivery portion. Each of the needles can extend at least 2 mm radially beyond an external surface of the expandable member when the expandable member is in the expanded, treatment configuration.
In another aspect, a method of delivering medication to an airway of a patient to treat a pulmonary disorder in the patient includes positioning a distal end of an elongate member in treatment location in an airway of the patient, the elongate member including a medication delivery device having an expandable member and a medication delivery portion; at least partially expanding the expandable member; and positioning the medication delivery portion at least partially or completely between two adjacent cartilage rings in an airway wall of the airway; maintaining the medication delivery portion in close contact with the airway wall of the airway while the medication delivery portion is positioned at least partially or entirely between the adjacent cartilage rings so that a medication in the medication delivery portion transfers into the airway wall to affect nerves that run along the airway so as to relieve airway obstruction in at least one airway distal to the treatment location.
The expandable member can be an inflatable balloon, and the at least partially expanding the expandable member include filling the balloon with a fluid.
The maintaining the medication delivery portion in close contact with the airway wall can include rotating the medication delivery portion between the adjacent cartilage rings. Rotating the medication delivery portion can include partially deflating the balloon, then rotating the medication delivery device using the adjacent cartilage rings as a guide, and then inflating the balloon.
Positioning the medication delivery portion between two adjacent cartilage rings can include viewing the medication delivery portion through the balloon with an optical element of bronchoscope positioned proximal of the balloon. Viewing the medication delivery portion through the balloon can include optically coupling the optical element of the bronchoscope to a proximal portion of the balloon.
Positioning the medication delivery portion between two adjacent cartilage rings can include viewing at least one marking element adjacent the medication delivery portion through the balloon with an optical element of bronchoscope positioned proximal of the balloon. Viewing the least one marking element through the balloon can include optically coupling the optical element of the bronchoscope to a proximal portion of the balloon.
Positioning a distal end of an elongate member in treatment location can include advancing the medication delivery device through a working channel of a flexible bronchoscope. The working channel of the flexible bronchoscope can include an inside diameter in the range of 1.0 mm to 6.0 mm.
The expandable member can be a stent, and the at least partially expanding the expandable member can include expanding the stent within the airway of the patient. The method can further include removing the stent from the airway following treatment. Removing the stent from the airway following treatment can include removing the stent between about one minute and about two years after placing the stent in the airway. Removing the stent from the airway following treatment can include removing the stent between about four months and eight months after placing the stent in the airway. Removing the stent from the airway following treatment can include removing the stent about six months after placing the stent in the airway.
Positioning the medication delivery portion between two adjacent cartilage rings can include moving the medication delivery portion relative to the expandable member.
The method can further include pressing a plurality of needles positioned on the medication delivery portion into the airway wall.
The expandable member can be a basket, and the at least partially expanding the expandable member can include expanding the basket in the airway.
In an embodiment, the nerves can comprise nerve trunks extending along an outer surface of the airway wall. In another embodiment, the nerves are disposed at least about 1 mm radially outward from an inner surface of the airway wall.
In a particular embodiment, the airway obstruction can be relieved in the airway that is distal to the treatment location without positioning the medication delivery portion in the airway that is distal to the treatment location.
The drawings discussed in the detailed description are described briefly as follows, in which:
The left and right vagus nerves 41, 42 originate in the brainstem, pass through the neck, and descend through the chest on either side of the trachea 20. The vagus nerves 41, 42 spread out into nerve trunks 45 that include the anterior and posterior pulmonary plexuses that wrap around the trachea 20, the left main bronchus 21, and the right main bronchus 22. The nerve trunks 45 also extend along and outside of the branching airways of the bronchial tree 27. Nerve trunks 45 are the main stem of a nerve, comprising a bundle of nerve fibers bound together by a tough sheath of connective tissue. The primary function of the lungs 10 is to exchange oxygen from air into the blood and to exchange carbon dioxide from the blood to the air. The process of gas exchange begins when oxygen rich air is pulled into the lungs 10. Contraction of the diaphragm and intercostal chest wall muscles cooperate to decrease the pressure within the chest to cause the oxygen rich air to flow through the airways of the lungs 10. For example, air passes through the mouth and nose, the trachea 20, then through the bronchial tree 27. The air is ultimately delivered to the alveolar air sacs for the gas exchange process.
Oxygen poor blood is pumped from the right side of the heart through the pulmonary artery 30 and is ultimately delivered to alveolar capillaries. This oxygen poor blood is rich in carbon dioxide waste. Thin semi-permeable membranes separate the oxygen poor blood in capillaries from the oxygen rich air in the alveoli. These capillaries wrap around and extend between the alveoli. Oxygen from the air diffuses through the membranes into the blood, and carbon dioxide from the blood diffuses through the membranes to the air in the alveoli. The newly oxygen-enriched blood then flows from the alveolar capillaries through the branching blood vessels of the pulmonary venous system to the heart. The heart pumps the oxygen-rich blood throughout the body. The oxygen spent air in the lung is exhaled when the diaphragm and intercostal muscles relax and the lungs and chest wall elastically return to the normal relaxed states. In this manner, air can flow through the branching bronchioles, the bronchi 21, 22, and the trachea 20 and is ultimately expelled through the mouth and nose.
The nervous system provides communication between the brain and the lungs 10 using electrical and chemical signals. A network of nerve tissue of the autonomic nervous system senses and regulates activity of the respiratory system and the vasculature system. Nerve tissue includes fibers that use chemical and electrical signals to transmit sensory and motor information from one body part to another. For example, the nerve tissue can transmit motor information in the form of nervous system input, such as a signal that causes contraction of muscles or other responses. The fibers can be made up of neurons. The nerve tissue can be surrounded by connective tissue, i.e., epineurium. The autonomic nervous system includes a sympathetic system and a parasympathetic system. The sympathetic nervous system is largely involved in “excitatory” functions during periods of stress. The parasympathetic nervous system is largely involved in “vegetative” functions during periods of energy conservation. The sympathetic and parasympathetic nervous systems are simultaneously active and generally have reciprocal effects on organ systems. While innervation of the blood vessels originates from both systems, innervation of the airways are largely parasympathetic in nature and travel between the lung and the brain in the right vagus nerve 42 and the left vagus nerve 41.
Some of the nerve tissue in the network of nerve trunks 45 coalesce into other nerves (e.g., nerves connected to the esophagus, nerves though the chest and into the abdomen, and the like). Some fibers of anterior and posterior pulmonary plexuses coalesce into small nerve trunks which extend along the outer surfaces of the trachea 20 and the branching bronchi and bronchioles as they travel outward into the lungs 10. Along the branching bronchi, these small nerve trunks continually ramify with each other and send fibers into the walls of the airways, as discussed in connection with
Vagus nerve tissue includes efferent fibers and afferent fibers oriented parallel to one another within a nerve branch. The efferent nerve tissue transmits signals from the brain to airway effector cells, mostly airway smooth muscle cells and mucus producing cells. The afferent nerve tissue transmits signals from airway sensory receptors, which respond to irritants, and stretch to the brain. While efferent nerve tissue innervates smooth muscle cells all the way from the trachea 20 to the terminal bronchioles, the afferent fiber innervation is largely limited to the trachea 20 and larger bronchi. There is a constant, baseline tonic activity of the efferent vagus nerve tissues to the airways which causes a baseline level of smooth muscle contraction and mucous secretion.
Notably, cartilage rings in the trachea do not extend around the entire circumference of the trachea, but instead are discontinuous on a posterior side of the trachea, which faces the esophagus. The discontinuity of the cartilage rings accommodates expansion of the esophagus into the tracheal space, for example, as food is swallowed. The shape of cartilage rings contributes to the cross-sectional shape of the trachea. Studies of the trachea have revealed a diversity of cross-sectional shapes in different patients, including elliptical, C-shaped, U-shaped, D-shaped, triangular, and circular. In addition, the cross-sectional shape of the trachea can change during the respiratory cycle from, for example, an elliptical shape during inspiration to, for example, a horseshoe shape during exhalation.
The cartilage rings in the left and right main bronchus are also incomplete.
The airway 100 includes a lumen 101 defined by an inner surface 102 of the airway 100. The illustrated inner surface 102 is defined by a folded layer of epithelium 110 surrounded by stroma 112a. A layer of smooth muscle tissue 114 surrounds the stroma 112a. A layer of stroma 112b is between the muscle tissue 114 and connective tissue 124. Mucous glands 116, blood vessels 120, and nerve fibers 122 are within the stroma layer 112b. Smooth muscle bands 114a extend longitudinally along the posterior side of the airway 100, which is relatively loose when compared to the other portions of the airway 100 that are supported by the cartilage rings 28. Bronchial artery branches 130 and nerve trunks 45 are exterior to a wall 103 of the airway 100. The illustrated arteries 130 and nerve trunks 45 are within the connective tissue 124 surrounding the airway wall 103 and can be oriented generally parallel to the airway 100. In
The lumen 101b of the airway 100b in
Further, although the agent delivery systems described herein advantageously allow for a compact profile that facilitates compatibility with the working channel of a flexible bronchoscope, the aspects described herein are not so limited. For example, as will be readily apparent to one of ordinary skill in the art upon a complete review of the present disclosure, the aspects disclosed herein are also scalable to be compatible with larger working lumens that may or may not be associated with a bronchoscope. Notably, the present disclosure is not limited solely to systems that are delivered via the working channel of a bronchoscope, but also encompasses systems delivered by other means, such as an independent sheath and/or delivery catheter.
Although the agent delivery system 2000 is positioned in the left main bronchi in this example, the agent delivery system 2000 can be positioned in other locations outside the lung, such as within the right main bronchi, the lobar bronchi, and bronchus intermedius. The bronchus intermedius is the portion of the right main bronchus between the upper lobar bronchus and the origin of the middle and lower lobar bronchi. The agent delivery system 2000 can also be positioned in higher generation airways (e.g., airway generations >2) to affect remote distal portions of the bronchial tree 27. The agent delivery system 2000 can be navigated through tortuous airways to perform a wide range of different procedures, such as, for example, to deliver an agent to affect nerve activity in a portion of a lobe, an entire lobe, multiple lobes, or one lung or both lungs. In some embodiments, the lobar bronchi are treated to affect nerve activity in lung lobes. For example, one or more treatment sites along a lobar bronchus may be targeted to affect nerve activity in an entire lobe connected to that lobar bronchus. Left lobar bronchi can be treated to affect the left superior lobe and/or the left inferior lobe. Right lobar bronchi can be treated to affect the right superior lobe, the right middle lobe, and/or the right inferior lobe. Lobes can be treated concurrently or sequentially. In some embodiments, a physician can treat one lobe. Based on the effectiveness of the treatment, the physician can concurrently or sequentially treat additional lobe(s). In this manner, different isolated regions of the bronchial tree can be treated.
In this example, the agent delivery system 2000 is coupled to a steering mechanism 2100 and a fluid supply portion 2200.
In the present example, the agent delivery system 2000 delivers one or more treatment agents to an airway wall at a treatment site to affect activity of the nerves 122 or the nerve trunks 45 at the treatment site. As noted above, it has been found that attenuating the transmission of nervous system signals can alter airway smooth muscle tone, airway mucus production, airway inflammation, and the like in airways distal to the treatment site. Attenuation can include, without limitation, hindering, limiting, blocking, and/or interrupting the transmission of signals. For example, the attenuation can include decreasing signal amplitude of nerve signals or weakening the transmission of nerve signals.
In the present example, an agent is delivered to an airway wall to attenuate nervous system signals of nerves 45 that extend along the airway wall 100. For example, an agent can affect nerves at least about 1 mm radially outward from an inner surface of the airway wall. In some examples, the agent affects nerves as deep as 8 mm radially outward from an inner surface of the airway wall. In some examples, the agent affects nerve trunks extending along an outer surface of the airway wall.
Exemplary non-limiting treatment agents include, without limitation, one or more antibiotics, anti-inflammatory agents, pharmaceutically active substances, bronchoconstrictors, bronchodilators (e.g., beta-adrenergic agonists, anticholinergics, etc.), nerve blocking drugs, photoreactive agents, neurotoxins such as botulinum toxin, serotype A or botulinum toxin, serotype B including or combinations thereof. For example, long acting or short acting nerve blocking drugs (e.g., anticholinergics) can be delivered to nerve tissue extending along an airway wall to temporarily or permanently attenuate signal transmission. Substances can also be delivered directly to the nerves 122 or the nerve trunks 45, or both, to chemically damage the nerve tissue.
Other examples of agents that can induce axonal degeneration include calcium ionophores. An ionophore is a lipid soluble molecule usually synthesized by microorganisms to transport ions across the lipid bilayer. Calcium specific ionophores artificially increase intracellular calcium in axons. Increased intracellular calcium induces axonal degeneration through a mechanism similar to what occurs after axotomy.
In another example, the agent can include molecules that deplete intracellular Nmnat (nicotinamide mononucleotide adenyltransferase). Nmnat are enzymes that catalyze the chemical reaction that changes ATP to NAD. Nmnats are essential survival factors for maintenance of healthy axons. Depletion of isoforms of these enzymes in axons induces degeneration that is consistent with the degeneration that occurs after axotomy.
In another example, an agent can be rotenone and any molecule that cause mitochondrial dysfunction. These agents work by interfering with the electron transport chain in mitochondria. Rotenone works by inhibiting transfer of electrons from iron sulfur centers in complex 1 to ubiquinone. This interferes with NADH during the ATP synthesis.
Other examples of agents can include chemotherapy agents. For example, platinum agents (cisplatin, carboplatin, oxaliplatin), Vinca alkaloids (vinscristine, viniblastine), Taxanes (paclitaxel, docetaxel), Epothilones (ixabepalone), bortezomib, thalidomide, and lenolidamide.
There are three broad categories within which agents applied to an airway may act on nerves to disrupt nerve signaling. In the first category, an agent applied to an airway wall comes into contact with the nerve axons, is retrogradely transported to the cell body, and is toxic to the cell body thereby killing the cell body and all axons derived from that cell body, a process known as suicide transport. The broad class of agents that can cause this category of disruption are ribosome-inactivating proteins (RIPs). Specific agents include, but are not limited to ricin, abrin, and saporin. Ricin, for example, has been studied extensively for delivery to peripheral nerves, causing retrograde somal ablation with 50 ng to 3 μg doses. These types of agents have the potential to cause long term effects on nerve transmission.
In a second category, an agent applied to an airway causes injury to a nerve axon at the site of contact with loss of axons distal to the treatment site. However, axons proximal to the treatment site and the cell body, itself, remain intact. Agents that can cause this category of disruption include those that cause general injury to cells at a treatment site, such as phenol (3%), ropivacaine (also referred to as rINN, a local anesthetic that been shown to ablate nerve axons), sodium tetradecyl sulfate (STS) (1%-3%), polidocanol, ethanol (99.5%), sugar (hypertonic [50%] dextrose solution), ethanolamine oleate (5%), and sodium morrhuate (5%). Other agents that can cause this category of disruption include those that can cause neuronal specific injury, such as arsenic, nitric oxide, and glutonate.
In a third category, an agent that is supplied to an airway interferes with and/or prevents nerve signal conduction past the treatment site. Some agents that can cause short term disruption include, but are not limited to, lidocain, bupivacaine, mepivacaine, procainamide, mexiletine, tocainide. Other agents that can cause longer term disruption include, but are not limited to, tetrodotoxin (blocking effects on the Na+ ion channel), tetraethylammonium (blocking effects on K+ ion channels), chlorotoxin (blocking effects on Cl− ion channels).
The agent delivery system 2000 generally includes the expandable member 2040 (illustrated in the form of a distensible balloon), an agent delivery portion 2020, a support element 2070, and an elongate member 2050.
An interior of the expandable member can be in fluid communication with the fluid supply 2200 via a lumen that extends through the elongate member 2050. The fluid can include, without limitation, a gas, a temperature controlled fluid, such as water, saline, or other fluid suitable for use in a patient.
Different types of materials can be used to form different components of the agent delivery system 2000. In some embodiments, the expandable member 2040 is made, in whole or in part, of a distensible, chemically inert, non-toxic, electrically insulating, and thermally conductive material.
For example, the expandable member 2040 may be made of polymers, plastics, silicon, rubber, polyethylene, nylon, polyethylene terephthalate (PET), combinations thereof, or the like. The expandable member can have, for example, a barrel length in the range of from about 5 mm to about 35 mm. The diameter of the deflated expandable member 2040 can be relatively small. For example, a maximum diameter of the expandable member 2040 can be in a range of about 1 mm to about 3 mm when the expandable member 2040 is fully collapsed. To treat a bronchial tree of a human, the diameter of the expandable member 2040 can be in a range of about 6 mm to about 20 mm. For enhanced treatment flexibility, the inflated expandable member 2040 diameter may be in a range of about 7 mm to about 25 mm. Of course, the expandable member 2040 can be other sizes to treat other organs or tissue of other animals.
The longitudinally extending, axial support 2070 is, in this example, a centrally located axial shaft. The axial support can include a shape memory material and/or stainless steel. Shape memory materials include, for example, shape memory metals or alloys (e.g., Nitinol), shape memory polymers, ferromagnetic materials, combinations thereof, and the like. The axial support can aid in pushability of the expandable member 2040 while allowing the expandable member 2040 to be formed of a lightweight, highly compliant material. For example, the axial support 2070 can function as a push rod to advance the expandable member 2040 in its flimsy, deflated state through the working conduit of the flexible bronchoscope 500 to a treatment site in an airway of the patient.
In some embodiments, the elongate member 2050 is made, in whole or in part, of any suitable flexible, chemically inert, non-toxic material for withstanding operating pressures without significant expansion. The elongate member 2050 can have a suitable length to be passed into the lung and bronchial tree.
The overall working length of the agent delivery system 2000 can range from 300 to 1000 millimeters in length, depending on the location of the bronchial tree where treatment is to be performed and, in some instances, the working length of the working channel of the flexible bronchoscope. Flexible bronchoscopes typically include a working length of 600 mm, but can range in length from 300 mm to 1000 mm. The agent delivery system 2000 can have a working length suitable for treatment of airways up to and including the main stem bronchi, or a working length for treatment of airways up to the and including the lobar bronchi. Working lengths up to 1000 mm are also within the scope of the present disclosure for treatment of airways distal the lobar bronchi. In one example, an agent delivery system 2000 with a working length of about 760 millimeters facilitates access to and treatment of the main stem bronchus. The agent delivery system 2000 can be flexible enough to accommodate a working channel with a bending radius of 3.1 mm or less, or, in some examples, 2.7 mm or less. Further the agent delivery system 2000, in a collapsed delivery state, can be advanced through a working channel having a diameter in the range of about 1.0 millimeters to about 6.0 millimeters, in one example. In other examples, the agent delivery system 2000, in a collapsed delivery state, can be advanced through a working channel having a diameter in the range of about 1.0 millimeters to about 4.0 millimeters. In other examples, the agent delivery system 2000, in a collapsed delivery state, can be advanced through a working channel having a diameter in the range of about 1.2 millimeters to about 3.2 millimeters. Other lengths are also possible.
The shapes and structure of the agent delivery portion 2020 and the expandable member 2040 can be selected such that the agent delivery portion 2020 and expandable member 2040 expand/deflate together. When the expandable member 2040 is inflated, the agent delivery portion 2020 is expanded with the expandable member 2040. When the expandable member 2040 is deflated, the agent delivery portion 2020 contracts with the expandable member 2040. The agent delivery portion 2020 may include a drug or other agent dried on an exterior surface of the expandable member 2040. The agent delivery portion 2020 can further include excipients such iopromid, urea, shellac and butyryl-trihexyl citrate (BTHC), that modulate between short term and long term release of the agent. In another example, the agent can be entrapped in a microsphere on the agent delivery portion that would open when the agent delivery portion 2020 engages an airway wall.
In another example, the agent delivery portion 2020 can include a strip of material that is coated with the agent and then coupled to the expandable member 2040. The strip of material can be formed of any material that is compatible with the expandable member, such as, for example, polytetrafluoroethylene (PTFE), nylon, polyethylene terephthalate (PET), and/or urethane.
In the present example, the agent delivery portion 2020 extends around an entire circumference of the expandable member 2040 and has a length ranging from 1.0 to 5.0 cm and width ranging from 0.1 mm to 25 mm. However, other sizes and shapes are within the scope of the present disclosure. Further, though preferable, it is not required that the agent delivery portion 2020 extend around the entire circumference of the expandable member 2040. In other example, the agent delivery portion 2020 extends around, for example an arc of 90, 180, or 270 degrees around the expandable member 2040. In other examples, the agent delivery portion 2020 can include of segments that form a non-continuous band around the expandable member 2040. In other examples, multiple, axially offset strips or segments could be used. Each strip could be sized to fit between adjacent cartilage rings. Such strips could range in width from 0.1 to 4.0 mm.
The balloon expandable agent delivery portion 2020 can be delivered into the airways of the lung with the expandable member 2040 deflated and the agent delivery portion 2020 contracted. The agent delivery portion 2020 and expandable member 2040 can be kept in a collapsed or closed configuration to allow the agent delivery system 2000 to pass easily through the lungs. The agent delivery system 2000 is moved through the airways until the agent delivery portion 2020 is at the desired treatment location. Once in position, fluid is allowed to flow through the elongate member 2050 and into the expandable member 2040 using any conventional valve and/or fluid control mechanism that would be readily apparent to one of ordinary skill of art upon a review of the entirety of the present disclosure. The fluid inflates the expandable member 2040 which in turn expands the agent delivery portion 2020. Flow of the fluid either into or out of the expandable member 2040 can be regulated such that the expandable member 2040 continues to inflate until the agent delivery portion 2020 is brought into contact with or proximate to the airway wall 100, as shown in
As shown in
The effects of the example treatment described above on distal airways will now be discussed with reference to
As shown in
Following treatment, as shown in
As a result of the treatment, the nerve supply along a section of the bronchial tree can be cut off. When the signals are cut off, the distal airway smooth muscle can relax, which can lead to the airway dilation seen in
All of these changes reduce airflow resistance so as to increase gas exchange in the lungs 10, thereby reducing, limiting, or substantially eliminating one or more symptoms, such as breathlessness, wheezing, chest tightness, and the like. Tissue surrounding or adjacent to the targeted nerve tissue may be affected but not permanently damaged. In some embodiments, for example, the bronchial blood vessels along the treated airway can deliver a similar amount of blood to bronchial wall tissues and the pulmonary blood vessels along the treated airway can deliver a similar amount of blood to the alveolar sacs at the distal regions of the bronchial tree 27 before and after treatment. These blood vessels can continue to transport blood to maintain sufficient gas exchange. In some embodiments, airway smooth muscle is not damaged to a significant extent. For example, a relatively small section of smooth muscle in an airway wall which does not appreciably impact respiratory function may be reversibly altered. If energy is used to destroy the nerve tissue outside of the airways, a therapeutically effective amount of energy does not reach a significant portion of the non-targeted smooth muscle tissue.
In addition to the near-term benefits, interrupting nervous system signal communication with distal airways has the long term effect of remodeling previously constricted airways beyond simply relaxing the smooth muscle tissue or reducing mucous production. For example, without nervous signals causing them to contract, the smooth muscle will begin to atrophy over time. Eventually, smooth muscle and muscle gland mass will decrease. In addition, there will be a decrease in airway wall fluid, such as edema and interstitial tissue fluid. As such, unlike temporary treatments that block nervous system signals for discrete periods of time, it is expected that the amount of obstruction in distal airways will continue to decrease over time following a treatment with the agent delivery systems of the present disclosure.
The agent delivery system 2100 is generally similar to the agent delivery system 2000 described above, with the exception of the inclusion of the marking elements 2160a and 2160b on either side of the agent delivery portion 2120. The marking elements could be, for example, radiopaque markers made of, for example, tungsten or platinum. The markers could be inks, films, or coatings that can be made of metal, conductive polymers, or other suitable materials formed by a deposition process (e.g., a metal, such as gold, tungsten, or platinum, deposition process), coating process, etc., and can comprise, in whole or in part, silver ink, silver or gold epoxy, combinations thereof, or the like.
Although shown as single elements arranged on opposite sides of the agent delivery portion 2120, a single marking element could be arranged on one side of the agent delivery portion 2120. In other examples, the marking elements can be arrayed circumferentially around the expandable member 2140 to facilitate visualization of the agent delivery portion 2120 on multiple sides.
As with the agent delivery system 2000 described above, the width of the agent delivery portion 2120 can be specifically tailored to fit entirely between two adjacent cartilage rings 28. In this example, the width of the agent delivery portion 2120 can be in a range of between about 0.1 mm and about 4.0 mm. Further, multiple axially offset strips and/or segments could include marking elements to facilitate placement between cartilage rings of the airway.
Visualization could be achieved by optically coupling an optical element of a bronchoscope to a portion of the expandable member 2140 to directly visualize the marking elements 2160a and 2160b, coating 2120, and/or the airway wall. Optical coupling is discussed in U.S. Provisional Patent Application No. 61/786,203, filed on Mar. 14, 2013, and U.S. patent application Ser. No. 13/894,920, filed on May 15, 2013, both of which are titled “Compact Delivery Pulmonary Treatment Systems and Methods for Improving Pulmonary Function,” the entire contents of each are incorporated herein by reference.
The agent delivery system 2200 is generally similar to the agent delivery system 2200 described above, with the exception that the agent delivery portion 2220 generally protrudes beyond a surface of adjacent surfaces of the expandable member 2240 to act as a positioner. The raised agent delivery portion 2220 is, in some examples, a band that stays in place due to friction between the band and the expandable member 2240. Such a raised delivery portion 2220 can be expandable together with the expandable member 2240. In other examples, the raised delivery portion 2220 can be a ring that is tethered to the expandable member 2240. Such a tether could include several sutures to a thin film that extends at least partially around a circumference of the expandable member 2240 to anchor the expandable member 2240. The thin film can extend entirely around the circumference of the expandable member. In yet another example, the raised delivery portion is a ring tethered to the expandable member 2240. In yet another example, the raised delivery portion is molded from the expandable member itself such that it is integral with the sidewall of the expandable member.
Positioners can facilitate positioning of the agent delivery portion 2220. Such positioners include, without limitation, bumps, bulges, protrusions, ribs or other features that help preferentially seat the agent delivery portion 2220 at a desired location, thus making it easy to administer the agent or to verify correct positioning.
The agent delivery portion 2220 can be a ring that is movable relative to the expandable member 2240. The agent delivery portion 2220 can serve as an intercartilaginous positioner. When the expandable member 2240 presses against the airway 100, the ring moves along the expandable member 2240 to preferentially position ring between cartilage rings 28, 28. The ring forming the agent delivery portion 2220 protrudes outwardly from the expandable member 2240 a sufficient distance to ensure that the agent delivery portion 2220 applies sufficient pressure to the airway wall to cause self-seating. The agent delivery system 2200 can be moved back and forth to help position the agent delivery portion 2220 next to soft compliant tissue in the space between the adjacent rings 28, 28.
The marking elements 2260a and 2260b can be coupled to either the expandable member 2240, the agent delivery system 2200, or both.
The needles can extend from, for example, 0.5 mm to 5 mm from a surface of the delivery portion 2320. As the expandable member 2340 is inflated, the needles 2380 can penetrate the airway wall to deliver the agent to an area proximate the nerve trunks 45. As with the previous embodiments, positioning and placement can be facilitated by optically coupling the expandable member 2340 to, for example, a bronchoscope. The combination of long needles and positioning elements can be particularly beneficial for avoiding cartilage rings while also effectively delivering an agent to a nerve trunk 45.
In this example, the expandable member 3040 is a basket that can be deployed from a lumen in the elongate element 3050. The movable arms can facilitate moving the basket 3040 from a collapsed delivery state to an expanded, delivery state. The arms 3055 and the basket 3040, which may be a conductive shape memory material such as Nitinol, can be resiliently biased outwardly such that when extended distally from elongate element 3050, they return to a radially expanded configuration as shown in
Advantageously, the open framework structure of the basket 3040 allows a patient to breath during treatment, as the agent detaches from the agent delivery portion 3220. The agent delivery portion 3220 can include, in this example, excipients such as polylactide (PLA), its copolymers with glycolide (PLGA), iopromid, urea, shellac and butyryl-trihexyl citrate (BTHC), or non-biodegradable substances such as fluoropolymer or styrene-isobutylene-styrene, or any combination thereof. The basket 3040 could be coated along the open framework that makes up the struts to form the agent delivery portion 3220. In another example, as depicted in
In this example, the marking elements 3260a and 3260b could be placed on the basket 3040 to aid in identification of the coated portion of the basket 3040 and aid in aligning the agent delivery portion 3220 between adjacent cartilage rings.
The stents can have a length in the range of 10 to 50 mm. The diameter of the stents in a collapsed state can be relatively small. For example, a maximum diameter of the stents in
In this example, the marking elements 4060a and 4060b could be placed on the stent 3040 to aid in identification of the coated portion of the stent 4040 and aid in aligning the agent delivery portion 4020 between adjacent cartilage rings.
The raised agent delivery portion 3120 is, in other examples, a band that stays in place due to friction between the band and the stent 3140. Such a raised agent delivery portion 3120 can be expandable together with the stent 3140. In other examples, the band is a thin film that extends at least partially around a circumference of the stent 3140 that is anchored the stent 2240 with several sutures. The thin film can extend entirely around the circumference of the stent 3140.
The stents in
In some cases, stents are positioned in a patient for relatively short periods of time. As noted above, dwell times for agent coated balloons can range from as short as 30 seconds to as long as 30 minutes. In some patients, it may not be acceptable to block an airway or a portion thereof with a balloon for this amount of time, especially for lower generation airways. For these patients, a temporary stent can be used placed in the airway for as short as a few minutes, to as long as a few weeks. For example, a stent could be placed in a patient for as short as 1 minute to as long as two days. In other examples, the treatment time may last between two days and two months.
In other examples, a stents is positioned in a patient for longer periods of time, ranging from about two months to about two days. In other examples, stents are placed in a patient for between around four months and eight months. In other examples, a stent is removed after about six months in a patient.
In general, the dwell time of the agent delivery device can vary depending upon the type of agent used and the type of agent delivery device, itself. For example, a wire stent can be maintained in-place for a long period of time and can be considered, in some examples, to be permanently implanted.
In other examples, a removable stent can be employed for chronic treatment of the airways. Such a device can be made of a non-embedding material, such as silicone. Such a device can be chronically positioned in the airway for time periods that are in some examples, between one week and two months, in other examples between twenty four hours and three to six months, and in other examples about one month.
In a further example, an agent is applied over a very short time frame. Such agents can be delivered by a balloon that, for example, completely occludes an airway up to about four to five minutes. If a ventilated device is used, such as a ventilated balloon, a short time frame delivery may last as long as about thirty minutes.
In another aspect, advantageously, agents that have higher levels of solubility can be utilized in combination with any of the devices disclosed above. Unlike drug delivery in the blood stream, drug delivery in the airways is not susceptible to solubility concerns associated with immersion in a moving fluid. The table below summarizes the solubility levels of various agents.
According to US Pharmacopea standards, the scale of solubility (part of solvent per part of solute) is as follows:
Typically, there is a cutoff of solubility levels of between 1000 to 10000 mg/L for drug delivery in devices used in the blood stream. By contrast, in the airway, agents with much higher solubility levels can be employed.
The shape and structure of a stent can be tailored for effective agent delivery. For example, a stent can include channels that contain an agent, with selectively exposed portions for agent delivery. In another example, a hollow stent is loaded with an agent, and is porous in areas of desired agent delivery. Other stents can include cavities loaded with an agent that are masked with a membrane designed to release the agent in a controlled manner over time.
The agent delivery systems discussed above can be used together with or in addition to energy delivery system, such as those described in U.S. Pat. No. 8,088,127, PCT Application No. PCT/US 2010/056424 filed Nov. 11, 2010 (Publication No. WO 2011/060200), U.S. application Ser. No. 12/913,702 filed on Oct. 27, 2010, U.S. application Ser. No. 12/944,666 filed Nov. 11, 2010, U.S. application Ser. No. 13/081,406 filed on Apr. 6, 2011, U.S. Provisional Application No. 61/543,759, and U.S. Provisional Patent Application No. 61/786,203, filed on Mar. 14, 2013.
For example a stent that delivers an agent can be used in combination with an energy delivery device to ensure airway patency during and following treatment as well as improve agent delivery. Certain agents disclosed above, such as sclerosing agent, have the potential to cause damage indiscriminately as they travel through the airway wall. As this destruction occurs, the stent can maintain the patency of the airway wall. An energy delivery device that delivers, for example, radiofrequency energy, ultrasound energy, microwave energy, or other type of energy to the airway wall can be used while the stent is in place to create scar tissue that will assist with the patency of the airway. Such scar formation may allow for the removal of the stent after a period of time, or, in the case of a bioabsorbable stent, facilitate the patency of the airway even after the structural integrity of the stent diminishes.
In other examples, an energy delivery device can facilitate transport of the agent to the targeted nerves in the airway wall. For example, applying ultrasound energy to an airway wall to which an agent has been applied may drive the agent deeper into the airway, with the mechanical vibrations pushing the agent towards nerve trunks that extend along the airway. In other examples, merely applying heat to the airway wall may increase blood flow, thereby facilitating agent transport within the airway wall. The beneficial effects of heat application and energy delivery could be realized through energy application prior to, during, or even after agent delivery. In some examples, the devices disclosed in the applications discussed above could include the agent delivery portions disclosed herein, or variations thereof. Such energy application systems could employ any of the cooling systems described in U.S. Provisional Patent Application Ser. No. 61/779,371, filed on Mar. 13, 2013, and incorporated herein by reference in its entirety. In other examples, a heated fluid, rather than a chilled fluid, can be circulated to aid in treatment with an agent. In other examples, the agents disclosed herein can be delivered via either the needle injection or needless injection devices and methods disclosed in U.S. Pat. No. 8,172,827, the entire contents of which are incorporated herein by reference.
Although the agent delivery systems and various aspects thereof described herein advantageously allow for a compact design that facilitates compatibility with the working channel of a flexible bronchoscope, the aspects described herein are not so limited. For example, as will be readily apparent to one of ordinary skill in the art upon a complete review of the present disclosure, the aspects disclosed herein are also scalable to be compatible with larger working lumens that may or may not be associated with a bronchoscope. Notably, the present disclosure is not limited solely to systems that are delivered via the working channel of a bronchoscope, but also encompasses systems delivered by other means, such as an independent sheath and/or delivery catheter.
The treatment systems and its components disclosed herein can also be used as an adjunct during another medical procedure, such as minimally invasive procedures, open procedures, semi-open procedures, or other surgical procedures (e.g., lung volume reduction surgery) that provide access to a desired target site. Various surgical procedures on the chest may provide access to lung tissue, cardiovascular tissue, respiratory tissue, or the like. Access techniques and procedures used to provide access to a target region can be performed by a surgeon and/or a robotic system. Those skilled in the art recognize that there are many different ways that a target region can be accessed.
The delivery devices disclosed herein can be used with guidewires, delivery sheaths, optical instruments, introducers, trocars, biopsy needles, or other suitable medical equipment. If the target treatment site is at a distant location in the patient (e.g., a treatment site near the lung root 24 of
Semi-rigid or rigid elongated assemblies can be delivered using trocars, access ports, rigid delivery sheaths using semi-open procedures, open procedures, or other delivery tools/procedures that provide a somewhat straight delivery path. Advantageously, the semi-rigid or rigid elongated assemblies can be sufficiently rigid to access and treat remote tissue, such as the vagus nerve, nerve branches, nerve fibers, and/or nerve trunks along the airways, without delivering the elongated assemblies through the airways. The aspects and techniques disclosed herein can be used with other procedures, such as bronchial thermoplasty.
The various embodiments and aspects described above can be combined to provide further embodiments and aspects. These and other changes can be made to the embodiments in light of the above-detailed description. The aspects, embodiments, features, systems, devices, materials, methods and techniques described herein may, in some embodiments, be similar to any one or more of the embodiments, features, systems, devices, materials, methods and techniques described in U.S. Pat. No. 8,088,127, PCT Application No. PCT/US 2010/056424 filed Nov. 11, 2010 (Publication No. WO 2011/060200), U.S. application Ser. No. 12/913,702 filed on Oct. 27, 2010, U.S. application Ser. No. 12/944,666 filed Nov. 11, 2010, U.S. application Ser. No. 13/081,406 filed on Apr. 6, 2011, and U.S. Provisional Application No. 61/543,759. Each of these applications is incorporated herein by reference in its entirety. In addition, the aspects, embodiments, features, systems, devices, materials, methods and techniques described herein may, in certain embodiments, be applied to or used in connection with any one or more of the embodiments, features, systems, devices, materials, methods and techniques disclosed in the above-mentioned applications and patents.
Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including but not limited to.”
In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments and aspects disclosed in the specification and the claims, but should be construed to include all possible embodiments and aspects along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.
The present application is a continuation application of U.S. application Ser. No. 14/776,998, filed Sep. 15, 2015, which claims the benefit of U.S. Provisional Application No. 61/799,642 filed Mar. 15, 2013, U.S. Provisional Application No. 61/870,373, filed Aug. 27, 2013, all of which are entitled “Systems, Devices, and Methods for Treating a Pulmonary Disorder with an Agent,” and all of which are incorporated herein by reference in their entireties.
| Number | Date | Country | |
|---|---|---|---|
| 20230075851 A1 | Mar 2023 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 14776998 | Sep 2015 | US |
| Child | 17462334 | US |
