U.S. patent application number 13/073443 was filed with the patent office on 2011-08-11 for device and method for intra-bronchial provision of a therapeutic agent.
This patent application is currently assigned to Spiration, Inc.. Invention is credited to Lauri J. DeVore, Hugo X. Gonzalez, Richard O. Shea, Steven Chase Springmeyer, John H. Wang.
Application Number | 20110196295 13/073443 |
Document ID | / |
Family ID | 27767801 |
Filed Date | 2011-08-11 |
United States Patent
Application |
20110196295 |
Kind Code |
A1 |
Gonzalez; Hugo X. ; et
al. |
August 11, 2011 |
DEVICE AND METHOD FOR INTRA-BRONCHIAL PROVISION OF A THERAPEUTIC
AGENT
Abstract
The present invention includes an intra-bronchial device,
system, and method for providing a therapeutic agent to a patient.
A device includes a flow control member for placement in an air
passageway communicating with a lung portion and when deployed in
the air passageway inhibits a therapeutic agent distal of the
control member from moving proximal of the control member, and
includes the therapeutic agent associated with the flow control
member. The control member may inhibit movement of the therapeutic
agent by limiting airflow, and may include a one-way valve limiting
exhalation of air from the lung portion. The control member may
include a flexible membrane impervious to air flow, or a separator
arranged to inhibit the movement of the therapeutic agent. The
control member may include at least one anchor, and the anchor may
be releasable from the air passageway for removal of the
intra-bronchial device.
Inventors: |
Gonzalez; Hugo X.;
(Woodinville, WA) ; Springmeyer; Steven Chase;
(Bellevue, WA) ; Shea; Richard O.; (Kenmore,
WA) ; Wang; John H.; (Sammanish, WA) ; DeVore;
Lauri J.; (Seattle, WA) |
Assignee: |
Spiration, Inc.
Redmond
WA
|
Family ID: |
27767801 |
Appl. No.: |
13/073443 |
Filed: |
March 28, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11204383 |
Aug 15, 2005 |
7942931 |
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13073443 |
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10317667 |
Dec 11, 2002 |
6929637 |
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11204383 |
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10081712 |
Feb 21, 2002 |
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10317667 |
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10178073 |
Jun 21, 2002 |
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10081712 |
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Current U.S.
Class: |
604/93.01 |
Current CPC
Class: |
A61B 2017/242 20130101;
A61B 17/12036 20130101; A61M 31/00 20130101; A61N 5/1027 20130101;
A61B 2217/005 20130101; A61M 31/002 20130101; A61M 2210/1035
20130101; A61M 25/04 20130101; A61B 17/12022 20130101; A61M
2025/0076 20130101; A61F 2002/043 20130101; A61B 17/12104 20130101;
A61B 17/12159 20130101; A61B 2017/22067 20130101; A61B 2017/22051
20130101; A61N 2005/1021 20130101; A61B 17/1204 20130101; A61B
2017/1205 20130101; A61M 1/0023 20130101; A61B 17/12172
20130101 |
Class at
Publication: |
604/93.01 |
International
Class: |
A61M 31/00 20060101
A61M031/00 |
Claims
1. A method for providing a therapeutic agent to a patient, the
method including the steps of: delivering a therapeutic agent to a
lung portion; and inhibiting movement of the therapeutic agent from
the lung portion.
2. The method of claim 1, wherein the inhibiting step includes the
further step of limiting airflow from the lung portion to inhibit
therapeutic agent distal of the control member from moving
proximal.
3. The method of claim 1, including the further step of maintaining
an inflation of the lung portion.
4. The method of claim 1, including the further step of maintaining
a collapse of the lung portion.
5. The method of claim 1, wherein the delivering step is performed
with one intra-bronchial device and the inhibiting step is
performed with another intra-bronchial device.
6. The method of claim 1, including the further step of performing
the delivering step again.
7. The method of claim 1, wherein the inhibiting step includes the
further step of implanting an intra-bronchial device in an air
passageway in communication with the lung portion.
8. The method of claim 7, wherein the delivery step includes
providing the therapeutic agent to the intra-bronchial device.
9. The method of claim 1, including the further step of terminating
the inhibition of movement.
10. The method of claim 1, wherein the therapeutic agent is one of
antimicrobial agents such as adrenergic agents, antibiotic agents
or antibacterial agents, antiviral agents anthelmintic agents,
anti-inflammatory agents, antineoplastic agents, antioxidant
agents, biological reaction inhibitors, botulinum toxin agents,
chemotherapy agents, diagnostic agents, gene therapy, agents,
hormonal agents, mucolytic agents, radioprotective agents,
radioactive agents including brachytherapy materials, tissue growth
inhibitors, tissue growth enhancers, and vasoactive agents.
11. An intra-bronchial device for providing a therapeutic agent to
a patient, the device comprising: means for delivering a
therapeutic agent into an air passageway of the patient; and means
for intra-bronchially inhibiting movement of the therapeutic agent
from the air passageway.
12. The intra-bronchial device of claim 11, wherein the movement is
inhibited by limiting exhalation from the air passageway.
13. The intra-bronchial device of claim 11, wherein the movement is
inhibited by limiting inhalation into the air passageway.
14. The intra-bronchial device of claim 11, wherein the movement is
inhibited by limiting movement of mucus from the air passageway.
Description
RELATED APPLICATION
[0001] This application is a continuation of U.S. patent
application Ser. No. 11/204,383, titled DEVICE AND METHOD FOR
INTRA-BRONCHIAL PROVISION OF A THERAPEUTIC AGENT and filed on Aug.
15, 2005, and is now pending. U.S. patent application Ser. No.
11/204,383 is a continuation of U.S. patent application Ser. No.
10/317,667, titled DEVICE AND METHOD FOR INTRA-BRONCHIAL PROVISION
OF A THERAPEUTIC AGENT and filed on Dec. 11, 2002, now U.S. Pat.
No. 6,929,637. U.S. patent application Ser. No. 10/317,667 is a
continuation-in-part of and claims priority based on United States
applications titled INTRA-BRONCHIAL AIRFLOW CONTROL DEVICE THAT
CONTROLS BIOLOGICAL INTERACTION WITH THE PATIENT filed Feb. 21,
2002, application Ser. No. 10/081,712; and INTRA-BRONCHIAL AIRFLOW
CONTROL DEVICE THAT CONTROLS BIOLOGICAL INTERACTION WITH THE
PATIENT filed Jun. 21, 2002, application Ser. No. 10/178,073. The
entire contents of each of the above-noted prior patent
applications are hereby incorporated by reference herein and made a
part of this specification.
BACKGROUND OF THE INVENTION
[0002] There is a continuing need for improved minimally invasive
delivery of therapeutic agents to all portions of the respiratory
system, particularly the lungs, bronchi and bronchioli, blood
vessels, and lymphatic system. There is also a continuing need for
improved minimally invasive access to lung tissue and
structures.
[0003] The airways in the lungs anatomically constitute an
extensive network of conduits that reach all lung areas and lung
tissues. The airways have extensive branching that distally
communicates with the parenchyma alveoli where gas exchange occurs,
and proximally with the trachea and atmosphere (air). Because of
the physiological characteristics of the airways, a therapeutic
agent placed in bronchi and bronchioli may be delivered focally,
localized, or systemically depending on the agent and the manner in
which it is placed.
[0004] Historically, there has been a limited use of airways for
delivery of therapeutic agents, diagnostic procedures, and
instrumentation for invasive procedures. The airways have
successfully been used for delivery of certain small particle
therapeutic agents, such as inhalers for asthma, administration of
gas anesthesia, and for introduction of certain visual diagnostic
tools in conjunction with a bronchoscope. Through the bronchoscope,
a limited number of invasive procedures are now being performed,
including biopsies and removal of foreign objects.
[0005] Treatment of certain lung diseases and conditions would
benefit from targeted intra-bronchial delivery of therapeutic
agents into the involved regions, particularly those associated
with the lungs such as pneumonia and lung cancer. Treatment would
be further benefited if the therapeutic agent is generally confined
to the involved regions. For example, treatment of a disease such
as pneumonia will benefit by being able to deliver an antibiotic to
the specific lung region involved. Furthermore, treatment of lung
cancer may benefit from non-invasive brachytherapy. However, the
full potential use of the airways for delivery of therapeutic
agents and invasive procedures has not been realized because
current technology is not able to isolate selected portions of the
airways and/or lung tissue where therapeutic agents or procedures
are to be delivered.
[0006] In view of the foregoing, there is a need in the art for a
new and improved device, system, and method for isolating selected
portions of airways without adversely effecting lung function or
structure while allowing delivery of a therapeutic agent, or
instrumentation. However, no such device, system, or method
presently exists. Aspects of the present invention are directed to
providing such an improved device and method.
SUMMARY OF THE INVENTION
[0007] The present invention includes an intra-bronchial device,
system, and method for providing a therapeutic agent to a patient.
The invention provides an intra-bronchial device including a member
arranged for placement in an air passageway and a therapeutic agent
associated with the member and arranged for provision to a patient.
The member may be further arranged for inhibiting the therapeutic
agent from moving proximal of the control member. The
intra-bronchial device may further include at least one anchor that
retain the intra-bronchial device within the air passageway when
the anchor is deployed, and at least one anchor may be releasable
from the air passageway for removal of the intra-bronchial
device.
[0008] The invention also provides an assembly including a
therapeutic agent arranged for intra-bronchial delivery into an air
passageway of a patient, and a flow control member arranged for
placement in the air passageway and inhibiting the therapeutic
agent from moving proximal of the control member. The flow control
member may be arranged to allow the therapeutic agent to be
associated with the flow control member after the flow control
member is placed in the air passageway. The flow control member may
be arranged to allow the therapeutic agent to be placed into the
air passageway distal of the flow control member after the flow
control member is placed in the air passageway.
[0009] The invention further provides an intra-bronchial device for
maintaining a therapeutic agent within an air passageway. The
device includes a flow control member arranged for placement in the
air passageway and inhibiting the therapeutic agent from moving
proximal of the control member, and the therapeutic agent. The
control member may inhibit movement of the therapeutic agent by
limiting flow from the air passageway. The control member may
inhibit movement of the therapeutic agent by limiting flow into the
air passageway, which limitation may be by limiting mucociliary
transport from the air passageway. The control member may include a
one-way valve. The one-way valve may permit inhalation of air into
the air passageway, or permit exhalation of air from the air
passageway. The control member may include a flexible membrane
impervious to air flow. The flexible membrane may be arranged in
cooperation with a wall of the air passageway to form a one-way
valve permitting airflow from the air passageway, or a one-way
valve permitting airflow into the air passageway. The control
member may include a separator arranged to inhibit the movement of
the therapeutic agent while allowing movement of air. The molecules
of the therapeutic agent may be associated with molecules larger
than air molecules, and the separator arranged to inhibit movement
of the associated molecules while allowing movement of air
molecules. The control member may include a semi-permeable membrane
arranged to retain the therapeutic agent distal of the control
member while permitting air and water molecules to be exhaled. The
control member may limit airflow from the air passageway
sufficiently to maintain inflation of a lung portion communicating
with the air passageway. The control member may allow airflow from
the air passageway sufficiently to prevent over-inflation of the
lung portion. The control member may further include at least one
anchor that retains the intra-bronchial device within the air
passageway when the anchor is deployed, and at least one anchor may
be releasable from the air passageway for removal of the
intra-bronchial device. The control member may be further arranged
to automatically terminate the inhibiting of movement by the
therapeutic agent. The automatic termination may be provided by
deterioration of the control member, or by dissolution of the
control member.
[0010] The control member may be further arranged to permit
mucociliary transport from the air passageway. The therapeutic
agent may be associated with at least a portion of the control
member. The therapeutic agent may overlie at least a portion of the
airflow control member, may be imbedded in at least a portion of
the airflow control member, may be absorbed in at least a portion
of the airflow control member, and/or may be co-mixed with at least
a portion of the airflow control member. The control member further
includes an absorptive member and the therapeutic agent is absorbed
by the absorptive member. The control member may include a cavity,
and the therapeutic agent carried in the cavity. The cavity may
include an absorptive member, and the therapeutic agent absorbed by
the absorptive member. The cavity may included a cover having an
orifice. The therapeutic agent may be one of antimicrobial agents
such as adrenergic agents, antibiotic agents or antibacterial
agents, antiviral agents, anthelmintic agents, anti-inflammatory
agents, antineoplastic agents, antioxidant agents, biological
reaction inhibitors, botulinum toxin agents, chemotherapy agents,
diagnostic agents, gene therapy agents, hormonal agents, mucolytic
agents, radioprotective agents, radioactive agents including
brachytherapy materials, tissue growth inhibitors tissue growth
enhancers, and vasoactive agents.
[0011] The invention still further provides a system for
intra-bronchially providing a therapeutic agent to a patient. The
system includes an intra-bronchial device including a flow control
device arranged for placement in an air passageway, and when
deployed, limits flow from the air passageway sufficiently to
inhibit a therapeutic agent distal of the control member from
moving proximal, and an introducer that introduces the therapeutic
agent in the lung portion distal of the airflow control member.
[0012] The invention yet still further provides a method for
providing a therapeutic agent to a patient. The method may include
the steps of delivering a therapeutic agent to a lung portion, and
inhibiting movement of the therapeutic agent from the lung portion.
The inhibiting step may include the further step of limiting
airflow from the lung portion to inhibit therapeutic agent distal
of the control member from moving proximal. The method may include
the further step of maintaining an inflation of the lung portion.
The method may include the further step of maintaining a collapse
of the lung portion. The delivering step may be performed with one
intrabronchial device and the inhibiting step is performed with
another intra-bronchial device. The method may include the further
step of performing the delivering step again. The inhibiting step
may include the further step of implanting an intra-bronchial
device in an air passageway in communication with the lung portion.
The delivery step may include providing the therapeutic agent to
the intra-bronchial device. The method may include the further step
of terminating the inhibition of movement. The therapeutic agent
may be one of antimicrobial agents such as adrenergic agents,
antibiotic agents or antibacterial agents, antiviral agents,
anthelmintic agents, anti-inflammatory agents, antineoplastic
agents, antioxidant agents, biological reaction inhibitors,
botulinum toxin agents, chemotherapy agents, diagnostic agents,
gene therapy agents, hormonal agents, mucolytic agents,
radioprotective agents, radioactive agents including brachytherapy
materials, tissue growth inhibitors, tissue growth enhancers, and
vasoactive agents.
[0013] The invention also provides an intra-bronchial device for
providing a therapeutic agent to a patient. The device including
means for delivering a therapeutic agent into an air passageway of
the patient, and means for intra-bronchially inhibiting movement of
the therapeutic agent from the air passageway. The movement may be
inhibited by limiting exhalation from the air passageway, by
limiting inhalation into the air passageway, and/or by limiting
movement of mucus from the air passageway.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] The features of the present invention which are believed to
be novel are set forth with particularity in the appended claims.
The invention, together with further objects and advantages
thereof, may best be understood by making reference to the
following description taken in conjunction with the accompanying
drawings, in the several figures of which like referenced numerals
identify identical elements, and wherein:
[0015] FIG. 1 is a sectional view of a healthy respiratory
system;
[0016] FIG. 2 is a perspective view of the bronchial tree detailing
the upper right lung lobe;
[0017] FIG. 3 illustrates an initial step in providing a
therapeutic agent to a patient that includes placing an
intra-bronchial device in an air passageway using a catheter or
bronchoscope, in accordance with the invention;
[0018] FIG. 4 illustrates a further step in placing a flow control
member of the intra-bronchial device in a bronchial sub branch
using a catheter or a bronchoscope;
[0019] FIG. 5 illustrates an intermediate step where the flow
control member has been inserted in the air passageway;
[0020] FIG. 6 illustrates a final step in inserting a flow control
member of the intra-bronchial device;
[0021] FIG. 7 is a longitudinal sectional view illustrating
releasing a therapeutic agent 105 distal of control member 90;
[0022] FIG. 8 is a longitudinal sectional view illustrating an
intra-bronchial device placed in an air passageway for providing a
therapeutic agent to a patient where the therapeutic agent is
associated with a control member, in accordance with the
invention;
[0023] FIG. 9 is a longitudinal sectional view illustrating an
intra-bronchial device placed in an air passageway for providing a
therapeutic agent to a patient, the control member of the
intra-bronchial device having a cavity for carrying the therapeutic
agent, in accordance with the invention;
[0024] FIG. 10 illustrates a control member similar to FIG. 9 with
a cover having an orifice to regulate release of the therapeutic
agent, in accordance with the invention;
[0025] FIG. 11 illustrates an intra-bronchial device for providing
a therapeutic agent with a control member having a one-way valve,
in accordance with the invention;
[0026] FIG. 12 illustrates the one-way valve of FIG. 11 in an open
configuration;
[0027] FIG. 13 is a longitudinal sectional view illustrating the
intra-bronchial device of FIG. 12 placed in an air passageway;
[0028] FIG. 14 is a longitudinal sectional view illustrating an
alternative embodiment of the intra-bronchial device of FIG. 11
having a valving mechanism arranged to open when the air pressure
in the lung portion reaches a predetermined level and to allow an
exhalation airflow to prevent over inflation of the lung portion,
in accordance with the invention;
[0029] FIG. 15 illustrates a side view of an anchored
intra-bronchial device for providing a therapeutic agent, in
accordance with the invention;
[0030] FIG. 16a illustrates the device of FIG. 15 placed in an air
passageway with an orientation that permits inhalation airflow 128
and inhibits exhalation flow, in accordance with the invention;
[0031] FIG. 16b illustrates the device of FIG. 15 with an
orientation that permits exhalation airflow 129 and inhibits
inhalation airflow, in accordance with the invention; and
[0032] FIG. 17 illustrates an assembly of a plurality of
intra-bronchial devices for providing a therapeutic agent and a
flow control member for inhibiting movement of the therapeutic
agent proximally, all placed in an air passageway branch, in
accordance with the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0033] In the following detailed description of exemplary
embodiments of the invention, reference is made to the accompanying
drawings that form a part hereof. The detailed description and the
drawings illustrate specific exemplary embodiments by which the
invention may be practiced. These embodiments are described in
sufficient detail to enable those skilled in the art to practice
the invention. It is understood that other embodiments may be
utilized, and other changes may be made, without departing from the
spirit or scope of the present invention. The following detailed
description is therefore not to be taken in a limiting sense, and
the scope of the present invention is defined by the appended
claims.
[0034] Throughout the specification and claims, the following terms
take the meanings explicitly associated herein unless the context
clearly dictates otherwise. The meaning of "a", "an", and "the"
include plural references. The meaning of "in" includes "in" and
"on." Referring to the drawings, like numbers indicate like parts
throughout the views. Additionally, a reference to the singular
includes a reference to the plural unless otherwise stated or
inconsistent with the disclosure herein. Additionally, throughout
the specification, claims, and drawings, the term "proximal" means
nearest the trachea, and "distal" means nearest the alveoli.
[0035] FIG. 1 is a sectional view of a healthy respiratory system.
The respiratory system 20 resides within the thorax 22 that
occupies a space defined by the chest wall 24 and the diaphragm
26.
[0036] The respiratory system 20 includes trachea 28; left mainstem
bronchus 30 and right mainstem bronchus 32 (primary, or first
generation); and lobar bronchial branches 34, 36, 38, 40, and 42
(second generation). FIG. 1 also illustrates segmental branches 44,
46, 48, 49, and 50 (third generation). Additional sub-branches are
illustrated in FIG. 2. The respiratory system 20 further includes
left lung lobes 52 and 54 and right lung lobes 56, 58, and 60. Each
bronchial branch and sub-branch communicates with a different
portion of a lung lobe, either the entire lung lobe or a portion
thereof. As used herein, the term "air passageway" is meant to
denote either a bronchi or bronchioli, and typically means a
bronchial branch of any generation.
[0037] A characteristic of a healthy respiratory system is the
arched or inwardly arcuate diaphragm 26. As the individual inhales,
the diaphragm 26 straightens to increase the volume of the thorax
22. This causes a negative pressure within the thorax. The negative
pressure within the thorax in turn causes the lung lobes to fill
with air. When the individual exhales, the diaphragm returns to its
original arched condition to decrease the volume of the thorax. The
decreased volume of the thorax causes a positive pressure within
the thorax, which in turn causes exhalation of the lung lobes.
[0038] Another characteristic of the respiratory system is the
mucus flow from the lungs, or mucociliary transport system. Many
pollution particles are inhaled as a person breathes, and the air
passageways function as a very effective filter. The mucociliary
transport system functions as a self-cleaning mechanism for all air
passageways, including the lungs. The mucociliary transport system
is a primary method for mucus clearance from distal portions of the
lungs and further constitutes a primary immune barrier for the
lungs. The surface of air passageways is formed with respiratory
epithelium (or epithelial membrane), which is covered with cilia
and coated with mucus. As part of the mucociliary transport system,
the mucus entraps many inhaled particles and moves them toward the
larynx 28. The mucociliary transport system includes the
metachronal ciliary beat of cilia on the respiratory epithelium
that moves a continuous carpet of mucus and entrapped particles
from the distal portions of the lungs past the larynx 28 and to the
pharynx for expulsion from the respiratory system. The mucociliary
transport system will also function as a self-clearing mechanism
removing therapeutic agents placed in a lung portion and entrapped
by the mucus. Additional description of the mucociliary transport
system is provided in INTRA-BRONCHIAL OBSTRUCTING DEVICE THAT
PERMITS MUCUS TRANSPORT filed May 9, 2002, application Ser. No.
10/143,353, which is owned by the Assignee, and which is
incorporated herein by reference.
[0039] FIG. 2 is a perspective view of the bronchi emphasizing the
upper right lung lobe 56. In addition to the bronchial branches
illustrated in FIG. 1, FIG. 2 illustrates subsegmental bronchial
branches 80, 82, 84, 86, 88, and 89 (fourth generation) providing
air circulation to superior right lung lobe 56. The fifth- and
sixth-generation bronchial branches are illustrated, but not given
reference numbers.
[0040] The air passageways branch out, much like the roots of a
tree. The bronchial segments branch into six generations or orders,
and the bronchioles branch into approximately another three to
eight generations or orders. Typically, each generation has a
smaller diameter than its predecessor. The inside diameter of a
generation varies depending on the particular bronchial branch, and
further varies between individuals. For example, a typical lobar
bronchus 42 (third generation) providing air circulation to the
upper right upper lobe 56 has an internal diameter of approximately
1 cm. A typical segmental bronchi 48 (fourth generation) has an
internal diameter of approximately 4 to 7 mm. The fifth and sixth
generations (no reference numbers) are each proportionately
smaller. The bronchial segments include annular ligaments and
irregularly located cartilages that provide structure and
resilience. The cartilages become increasingly sparse as the
bronchial segments become smaller in diameter. The bronchioles do
not have ligaments and cartilages. Furthermore, the inside
diameters of air passageways is not static. They expand when a
person inhales and contract when a person exhales.
[0041] FIGS. 3-7 illustrate a series of steps in providing a
therapeutic agent to a patient, in accordance with the invention.
FIG. 3 illustrates an initial step that includes placing an
intra-bronchial device in an air passageway 50 using a catheter or
bronchoscope. The invention disclosed herein is not limited to use
with the particular method illustrated herein, and may be used in
any air passageway or body lumen. Catheter 70 may be used alone to
perform the insertion, may be extended from a bronchoscope, or used
in conjunction with a bronchoscope. For purposes of this
description, the insertion will be described with reference to only
the catheter 70. Provision of a therapeutic agent is initiated by
feeding a conduit, such as a catheter 70 down the trachea 28, into
the right mainstem bronchus 32, into the bronchial branch 42 and
into and terminating within the sub-branch 50. The sub-branch 50 is
the air passageway that communicates with the lung portion 66 to be
treated. The catheter 70 is preferably formed of flexible material
such as polyethylene. Also, the catheter 70 is preferably preformed
with a bend 72 to assist the feeding of the catheter from the right
mainstem bronchus 32 into the bronchial branch 42, or could be
deformed to conform to different curvature and angles of a
bronchial tree.
[0042] FIG. 4 illustrates a further step in placing a flow control
member 90 of the intra-bronchial device in a bronchial sub-branch
50 using a catheter or a bronchoscope. The control member 90 may be
formed of resilient or collapsible material to enable the control
member 90 to be fed through the conduit 70 in a collapsed state. A
stylet 92 is used to push the control member 90 to the end 77 of
the catheter 70 for inserting the control member 90 within the air
passageway 50 adjacent to the lung portion 66 to be provided with
the therapeutic agent.
[0043] FIG. 5 illustrates an intermediate step where the flow
control member 90 has been inserted in air passageway 50, in
accordance with the invention. Flow control member 90 has been
pushed from the end 77 of the catheter 70 and expanded upon
placement in the air passageway 50 to limit exhalation airflow and
mucus flow (mucociliary transport) from the lung portion 66. This
causes the lung portion 66 to be maintained in an expanded state.
Because the exhalation airflow and the mucus flow (mucociliary
transport) are limited, any therapeutic agent distal of the flow
control member 90 will be inhibited from moving proximal of control
member 90 and substantially confined to the lung portion 66 for
provision of therapy.
[0044] FIG. 6 illustrates a final step in inserting a flow control
member 90 of the intra-bronchial device, in accordance with the
invention. The catheter 70 and the stylet 92 are being withdrawn
from the patient, leaving the expanded flow control member 90 in
air passageway 50.
[0045] The control member 90 may be any shape and composed of any
material suitable for accomplishing its purpose. Possible shapes
include spherical, cylindrical, oval, and conical. For example,
control member 90 may be a conical shaped plug arranged to inhibit
proximal movement of a therapeutic agent by sealing air passageway
50 against proximal flow of air and mucus. Control member 90 may be
a solid member, a composition of materials, or a membrane that
retains a shape or is carried on a frame. More specifically, the
control member 90 has an outer dimension 91, and when expanded,
enables contact with an air passageway inner dimension 51. The
contact may be arranged in any manner to inhibit a therapeutic
agent distal of the control member 90 from moving proximal to
control member 90. As used in this specification, including the
description and claims, the meaning of word "inhibit" and its
derivatives, such as "inhibiting," include reducing, diminishing,
hindering, restraining, preventing, precluding, or prohibiting,
unless otherwise indicated.
[0046] The intra-bronchial device is described in this
specification, including the detailed description and the claims,
in terms of limiting flow from a lung portion communicating with an
air passageway. In some lungs, a portion of a lung may receive air
from collateral air passageways. Controlling the airflow or
mucociliary transport in one of the collateral air passageways may
reduce the flow from the lung portion communicating with that air
passageway, but may not completely control flow from the lung
portion.
[0047] FIG. 7 is a longitudinal sectional view illustrating
releasing a therapeutic agent 105 distal of control member 90, in
accordance with the invention. In this embodiment, control member
90 generally has conical configuration, and may be hollow. More
specifically, the control member 90 includes a periphery that
renders it generally circular at its base, referred to herein as
generally circular base 94. The control member 90 further includes
a circumferential, generally conical sidewall 96 that extends from
the outer periphery of generally circular base 94. The sidewall 96
has an exterior perimeter surface 98 that defines the outer
periphery 91 of the control member 90. The control member 90 is
arranged so that the outer periphery 91 of its exterior perimeter
surface 98 contacts the air passageway inner dimension 51 of
bronchial wall 100 to form a seal that limits air and/or mucus from
moving past control member 90. The degree of inhibition may be
varied by changing the, structure of the control member 90.
[0048] Once the control member 90 is paced in the air passageway
50, a final step includes releasing the therapeutic agent 105
distal of the control member 90. Catheter 70 may be used to
discharge therapeutic agent 105, or another thin catheter arranged
for delivery of the therapeutic agent 105 may be used. The tip 77
of catheter 70 is guided between the exterior perimeter surface 98
and the bronchial wall 100, and advanced until tip 77 is distal of
control member 90. The therapeutic agent 105 is released from the
tip 77, and the catheter 70 is withdrawn from the patient.
Additional doses of the therapeutic agent 105 may be administered
by again placing a delivery catheter in the air passageway 50 and
releasing additional therapeutic agent 105 distal of the control
member 90.
[0049] In an alternative embodiment, the therapeutic agent 105 may
be released first, and the control member 90 then placed in the air
passageway 50 in position to inhibit movement of the therapeutic
agent 105. In a further alternative embodiment, the control member
90 may be made of a self-sealing, pierceable material such as a
membrane, and the tip 77 arranged to pierce through the control
member 90 and discharge the therapeutic agent 105 distal of the
control member 90. In yet a further embodiment, the control member
90 may include an absorbable material, and the tip 77 arranged to
discharge the therapeutic agent 105 into the absorbable material
for release from the absorbable material distal of the control
member 90.
[0050] In another embodiment, control member 90 may include a
plurality of longitudinal ribs (not shown) on the outer peripheral
surface 91. When the control member 90 is placed in the air
passageway 50, the ribs and the interior wall of the air passageway
define at least one peripheral flow pathway. The dimensioning and
spacing of the longitudinal ribs may be selected to define the size
of the peripheral flow pathway and the degree to which airflow
and/or mucociliary transport are inhibited. The larger a flow
pathway the less a flow will be limited.
[0051] In a still further alternative embodiment, the control
member 90 is arranged to automatically terminate inhibition of
proximal movement of the therapeutic agent 105. The inhibition may
be automatically terminated by a dissolving, deteriorating, or
other structural characteristic that causes the control member 90
to terminate forming a seal with the air passageway wall 100
without any outside act or step being taken. For example, all or a
portion of the control member 90 may be made from a foam material
arranged to dissolve or deteriorate after a predetermined length of
time. Alternatively, all or a portion of control member 90 may be
made from a sugar that will dissolve after a predetermined length
of time. By way of further example, control member 90 may be
arranged to dissolve or deteriorate after several days in the air
passageway 50. This could allow treatment of localized pneumonia by
isolating the involved lung portion with the control member 90. An
antibiotic agent suitable for treating pneumonia may be placed in
the lung portion 66, and retained in the lung portion by control
member 90 for several days. After that period of time, the control
ember 90 would automatically deteriorate or dissolve, and be
removed from the air passageway 50 by absorption, mucociliary
transport, coughing, or some other mechanism without outside
action. This would terminate the isolation and return the lung
portion to normal functioning.
[0052] The term "therapeutic agent" is broadly used in this
specification, including the description and claims, and includes
anything presented for treatment, curing, mitigating, or preventing
deleterious conditions in humans and animals. The term "therapeutic
agent" also includes substances and agents for combating a disease,
condition, or disorder of a patient, and includes drugs,
diagnostics, and instrumentation.
[0053] "Therapeutic agent" also includes anything used in medical
diagnosis, or in restoring, correcting, or modifying physiological
functions. The term "therapeutic agent" may also mean a medicant or
a medicine.
[0054] The therapeutic agent is selected according to the treatment
objective and biological action desired. General classes of
therapeutic agents include anti-microbial agents such as adrenergic
agents, antibiotic agents or antibacterial agents, antiviral
agents, anthelmintic agents, anti-inflammatory agents,
antineoplastic agents, antioxidant agents, biological reaction
inhibitors, botulinum toxin agents, chemotherapy agents, diagnostic
agents, gene therapy agents, hormonal agents, mucolytic agents,
radioprotective agents, radioactive agents including brachytherapy
materials, tissue growth inhibitors, tissue growth enhancers, and
vasoactive agents.
[0055] The therapeutic agent may be selected from any class
suitable for the therapeutic objective. For example, if the
objective is treating a disease or condition associated with lungs
such as acute or chronic pneumonia, the therapeutic agent may
include antibiotics such as penicillin, ceftriaxone, tobramycin,
vancomycin. By way of further example, if the desired treatment
objective is treatment of cancer in lung or nearby tissue, the
therapeutic agent may include radioactive material in the form of
radioactive seeds providing radiation treatment directly into the
tumor or close to it. Further, the therapeutic agent may be
selected or arranged to provide therapeutic activity over a period
of time.
[0056] FIG. 8 is a longitudinal sectional view illustrating an
intra-bronchial device placed in an air passageway 50 for providing
a therapeutic agent 105 to a patient, where the therapeutic agent
105 is associated with a control member 90, in accordance with the
invention. For purposes of clarity in the specification and
drawings, embodiments of the invention are generally illustrated
with control member 90 as the only element of the intra-bronchial
device. Alternative embodiments of an intra-bronchial device
according to an aspect of the invention may include additional
elements, such as structural members, anchors, and other
members.
[0057] In accordance with a broad aspect of the present invention
the therapeutic agent 105 may be associated with the control member
90 of an intra-bronchial device in any manner known in the art
suitable for release or provision to the patient. An embodiment of
the invention is arranged to release of therapeutic agent 105
distal of the intra-bronchial device for providing focal and
systemic treatments. Other embodiments are arranged to provide the
therapeutic agent 105 to the tissue contact area between the
intra-bronchial and the wall of the air passageway 100. FIG. 8
illustrates an embodiment where the therapeutic agent 105 is
directly carried by or associated with the intra-bronchial device
for release and provision to the patient. Alternatively, the
therapeutic agent may-be carried by or associated with another
element that is coupled to the control member 90 as illustrated in
FIGS. 15 and 16. The therapeutic agent 105 may be associated with
the control member 90 in many different ways. It may be carried on
proximal, distal, or both proximal and distal portions of the
device as may be required by the intended therapeutic action and
limitations of the selected therapeutic agent. FIG. 8, for example,
illustrates an embodiment where therapeutic agent 105 overlies the
surface of generally circular base 94 of control member 90. If the
control member 90 is a membrane or generally hollow structure, the
therapeutic agent 105 may be associated by overlayment on any
suitable surface or surfaces, including an interior surface, or by
another member coupled to the control member 90.
[0058] Therapeutic agent 105 may be associated with all or any
portion of the control member 90 in any manner known to those
skilled in the art, and as required by the therapeutic action
desired and the limitations of the selected therapeutic agent 105.
Association methods include overlayment, absorption, and imbedding,
which may be by any method known to those in the art, including
spraying, dipping, ion implantation, and painting. Alternative
embodiments of the invention may include associating therapeutic
agent 105 by impregnation, co-mixing, or absorption into control
member 90 in any manner known to those skilled in the art, and as
required by therapeutic action desired and the limitations of the
selected therapeutic agent 105. Co-mixing includes combining the
therapeutic agent 105 with a carrier or the material of control
member 90 in such a manner that the therapeutic agent 105 is
releasable from the mix. An antimicrobial therapeutic agent 105 may
be absorbed into at least a portion of control member 90.
[0059] An aspect of the invention and a flow control member, such
as control member 90, is directed toward targeted intra-bronchial
delivery of a therapeutic agent that treats diseases and conditions
of the patient, particularly those associated with the lungs such
as inflammatory, infectious, and neoplastic diseases. Treatment of
certain lung diseases and conditions will benefit from targeted
intra-bronchial delivery of a therapeutic agent 105 into the
involved regions. Treatment will be further benefited if the
therapeutic agent 105 is generally confined to the involved
regions. For example, treatment of pneumonia will benefit by being
able to deliver an antibiotic to the specific lung region involve.
Treatment will also be benefited by isolating the involved lung
portion to prevent disease dissemination. By inhibiting exhalation
and/or mucociliary transport, control member 90 meets these
treatment goals by generally confining the therapeutic agent to the
lung portion, and by isolating the lung portion to prevent disease
dissemination. Depending on the course of treatment desired,
control member 90 may be arranged to allow the lung portion to be
or remain inflated by allowing inhalation airflow and limiting
exhalation airflow, or to collapse the lung portion by limiting
inhalation airflow.
[0060] Still further, the therapeutic agent may be associated with
an element of an intra-bronchial device, which in turn is coupled
to control member 90. Such elements may include structural members,
or anchors for example. The therapeutic agent may be associated
with control member 90 either before pr after it is inserted into
air passageway 50, or renewed after insertion.
[0061] FIG. 9 is a longitudinal sectional view illustrating an
intra-bronchial device placed in an air passageway 50 for providing
a therapeutic agent 105 to a patient, the control member 90 of the
intra-bronchial device having a cavity 110 for carrying the
therapeutic agent 105 in accordance with the invention. Control
member 90 includes a cavity 110 that carries therapeutic agent 105.
While the cavity 110 is illustrated in FIG. 9 as cylindrical in
configuration, it may be of any shape. Radioactive seeds may be
carried in cavity 110. A plurality of intra-bronchial devices may
be placed in a lung portion, thus allowing providers to group or
cluster the radioactive seeds in a manner similar to that used to
treat tumors in other portions of the body, such as prostate,
breast, and brain tumors.
[0062] In another embodiment, the cavity 110 of control member 90
may include an absorptive member (not shown) that carries the
therapeutic agent 105. The absorptive member may occupy all or at
least a portion of the cavity 110. The absorptive member may be any
material and any configuration known to those skilled in the art,
and as required by the limitations of selected therapeutic agent
105.
[0063] FIG. 10 illustrates a control member 90 similar to FIG. 9
with a cover 112 having an orifice 114 to regulate release of the
therapeutic agent 105, in accordance with the invention. The
orifice 114 of cavity cover 112 limits the release of the
therapeutic agent 105 from cavity 110. Orifice 114 is sized and
located to regulate the release of therapeutic agent from cavity
110.
[0064] FIGS. 11-13 illustrate an intra-bronchial device for
providing a therapeutic agent 105 with a control member 120 having
a one-way valve, in accordance with the invention. FIG. 11
illustrates the control member 120 with the one-way valve in a
closed configuration, and FIG. 12 illustrates the one-way valve in
an open configuration. Control member 120 includes a structure
similar to that described in U.S. Pat. No. 6,293,951, which is
owned by the assignee of this application, and which is
incorporated herein by reference. However, the control member 120
and one-way valve of the instant invention are structured and
arranged when deployed in an air passageway to permit inhalation of
air into the lung portion while inhibiting exhalation of air from
the lung portion.
[0065] The one-way valve may be centrally positioned in the control
member 120. Control member 120 includes a generally circular base
134 and a circumferential generally cylindrical sidewall 136.
Control member 120 further includes resilient reinforcement rib
130. To form the one-way valve, the base 134 is made from a
resilient material, and includes a slit 122 to form a valving
structure. On either side of the slit 122 is a tether 124 and 126,
which extend to the resilient reinforcement rib 130. As illustrated
in FIG. 13, control member 120 is configured for placement in the
air passageway 50 so that the one-way valve structure opens to
permit inhalation airflow 128 (in the direction indicated by the
arrow), and closes to limit exhalation airflow. The therapeutic
agent 105 is associated with the control member 120 as described in
conjunction with FIG. 8.
[0066] FIG. 13 is a longitudinal sectional view illustrating the
intra-bronchial device placed in the air passageway 50. The
intra-bronchial device may be placed in the air passageway 50 using
any method known to those skilled in the art, including the method
described in conjunction with FIGS. 3-6. The one-way valve
structure opens to permit inspiration airflow 128 (in the direction
indicated by the arrow), but limits exhalation airflow. This
orientation permits air to be inhaled into the distal lung portion,
which may assist in delivering the therapeutic agent 105 to the
distal lung portion communicating with the air passageway 50.
Conversely, the one-way valve may be arranged to permit exhaustion
airflow but preclude inspiration, if advantageous.
[0067] The contact between the outer dimension 91 and air
passageway inner dimension 51 may be arranged to form a mucus seal
stopping or limiting proximal mucus movement. The one-way valve
will limit airflow from the lung portion 66 and maintain it in an
inflated condition. Any therapeutic agent 105 released distally of
control member 90 will be inhibited from moving proximally by the
one-way valve and the mucus seal.
[0068] An aspect of the invention provides for arranging and
carrying therapeutic agent 105 on distal portion of a control
member in a manner to promote intra-bronchial delivery. FIG. 13
illustrates therapeutic agent 105 associated with a distal portion
of base 134 of control member 120, which also forms a moveable part
of the valve. In this structural arrangement, therapeutic agent 105
is physically exposed to the targeted distal lung portion, and
movement of the valve with inhalation 128 and against exhalation
may aid release of therapeutic agent 105. The structure of control
member 120 will inhibit the released therapeutic agent 105 from
moving proximally, although therapeutic agent 105 may move proximal
to the control member by escaping through the valve, between the
wall 100 and control member 120, or by mucociliary transport.
[0069] FIG. 14 is a longitudinal sectional view illustrating an
alternative embodiment of the intra-bronchial device of FIGS. 11-13
having a valving mechanism arranged to open when the air pressure
in the lung portion reaches a predetermined level and to allow
exhalation airflow to prevent over inflation of the lung portion,
in accordance with the invention. Control member 130 is
substantially similar to control member 120, however, the fixation
points of the tethers 124 and 126 has been moved radially away from
the slit 122, and the thickness of portions of the base 134
proximate to the slit 122 has been reduced to provide lips 137 and
138. The lips 117 and 118 are arranged to open when the air
pressure in the lung portion reaches a predetermined level and to
allow exhalation airflow 129 (in the direction indicated by the
arrow) to prevent over inflation of the lung portion.
[0070] FIGS. 15, 16a, and 16b illustrate an anchored
intra-bronchial device 200 for providing a therapeutic agent 105,
in accordance with the invention. Intra-bronchial device 200
includes a-flow control member 290 and distal anchors carried on a
central support structure. FIG. 15 is a side view of the device
200. FIG. 16a illustrates the device 200 placed in an air
passageway with an orientation that permits inhalation airflow 128
and inhibits exhalation flow, and FIG. 16b illustrates the device
200 with an orientation that permits exhalation airflow 129 and
inhibits inhalation air flow. Anchored and removable
intra-bronchial devices are disclosed in co-pending applications
"REMOVABLE LUNG REDUCTION DEVICES, SYSTEMS, AND METHODS" filed Sep.
11, 2001, application Ser. No. 09/951,105; "REMOVABLE ANCHORED LUNG
VOLUME REDUCTION DEVICES AND METHODS" filed Mar. 20, 2002,
application Ser. No. 10/104,487; "REMOVABLE ANCHORED LUNG VOLUME
REDUCTION DEVICES AND METHODS" filed Apr. 16, 2002, application
Ser. No. 10/124,790; and "REMOVABLE ANCHORED LUNG VOLUME REDUCTION
DEVICES AND METHODS" filed May 17, 2002, application Ser. No.
10/150,547, (collectively referred to as "Applications for Anchored
Devices") which are owned by the Assignee/and which are
incorporated herein by reference. The Applications for Anchored
Devices generally disclose and describe the structure, operation,
placement, and removal of anchored intra-bronchial devices, such as
intra-bronchial device 200.
[0071] The structure of anchored intra-bronchial device 200
includes support structure 201 and a control member 290. Support
structure 201 includes a central support structure 209, an anchor
base 261, and optionally control member support members 202, 203,
204, 205, 206 and 208. The anchor base 261 includes an anchor base
aperture 265, anchor base angle 263, and anchors 212, 214, and 216,
which include anchor ends 222, 224, and 226, and stops 252, 254,
and 256, respectively. Central support structure 209 extends both
proximal and distal of control member 290, and carries anchor base
261 proximal of control member 290. Central support structure 209
also distally carries the cavity 110 that is arranged for carrying
the therapeutic agent 105. The linear plane of anchors 212, 214,
and 216 intersect anchor base 261 at anchor base angle 263. Anchor
base angle 263 is selected to optimize anchor deployment force and
anchor releaseability. Stops 252, 254, and 256 include a flat area
to limit the piercing of the air passageway wall by anchor ends
222, 224, and 226. In alternative embodiments, the stops can be any
configuration or shape known to those skilled in the art to limit
the piercing.
[0072] The anchors 212, 214, and 216 are arranged to be collapsible
into a configuration for being fed through the conduit 70 in a
collapsed state, and to move to an anchoring configuration upon
deployment in the air passageway 50 for engaging the interior wall
of the air passageway 50. The anchors are further arranged to be
releaseable from the interior wall of the air passageway by
engaging the intra-bronchial device 200 with an instrument, and
drawing device 200 into the conduit 70 and removing it from the
patient. The Applications for Anchored Devices provide additional
descriptions of anchored structures, of anchoring an
intra-bronchial device in an air passageway, and of releasing the
anchors and removing the intra-bronchial device from an air
passageway.
[0073] Flow control member 290 is similar to flow control member
90. Flow control member 290 may be formed of a flexible membrane or
a solid material, is generally impervious to airflow, and may be
formed of a silicone or polyurethane, for example. Flow control
member 290 may have any shape suitable for accomplishing its
purpose, and optimally is collapsible to enable it to be fed
through the conduit 70 in a collapsed state. Control member 290 may
either be supported by its own structure, or may be carried on and
supported by control member support members, such as members 202,
203, 204, 205, 206 and 208. Control member 290 is arranged to be
carried on the support structure 201 and to have its generally
circular base orientated distally. Control member 290 is secured to
the central support structure 109, and may be additionally secured
to the support members at its larger diameter 91. It may be secured
by adhesive, or other manner known in the art. Control member 290
may be structurally arranged, or loosely carried on support members
102, 103, 104, 105, 106, and 108, such that it expands radially
outwardly when airflow is directed toward the generally circular
base 94 to form a seal against the wall of the air passageway 50
and limits air and mucus flow. Control member 290 may be further
structurally arranged to contract when the airflow reverses to
diminish or break the seal and permit airflow. While FIGS. 15, 16a,
and 16b illustrate anchoring an intra-bronchial device 200 having a
flow control member 290 that is formed of a flexible membrane, in
alternative embodiments, anchoring may be used with any type of
intra-bronchial device that provides a therapeutic agent.
Furthermore, while FIGS. 15 and 16 illustrate the anchors being
carried on a support structure, in alternative embodiments the
anchors may be carried on the flow control member or in any other
manner associating the anchors with the intra-bronchial device. In
further alternative embodiments, the anchors may be positioned
distal of the control member and/or proximal of the control
member.
[0074] Control member 290 may include a separator or filtration
element, or semi-permeable membrane, arranged to allow movement of
air and water vapor molecules, but to inhibit movement of larger
molecules and mucociliary transport. For example, a separator
element such as a NUCLEPORE.RTM. polycarbonate track etch membrane,
a registered trademark of Whatman, Inc., of Newton, Mass., could be
used for all or a portion of the control member 290. The molecules
of the therapeutic agent 105 are associated with molecules larger
than air and water molecules, and the separator is arranged to
inhibit movement of the larger associated molecules while allowing
movement of the smaller air and water vapor molecules.
[0075] FIG. 17 illustrates an assembly of a plurality of
intra-bronchial devices 300a-c for providing a therapeutic agent
105 and a flow control member 330 for inhibiting movement of the
therapeutic agent 105 proximally, all placed in an air passageway
branch, in accordance with the invention. Intrabronchial device 330
is substantially similar in construction, placement, and operation
to intra-bronchial device 120 except that it does not carry a
therapeutic agent 105. Intra-bronchial device 300a-c is similar in
construction, placement, and operation to intra-bronchial device
120 except the one-way valve structure is omitted. Free passage of
air and moisture is permitted past intra-bronchial devices 300
through aperture 310 as depicted by arrow 320. An alternative
embodiment of the intra-bronchial devices 300 and 330 may provide
for mucociliary transport.
[0076] Use of multiple cooperating intra-bronchial devices as
illustrated in FIG. 17 may be advantageous in treating and
diagnosing certain diseases and conditions, or in certain patients,
or when using certain types of intra-bronchial devices. For
example, a plurality of intra-bronchial devices may be required or
used to provide proper dosing of therapeutic agent 105 to a lung
portion. Intra-bronchial devices that do not provide flow control
may be more simple to install, may be less expensive to
manufacture, and may typically have a smaller outer periphery 91
diameter in a range of 2-3 mm. In addition, the targeted bronchial
branches may be too small for placement of an intra-bronchial
device that provides flow control, which is presently in the range
of 3-5 mm. A plurality of miniature intra-bronchial devices 300
carrying therapeutic agent 105 may be driven distal into the
bronchial tree and lung tissue to treat localized disease, down to
possibly 2 mm in diameter, or possibly into the bronchioli
once-smaller devices are developed. Such miniature intra-bronchial
devices 300 may be guided by very small diameter bronchoscopes, or
other types of high resolution imaging techniques that may include
using ancillary catheters arid possibly a guidewire. For example,
miniature devices could be used to treat a localized fungus disease
close to the surface of the lungs, or as a method to place
chemotherapy for lung cancer. The therapeutic agent 105 may be
localized and confined to the lung portion by an intra-bronchial
device 330 placed in a larger air passageway, such as air
passageway 42.
[0077] Intra-bronchial device 300 may be any member that does not
significantly obstruct flow of air. For example, the
intra-bronchial device carrying therapeutic agent 105 may be a
tubular member coated with therapeutic agent 105, which may be
balloon expandable as is known in the art, or may be
self-expanding.
[0078] Additional intra-bronchial devices and methods for providing
a therapeutic agent to a patient are disclosed and claimed in
INTRA-BRONCHIAL AIRFLOW CONTROL DEVICE THAT CONTROLS BIOLOGICAL
INTERACTION WITH THE PATIENT filed Feb. 21, 2002, application Ser.
No. 10/081,712; and INTRA-BRONCHIAL AIRFLOW CONTROL DEVICE THAT
CONTROLS BIOLOGICAL INTERACTION WITH THE PATIENT filed Jun. 21,
2002, application Ser. No. 10/178,073, which are incorporated
herein by reference.
[0079] While particular embodiments of the present invention have
been shown and described, modifications may be made, and it is
therefore intended in the appended claims to cover all such changes
and modifications that fall within the true spirit and scope of the
invention.
* * * * *