U.S. patent application number 10/370646 was filed with the patent office on 2003-12-04 for apparatus and method for delivering therapeutic and diagnostic agents.
This patent application is currently assigned to Scimed Life Systems, Inc.. Invention is credited to Mueller, Richard.
Application Number | 20030225370 10/370646 |
Document ID | / |
Family ID | 22457373 |
Filed Date | 2003-12-04 |
United States Patent
Application |
20030225370 |
Kind Code |
A1 |
Mueller, Richard |
December 4, 2003 |
Apparatus and method for delivering therapeutic and diagnostic
agents
Abstract
The present invention provides an drug-delivery tool and method
for delivering a selected diagnostic or therapeutic agent to a
target site within a selected body tissue, such as the myocardium
of the heart. In one embodiment, the drug-delivery tool is
configured to be introduced percutaneously for intravascular
delivery into temporary cavities formed in the myocardium from the
epicardial surface. In another embodiment, the drug-delivery tool
is configured for intraoperative use, to be introduced
thoracoscopically or through a thoracotomy, to form temporary
cavities in the myocardium from the epicardial surface. The
drug-delivery tool generally comprises an accessing device having a
tissue-penetrating implement in its distal-end region, and means
for delivering a selected agent in a cavity formed by the
implement. In an exemplary use, wherein a patient's heart is
treated with an agent for transferring genetic information to the
heart tissue, the distal end of the accessing device is conditioned
adjacent a selected region of the heart wall, and the
tissue-penetrating implement is advanced to form a temporary
channel in the myocardium. The gene-therapy agent is introduced
into the cavity by the delivery means and retained therein by means
overcoming the intra-myocardial pressures. In one embodiment, the
treated tissue is stunned, ischemic or hibernating organ tissue
that has at least partially lost its normal capillary ability at
natural vasomotion.
Inventors: |
Mueller, Richard; (Byron,
CA) |
Correspondence
Address: |
PENNIE & EDMONDS LLP
1155 Avenue of the Americas
New York
NY
10036
US
|
Assignee: |
Scimed Life Systems, Inc.
|
Family ID: |
22457373 |
Appl. No.: |
10/370646 |
Filed: |
February 20, 2003 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10370646 |
Feb 20, 2003 |
|
|
|
09566196 |
May 5, 2000 |
|
|
|
6565528 |
|
|
|
|
60133179 |
May 7, 1999 |
|
|
|
Current U.S.
Class: |
604/106 ;
604/107 |
Current CPC
Class: |
A61M 2025/0089 20130101;
A61B 2018/00392 20130101; A61B 2017/22082 20130101; A61B 17/221
20130101; A61B 17/3207 20130101; A61B 2017/00247 20130101; A61B
2090/064 20160201; A61B 2017/22077 20130101; A61B 2017/2212
20130101; A61M 2210/125 20130101 |
Class at
Publication: |
604/106 ;
604/107 |
International
Class: |
A61M 029/00 |
Claims
It is claimed:
1. A drug-delivery tool for delivering a drug to an internal member
of a tissue, such as a heart-wall, comprising: (a) an accessing
device having distal and proximal ends, an inner lumen extending
therebetween, a drug-delivery reservoir adapted to hold such drug,
and user-control structure at the accessing device's proximal end,
(b) a tissue-penetrating implement carried at the accessing
device's distal end for axial movement into and out of the lumen,
the implement having first and second expandable members which are
disposed in a substantially co-extension condition, when the
implement is disposed in a retracted condition within the lumen,
and an expanded, spaced-apart condition when the implement is
advanced to an extended condition out of the lumen, at least one of
the members having a tip for penetrating such tissue, (c) a first
operative connection between the control structure and the
implement which is operable, upon user activation of the control
structure, to advance the implement from its retracted to its
extended condition, wherein, with the accessing device's distal end
placed against a surface region of the tissue, the implement is
advanced into the tissue, causing the two expandable members to
expand to form a cavity within the tissue, and (d) a second
operative connection between the control structure and the
reservoir which is operable, upon user activation of the control
structure, to deliver drug from the reservoir into such cavity,
wherein placement of the accessing device's distal end against a
surface region of such tissue, and activation of the control
structure results in the delivery of drug into a cavity within the
tissue.
2. The tool of claim 1, wherein the implement includes at least two
expandable elements which move away from one another as the
implement is being advanced, from its retracted to its extended
condition, into such tissue, to form a cavity in the tissue.
3. The tool of claim 1, wherein the second expandable member of the
tissue-penetrating implement defines a lumen having a plurality of
openings that permit direct communication of an drug passed into a
cavity formed by the tool with at least about 90% of the surface
area of the tissue directly bordering the drug receiving space.
4. The tool of claim 1, wherein the accessing device is a flexible
catheter accessing device; and further comprising (i) a pull-wire
assembly extending longitudinally through the catheter accessing
device, the pull-wire assembly being operable to deflect the distal
end of the accessing device substantially within a plane; and (ii)
one or more force contact transducers mounted at the distal end of
the accessing device within the deflection plane.
5. The tool of claim 4, further comprising one or more additional
force contact transducers mounted at the distal end of the
accessing device outside of the deflection plane.
6. The tool of claim 1, wherein the accessing device is
incorporated in an endoscope assembly.
7. The tool of claim 1, wherein the tissue-penetrating implement
includes (i) a cutting or slicing tip on the first expandable
member, and (ii) one or more resiliently flexible second expandable
members being adapted to expand radially outward in their normal
state.
8. The tool of claim 1, wherein a drug-delivery passage is formed
by an elongate conduit having an internal lumen that extends
between tissue-penetrating implement and drug-delivery reservoir;
the conduit being adapted for sliding movement within the accessing
device, coupled with movement of the tissue-penetrating
implement.
9. The tool of claim 8, for use in delivering a selected drug
having a net negative charge, further comprising first and second
electrodes adapted to be placed in electrical communication with a
power supply, with the first electrode being disposed at a distal
region of the tissue-penetrating implement and the second electrode
being disposed proximally of the tissue-penetrating implement;
wherein generation of a positive charge at the first terminal is
effective to draw at least a member of the negatively charge
species from the drug-delivery passage into the expandable members
of the tissue-penetrating implement.
10. The tool of claim 1, for use with solid or semi-solid agents,
wherein the second expandable member of the tissue-penetrating
implement comprises a plurality of resiliently flexible expandable
members disposed at spaced positions about the longitudinal axis of
the tool so as to define a cage or skeleton capable of holding such
an agent as it is placed in a cavity formed by the implement.
11. The tool of claim 1, wherein at least one of the expandable
members has a tissue-penetrating tip, and at least one of the
expandable members has a cutting tip for slicing tissue in the
direction of expansion of the implement members, to produce a
drug-receiving for the which move away from one another as the
implement is being advanced into such tissue, from its retracted to
its extended condition, to form a drug-receiving pocket in the
tissue.
12. The tool of claim 1, 3, 2, 4, or 5, wherein the first
expandable member further comprises construction from a shape
memory material capable of a first remembered curved shape, and a
second, stress induced linear shape causing the first expandable
member to cut in an arc shape as it is advanced through a
tissue.
13. The tool of claims 1, 2, 4, or 5, wherein the second expandable
member comprises a ribbed balloon, wherein each rib defines a lumen
in communication with the drug-delivery reservoir, and each rib
further defines a plurality of exit ports from the rib lumen that
the drug may perfuse through into the formed cavity.
14. The tool of claims 1, 2, 4, or 5, wherein the first expandable
member is formed in a cork-screw shape tubular member defining a
lumen within exiting at an end distal to the accessing device and
in communication with the drug-delivery reservoir, the first
expandable member is rotatable along its axis to permit it to screw
into a tissue upon axial rotation, and upon stopping axial
rotation, withdraw into the lumen of the accessing device thereby
pulling the tissue up into the lumen of the accessing device until
such tissue is sealably urged against the accessing implement's
lumen edge causing a seal to form between the accessing implement's
lumen edge and the tissue, and further causing a cavity to form
between the distal region of the first expandable member and the
tissue adjacent to that region.
15. A method for delivering a selected diagnostic or therapeutic
agent to a target site within a selected body tissue, comprising:
(i) forming a cut or slice extending from a wall of the selected
tissue to the target site; (ii) moving the tissue bordering the cut
or slice radially outward, thereby forming a cavity within the
tissue at the target site; (iii) delivering a selected agent into
the cavity; and (iv) permitting the cavity to collapse once a
selected amount of the agent has been delivered therein.
16. The method of claim 15, wherein step (i) is effected using a
cutting or slicing implement that is configured to avoid the
removal of tissue along the region of the cut or slice beyond the
inherent cellular injury due to the cutting or slicing.
17. The method of claim 15, wherein the implement is a blade edge
or tip.
18. The method of claim 15, wherein the cut or slice formed in step
(i) is made along a substantially linear axis, with the axis being
oriented generally normal to the wall of the selected tissue.
19. The method of claim 16, wherein the agent is delivered using an
elongate agent-delivery conduit defining a passage or lumen
terminating at a distal orifice through which the agent can exit;
and wherein, during delivery of the agent, the orifice does not
make substantial contact with the selected tissue, thereby
maximizing the tissue surface area available for contact with the
agent.
20. The method of claim 15, wherein the selected tissue is heart
tissue, and the cut or slice is formed from an endocardial wall, a
septal wall, or an epicardial wall.
21. The method of claim 18, wherein the selected tissue is
myocardial tissue, and the selected agent includes a species having
angiogenic properties.
22. The method of claim 15, wherein the selected tissue is
myocardial tissue, and the selected agent includes a nucleic
acid.
23. The method of claim 15, wherein the selected tissue is stunned,
ischemic or hibernating organ tissue that has at least partially
lost its normal capillary ability at natural vasomotion.
24. An drug-delivery tool for delivering a selected diagnostic or
therapeutic agent to a target site within a selected body tissue,
comprising: an accessing device having proximal and distal ends,
with a lumen extending between said ends and terminating at an
orifice at said distal end; a tissue-penetrating implement movable
between a retracted condition, within a distal region of said
lumen, and an extended condition, extending out of said orifice;
wherein said implement includes (i) a tip configured to penetrate a
selected body tissue when the distal end of the accessing device is
placed thereagainst and the implement is moved from its retracted
condition to its extended condition, and (ii) an expandable member
disposed proximal of said tip for following the tip to a target
site within such tissue, and adapted to expand radially, with the
implement at its extended condition, with sufficient force to form
a cavity at the target site by pressing the tissue at the target
site away from the longitudinal axis of the implement; and an
agent-delivery passage extending longitudinally through at least a
member of said accessing device, with a distal end of said passage
defining an exit port facing said expandable member for directing a
selected agent, passed through the passage, into a central region
of the expandable member and any such cavity formed thereby.
25. The drug-delivery tool of claim 24, wherein said expandable
member of said tissue-penetrating implement defines a plurality of
openings that permit direct communication of an agent passed into a
cavity formed by said implement with at least about 90% of the
surface area of the tissue directly bordering the cavity.
26. The drug-delivery tool of claim 24, wherein the accessing
device is a flexible catheter accessing device; and further
comprising (i) a pull-wire assembly extending longitudinally
through said catheter accessing device, said pull-wire assembly
being operable to deflect a distal-end region of said accessing
device substantially within a plane; and (ii) one or more
ultrasound transducers mounted at the distal end of the accessing
device within said deflection plane.
27. The drug-delivery tool of claim 26, further comprising one or
more additional ultrasound transducers mounted at the distal end of
the accessing device outside of said deflection plane.
28. The drug-delivery tool of claim 24, wherein the accessing
device is incorporated in an endoscope assembly.
29. The drug-delivery tool of claim 24, wherein the
tissue-penetrating implement includes (i) a cutting or slicing tip
at its distal-end region, and (ii) one or more resiliently flexible
expandable members extending proximally therefrom, with said
expandable members being adapted to expand radially outward in
their normal state.
30. The drug-delivery tool of claim 29, further comprising an
actuation line attached to a proximal end of said implement and
extending to the proximal end of said accessing device, with said
line being adapted for sliding movement within said accessing
device; whereupon movement of said accessing device effects
movement of said implement.
31. The drug-delivery tool of claim 24, wherein said agent-delivery
passage is formed by an elongate conduit having an internal lumen
that extends between the proximal end of the accessing device and a
distal-end region of the accessing device; said conduit being
adapted for sliding movement within said accessing device, coupled
with movement of said tissue-penetrating implement.
32. The drug-delivery tool of claim 24, for use in delivering a
selected agent having a net negative charge, further comprising
first and second electrodes adapted to be placed in electrical
communication with a power supply, with the first electrode being
disposed at a distal region of said tissue-penetrating implement
and the second electrode being disposed proximally of the
implement; wherein generation of a positive charge at said first
terminal is effective to draw at least a member of the negatively
charge species from the agent-delivery passage into the expandable
member of the tissue-penetrating implement.
33. The drug-delivery tool of claim 24, for use with solid or
semi-solid agents, wherein said expandable member of said
tissue-penetrating implement comprises a plurality of resiliently
flexible expandable members disposed at spaced positions about the
longitudinal axis of the implement so as to define a cage or
skeleton capable of holding such an agent as it is placed in a
cavity formed by the implement.
34. An drug-delivery tool for delivering a selected diagnostic or
therapeutic agent to a target site within a selected body tissue,
comprising: (i) an accessing device having proximal and distal
ends, with a lumen extending between said ends and terminating at
an orifice at said distal end; (ii) a tissue-penetrating implement
movable between a retracted condition, within a distal region of
said lumen, and an extended condition, extending out of said
orifice; wherein said implement includes (i) a tip configured to
penetrate a selected body tissue when the distal end of the
accessing device is placed thereagainst and the implement is moved
from its retracted condition to its extended condition, and (ii) a
cage member disposed proximal of said tip for following the tip to
a target site within such tissue, and adapted to assist in the
formation and maintenance of a cavity at the target site by
pressing the tissue at the target site away from the longitudinal
axis of the implement as it is inserted therein and having
sufficient rigidity to resist inwardly directed forces of the
tissue tending to collapse the cavity; and (iii) an agent-delivery
passage extending longitudinally through at least a member of said
accessing device, with a distal end of said passage defining an
exit port facing said cage member for directing a selected agent,
passed through the passage, into a central region of the cage
member and any such cavity formed thereby.
35. A method for delivering a selected diagnostic or therapeutic
agent to a target site within a selected body tissue, comprising:
(iv) forming a cut or slice extending from a wall of the selected
tissue to the target site; (v) moving the tissue bordering the cut
or slice radially outward, thereby forming a cavity within the
tissue at the target site; (vi) delivering a selected agent into
the cavity; and (vii) permitting the cavity to collapse once a
selected amount of the agent has been delivered therein.
36. The drug-delivery tool of claim 34, wherein at least 90% of the
surface area of the tissue bordering the cavity is directly exposed
to the cavity, so that an agent delivered into the cavity can pass
directly into the exposed tissue.
37. The method of claim 35, wherein step (i) is effected using a
cutting or slicing implement that is configured to avoid the
removal of tissue along the region of the cut or slice beyond the
inherent cellular injury due to the cutting or slicing.
38. The method of claim 35, wherein the implement is a blade edge
or tip.
39. The method of claim 35, wherein the cut or slice formed in step
(i) is made along a substantially linear axis, with the axis being
oriented generally normal to the wall of the selected tissue.
40. The method of claim 35, wherein the agent is delivered using an
elongate agent-delivery conduit defining a passage or lumen
terminating at a distal orifice through which the agent can exit;
and wherein, during delivery of the agent, the orifice does not
make substantial contact with the selected tissue, thereby
maximizing the tissue surface area available for contact with the
agent.
41. The method of claim 35, wherein the selected tissue is heart
tissue, and the cut or slice is formed from an endocardial wall, a
septal wall, or an epicardial wall.
42. The method of claim 35, wherein the selected tissue is
myocardial tissue, and the selected agent includes a species having
angiogenic properties.
43. The method of claim 35, wherein the selected tissue is
myocardial tissue, and the selected agent includes a nucleic
acid.
44. The method of claim 35, wherein the selected tissue is stunned,
ischemic or hibernating organ tissue that has at least partially
lost its normal capillary ability at natural vasomotion.
44. The tool of claim 1, wherein the accessing device is
incorporated in an open surgical assembly.
Description
[0001] This application claims benefit of U.S. Provisional Patent
Application No. 60/133,179 filed May 7, 1999, which is incorporated
herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention is directed to an drug-delivery tool
and method of delivering selected therapeutic and/or diagnostic
agents to target sites in selected body tissues. More particularly,
the invention provides for the creation of temporary cavities in
desired layers of a selected tissue, for example, myocardial tissue
of the heart, and for the delivery of one or more selected agents
therein.
BACKGROUND OF THE INVENTION
[0003] Intra-muscular needle injection of therapeutic compounds is
well known in the medical arts, as is intra-coronary injection
where pre-existing intra-coronary arteries provide perfusate
conduits. In heart disease, the existing coronary artery in-flows
to capillary beds is often compromised. Newly developed gene and
protein therapeutic agents hold promise in their ability to act on
the surviving smaller capillary beds to grow and expand them. As
has been witnessed, the intra-myocardial cellular lattice limits
angiogenic response to about 5-10 mm and similar limits occur with
direct needle injections in stunned or ischemic heart tissue. The
physician must work within an environment of compromised capillary
bed vascularity. Physicians are further limited to some degree by
drug viscosity--where the drug viscosity is too low, rapid wash-out
can occur; and where too high, capillary occlusion can occur--as
well as by high infusate pressure induced cellular damages. These
problems are not typical of common healthy muscle tissue injections
in the arm or leg. The prior art teaches the creation of permanent
channels with the use of lasers, radio frequency heating and
mechanical cutting means. Such channels often compromise the
capillaries that are sought to be accessed with a drug, wash out
readily, and resolve ultimately as fibrous connective scar tissue.
Needle and membrane tools may improve access to capillaries but
offer no stretching forces and don't offer unobstructed capillary
access.
SUMMARY OF THE INVENTION
[0004] One embodiment of the invention provides a drug-delivery
tool for delivering a drug to an internal member of a tissue, such
as a heart-wall. The tool comprises an accessing device having
distal and proximal ends, an inner lumen extending therebetween, a
drug-delivery reservoir adapted to hold such drug, and a
user-control structure at the accessing device's proximal end. The
tool further includes a tissue-penetrating implement carried at the
accessing device's distal end for axial movement into and out of
the lumen. The implement has first and second expandable members
which are disposed in a substantially co-extension condition, when
the implement is disposed in a retracted condition within the
lumen. Alternatively, the implement may assume an expanded,
spaced-apart condition when the implement is advanced to an
extended condition out of the lumen. At least one of the members
has a tip for penetrating such tissue. A first operative connection
exists between the control structure and the implement that is
operable, upon user activation of the control structure, to advance
the implement from its retracted to its extended condition. When
the accessing device's distal end is placed against a surface
region of the tissue, the implement is advanced into the tissue,
causing the two expandable members to expand to form a cavity
within the tissue. A second operative connection exists between the
control structure and the reservoir that is operable, upon user
activation of the control structure, to deliver drug from the
reservoir into such cavity. Placement of the accessing device's
distal end against a surface region of such tissue, and activation
of the control structure results in the delivery of drug into a
cavity within the tissue.
[0005] In another embodiment, the implement includes at least two
expandable elements which move away from one another as the
implement is being advanced, from its retracted to its extended
condition, into such tissue, to form a cavity in the tissue.
[0006] In yet another embodiment, the second expandable member of
the tissue-penetrating implement defines a lumen having a plurality
of openings that permit direct communication of an drug passed into
a cavity formed by the tool with at least about 90% of the surface
area of the tissue directly bordering the drug receiving space.
[0007] In a particularly preferred embodiment, the accessing device
is a flexible catheter accessing device; and further comprises a
pull-wire assembly extending longitudinally through the catheter
accessing device, the pull-wire assembly being operable to deflect
the distal end of the accessing device substantially within a
plane; and one or more force contact transducers mounted at the
distal end of the accessing device within the deflection plane.
This embodiment may further comprise one or more additional force
contact transducers mounted at the distal end of the accessing
device outside of the deflection plane.
[0008] In another embodiment, the first expandable member further
comprises construction from a shape memory material capable of a
first remembered curved shape, and a second, stress induced linear
shape causing the first expandable member to cut in an arc shape as
it is advanced through a tissue upon extension from the confines of
the accessing device lumen.
[0009] In still another embodiment, the second expandable member
comprises a ribbed balloon, wherein each rib defines a lumen in
fluid communication with the drug-delivery reservoir, and each rib
further defines a plurality of exit ports from the rib lumen that
the drug may perfuse through into the formed cavity.
[0010] In another embodiment, the first expandable member is formed
in a cork-screw shape tubular member defining a lumen within
exiting at an end distal to the accessing device and in
communication with the drug-delivery reservoir, the first
expandable member is rotatable along its axis to permit it to screw
into a tissue upon axial rotation, and upon stopping axial
rotation, withdraw into the lumen of the accessing device thereby
pulling the tissue up into the lumen of the accessing device until
such tissue is sealably urged against the accessing implement's
lumen edge causing a seal to form between the accessing implement's
lumen edge and the tissue, and further causing a cavity to form
between the distal region of the first expandable member and the
tissue adjacent to that region.
[0011] In one embodiment, some of the expandable members of the
tissue-penetrating implement define lumens with a plurality of
openings in fluid communication with the drug-delivery reservoir
such that a drug may be introduced into a formed cavity with at
least about 90%, and preferably greater than about 95%, of the
surface area of the tissue directly bordering the cavity.
[0012] The accessing device can be, for example, a flexible
catheter accessing device or the accessing device of an
endoscope-type tool. In an embodiment of the former (i.e., a
catheter-type tool), the tool further includes (i) a pull-wire
assembly extending longitudinally through the catheter accessing
device, with the pull-wire assembly being operable to deflect a
distal-end region of the accessing device substantially within a
plane; and (ii) one or more (for example, two) ultrasound or force
contact transducers mounted on opposing sides of the orifice at the
distal end of the accessing device within the deflection plane.
Optionally, one or more (for example, two) additional transducers
can be mounted at the distal end of the accessing device outside of
the deflection plane.
[0013] One aspect of the present invention provides an
drug-delivery tool for delivering a selected diagnostic or
therapeutic agent to a target site within a selected body tissue,
such as myocardial tissue of the heart. Generally, the
drug-delivery tool includes an accessing device having proximal and
distal ends, with a lumen extending between such ends and
terminating at an orifice at the distal end. A tissue-penetrating
implement is movable between a retracted condition, within a distal
region of the lumen, and an extended condition, extending out of
the orifice. The tissue-penetrating implement includes a tip
configured to penetrate a selected body tissue when (i) the distal
end of the accessing device is placed thereagainst and (ii) the
implement is advanced from its retracted condition to its extended
condition. In addition, the tissue-penetrating implement includes a
first expandable member, disposed proximal of the tip, for
following the tip to a target site as the tip penetrates the
selected tissue. A second expandable member, also proximal to the
tip of the implement, is adapted to expand radially as the
implement is advanced to its extended condition, with a force
sufficient to form a cavity at the target site by pressing the
tissue adjacent the penetration site away from the longitudinal
axis of the implement. An agent-delivery passage or conduit extends
longitudinally through at least a member of the accessing device,
with a distal end of the passage defining an exit port facing the
expandable member of the tissue-penetrating implement. By this
construction, an agent, passed or drawn through the passage and out
of the exit port, is directed into a central region of the
expandable member, and any cavity formed thereby.
[0014] In one embodiment, the tissue-penetrating implement of the
drug-delivery tool includes (i) a cutting or slicing tip at its
distal-end region, and (ii) one or more resiliently flexible
expandable members extending proximally therefrom, with the
expandable members being adapted to expand radially outward in
their normal state. The expandable members can be, for example,
wires or filaments made of Nintinol, or the like. Movement of the
tissue-penetrating implement can be effected using an actuation
line attached at one end to a proximal end of the implement and
attached at its other end to a manually operable deflection
mechanism at a proximal end of the drug-delivery tool. By this
construction, sliding movement of the line within the accessing
device is transmitted to the implement--causing the implement to
move.
[0015] The agent-delivery passage of the drug-delivery tool can be
formed, for example, by an elongate conduit having an internal
lumen that extends between the proximal end of the accessing device
and a distal-end region of the accessing device. In one embodiment,
such a conduit is adapted for sliding movement within the accessing
device, coupled with movement of the tissue-penetrating
implement.
[0016] One embodiment of the drug-delivery tool, particularly
useful for delivering a selected agent having a net negative charge
(for example, DNA), further comprises first and second electrodes
adapted to be placed in electrical communication with a power
supply. The first electrode, in this embodiment, is disposed at a
distal region of the tissue-penetrating implement and the second
electrode is disposed proximally of the implement. Generation of a
positive charge at the first terminal is effective to draw at least
a portion of the negatively charge species from a supply or holding
reservoir, through the agent-delivery passage, and into the
expandable member of the tissue-penetrating implement.
[0017] Another embodiment of the drug-delivery tool is particularly
well suited for placing a solid or semi-solid agent in a cavity
formed by the cavity forming implement and then permitting the
agent to move outwardly as portions of it dissolve or otherwise
slough off. In one particular construction, the expandable member
of the tissue-penetrating implement includes a plurality of
resiliently flexible expandable members (for example, wires or
filaments of Nintinol, or the like) disposed at spaced positions
about the longitudinal axis of the implement so as to define a cage
or skeleton capable of holding the agent as it is placed in a
cavity formed by the implement. The cage is provided with open
regions between its expandable members sufficient to provide direct
exposure of the agent to at least about 95% of the tissue bordering
the cavity.
[0018] Another general embodiment of the drug-delivery tool of the
invention includes (i) an accessing device having proximal and
distal ends, with a lumen extending therebetween and terminating at
an orifice at the distal end; (ii) a tissue-penetrating implement
movable between a retracted condition, within a distal region of
the lumen, and an extended condition, extending out of the orifice;
with the implement including (a) a tip configured to penetrate a
selected body tissue when the distal end of the accessing device is
placed thereagainst and the implement is moved from its retracted
condition to its extended condition, and (b) a cage member disposed
proximal of the tip for following the tip to a target site within
such tissue, and adapted to assist in the formation and maintenance
of a cavity at the target site by pressing the tissue at the target
site away from the longitudinal axis of the implement as it is
inserted therein and having sufficient rigidity to resist inwardly
directed forces of the tissue tending to collapse the cavity; and
(iii) an agent-delivery passage extending longitudinally through at
least a member of the accessing device, with a distal end of the
passage defining an exit port facing the cage member for directing
a selected agent, passed through the passage, into a central region
of the cage member and any such cavity formed thereby.
[0019] The cage member can comprise, for example, a plurality of
expandable elements disposed about the central, longitudinal axis
of the implement, with open regions between adjacent expandable
members. Preferably, at least about 95% of the cage member is open.
The cage member can be expandable (tending to flex outwardly), or
generally non-expandable.
[0020] In another of its aspects, the present invention provides a
method for delivering a selected diagnostic or therapeutic agent to
a target site within a selected body tissue.
[0021] According to one general embodiment, the method includes the
steps of:
[0022] (i) forming a cut or slice extending from a wall of the
selected tissue to the target site;
[0023] (ii) moving or pressing the tissue bordering the cut or
slice radially outward, thereby forming a cavity within the tissue
at the target site;
[0024] (iii) delivering a selected agent into the cavity, with the
cavity being maintained; and
[0025] (iv) permitting the cavity to collapse once a selected
amount of the agent has been delivered therein.
[0026] In one embodiment, at least about 90% (and preferably
greater than 95%) of the surface area of the tissue bordering the
cavity is directly exposed to the cavity, so that the agent
delivered into the cavity can pass directly into the exposed
tissue.
[0027] Step (i) of the method (i.e., cutting/slicing) is preferably
effected using a cutting or slicing implement, such as a blade edge
or tip, that is configured to avoid the removal of tissue along the
region of the cut or slice beyond the inherent cellular injury due
to the cutting or slicing.
[0028] According to one embodiment, the cut or slice formed in step
(i) is made along a substantially linear axis, with the axis being
oriented generally normal to the wall of the selected tissue.
Ultrasound can be used to achieve such orientation.
[0029] The agent can be delivered using, for example, an elongate
agent-delivery conduit defining a passage or lumen terminating at a
distal orifice through which the agent can exit. Preferably, during
delivery of the agent using such a tool, the orifice does not make
substantial contact with the selected tissue, thereby maximizing
the tissue surface area available for contact with the agent.
[0030] In one embodiment, the selected tissue is heart tissue (for
example, myocardial tissue), and the cut or slice is formed from an
endocardial wall, a septal wall, or an epicardial wall.
[0031] In another embodiment, the selected tissue is stunned,
ischemic and/or hibernating organ tissue that has at least
partially lost its normal capillary ability at vasomotion. The
greater surface area and capillary access provided by practicing
the present invention permits the agent to be moved through
micro-capillaries even where assistance by natural vasomotion is
greatly diminished or unavailable.
[0032] A wide variety of agents can be delivered using the present
invention. The selected agent can be, for example, an angiogenic
agent (for example, a protein and/or nucleic acid). In one
embodiment, the agent is a nucleic acid, for example, naked DNA,
intended for delivery to heart tissue.
[0033] A further aspect of the present invention provides a method
where the normal pressure drug tissue treatment area of 5-10 mm
obtained with direct needle injection or TMR can be improved upon
by creating a temporary cavity having significantly greater direct
capillary access due to surface area, lack of non-perfusing
delivery implement to cell contact patches and implement stretching
force.
[0034] These and other features and advantages of the present
invention will become clear from the following description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0035] The structure and manner of operation of the invention,
together with the further objects and advantages thereof, may best
be understood by reference to the following description taken in
conjunction with the accompanying drawings, in which:
[0036] FIG. 1 is an elevational view of a steerable catheter
assembly, with its distal end region enlarged and in section
showing a tissue-penetrating implement therein, as taught by an
embodiment of the present invention;
[0037] FIG. 2 is a side sectional view showing two angle-mounted
ultrasound transducers on the distal end of a steerable catheter
accessing device, in accordance with an embodiment of the present
invention;
[0038] FIG. 3 is a cross sectional view of the catheter assembly
shown in FIG. 1, taken laterally across a mid-member of the
catheter accessing device;
[0039] FIG. 4 is a side sectional view of the catheter-assembly
distal-end region of FIG. 1, taken longitudinally therealong, with
the tissue-penetrating implement inserted into a selected tissue to
form a cavity therein for receiving a selected agent;
[0040] FIG. 5A illustrates a section of normal myocardial
tissue;
[0041] FIG. 5B illustrates a section of myocardial tissue with a
temporary cavity formed therein;
[0042] FIG. 6 is a side elevational view, with members shown in
cross section, of an endoscope-type agent delivery tool having a
tissue-penetrating implement like that of the catheter assembly of
FIG. 1;
[0043] FIGS. 7(A)-7(C) illustrate an accessing device, shown in
section, with a movable implement for forming a cavity in a
selected tissue and delivering a selected agent therein, in
accordance with the teachings of one embodiment of the present
invention; and,
[0044] FIGS. 8(A)-8(C) illustrate an accessing device, shown in
section, with a movable implement for forming a cavity in a
selected tissue and placing a selected agent therein, in accordance
with an embodiment of the present invention.
[0045] FIGS. 9(a-d) depict an embodiment having a force contact
transducer.
[0046] FIGS. 10(a-b) depict a corkscrew shaped expandable member
embodiment.
[0047] FIGS. 11(a-c) depict a balloon expandable member
embodiment.
[0048] FIGS. 12(a-c) depict an arc cutting embodiment.
DETAILED DESCRIPTION OF THE INVENTION
[0049] The following discussion of the preferred embodiments of the
present invention is merely exemplary in nature. Accordingly, this
discussion is in no way intended to limit the scope of the
invention.
[0050] An exemplary drug-delivery tool which embodies various
features of the invention is shown in FIGS. 1 through 4. As will
become apparent, the illustrated drug-delivery tool is particularly
well suited for percutaneous introduction into a subject for
intravascular delivery of a selected agent into temporary cavities
formed in a desired layer of a selected tissue. With initial
reference to FIG. 1, a catheter assembly (which may be disposable,
in whole or in part), indicated generally by the reference numeral
12, includes a control structure (hand unit) 14 attached to a
steerable catheter accessing device 16 having a controllably
deflectable distal-end member. Steering of the catheter assembly
can be accomplished in a variety of ways. For example, the catheter
assembly can include steering components like those disclosed in
U.S. Pat. No. 5,876,373, entitled "Steerable Catheter," to Giba et
al.; and/or in co-pending U.S. Provisional patent application Ser.
No. 09/080,175 filed May 16, 1998, entitled, "Drug Delivery
Module," to Glines et al.; and/or in published European Patent
Application No. EP 0 908 194 A2, each of which is expressly
incorporated herein by reference. Briefly, in the illustrated
embodiment, a pull wire 18, having an enlarged head member 18a at
its distal end, extends from the tip of catheter accessing device
16, through a wire-guide channel 19 extending through catheter
accessing device 16, to control structure (hand unit) 14, whereat
the wire's proximal end is coupled to a deflection or steering
actuator assembly. Rotation of a deflection knob 20, which is
threadedly mounted along a forward end of the hand unit, causes the
pull wire to be pulled backward, or the catheter accessing device
to be pushed forward, relative to one another, thereby inducing
deflection of the distal end of the steerable catheter accessing
device. Rather than running the pull wire through a channel
extending through the catheter accessing device, another embodiment
provides the pull wire extending longitudinally along the interior
wall of the catheter accessing device (FIG. 3). Other steering
mechanisms and arrangements, suitable for use herein, will be
apparent to those skilled in the art. In yet another preferred
embodiment, the catheter is further guided by a coaxial second
catheter as described in co-pending application U.S. Ser. No.
09/052,971 and PCT publication WO 9949773A2 titled "Delivery
catheter system for heart chamber" by Payne, filed Mar. 31, 1998,
both herein incorporated in their entireties by reference.
[0051] Catheter accessing device 16 is dimensioned to be placed in
the vasculature of a subject and steered therethrough until the tip
is disposed adjacent a selected region of tissue, for example, a
surface or wall within a heart chamber (such as against the
endocardial wall within the heart's left ventricle).
[0052] Visualization enhancement aids, including but not limited to
radiopaque markers, tantalum and/or platinum bands, foils, and/or
strips can be placed on the various components of drug-delivery
tool-catheter assembly 12, including on the deflectable end member
of catheter accessing device 16. In one embodiment, for example, a
radio-opaque marker (not shown) made of platinum or other suitable
radio-opaque material is disposed adjacent the tip for
visualization via fluoroscopy or other methods. In addition, or as
an alternative, one or more ultra-sonic transducers can be mounted
on the catheter accessing device at or near its tip to assist in
determining its location and/or placement (for example, degree of
perpendicularity) with respect to a selected tissue in a subject,
as well as to sense wall contact with, and/or wall thickness of,
the tissue. Ultra-sonic transducer assemblies, and methods of using
the same, are disclosed, for example, in published Canadian Patent
Application No. 2,236,958, entitled, "Ultrasound Tool for Axial
Ranging," to Zanelli et al., and in co-pending U.S. patent
application Ser. No. 08/852,977, filed May 7, 1997, entitled,
"Ultrasound Tool for Axial Ranging," to Zanelli et al., each of
which is expressly incorporated herein by reference. In one
embodiment of the present invention, depicted in FIG. 2, two
transducers, denoted as 26 and 28, are angle mounted at the tip of
catheter accessing device 16 in the axis of pull-wire deflection.
This construction permits an operator to determine, by comparing
signal strength, whether the catheter tip region is perpendicular
to a selected tissue surface or wall. Additionally, this
two-transducer arrangement provides an operator with information
useful for determining an appropriate adjustment direction for
improving perpendicularity, as compared to single-transducer
arrangements that, while capable of indicating perpendicularity by
signal strength amplitude, are generally incapable of indicating a
suitable direction in which to move the tip to improve
perpendicularity. In a related embodiment, third and fourth
transducers (not shown) are added, off of the deflection axis, to
aid an operator with rotational movement and rotational
perpendicularity in the non-deflecting plane of the subject tissue
surface. Each of the above ultrasound transducers may preferably be
substituted with force contact transducers described in co-pending
U.S. patent application Ser. No. 60/191,610 by C. Tom titled
"Apparatus and method for affecting a body tissue at its surface",
filed Mar. 23, 2000, [Attorney docket 5756-0011] herein
incorporated by reference. An additional benefit of using a force
contact transducer is that the contact force and incident angle are
know to the user enabling the user to achieve a seal between the
distal end of the accessing device and a tissue such that a seal is
formed between the two preventing administered drug from seeping
out of a formed cavity.
[0053] In some preferred embodiments, one or more elongate lumens
may extend between the proximal and distal ends of the catheter
accessing device, with (i) at least one lumen being dimensioned to
accommodate a cavity forming implement for axial movement along a
region of the assembly's distal end, and (ii) at least one lumen
being configured to permit passage of one or more selected
therapeutic and/or diagnostic agents from an agent-supply region
(for example, a reservoir in the hand unit) to, and out of, a
terminal orifice at the assembly's distal end. The just-described
items (i) and (ii) can be achieved using a single lumen, or
multiple lumens. In one embodiment, for example, catheter accessing
device 16, as depicted in FIG. 1, is preferably formed with an
outer diameter of between about 2.25 to 2.75 mm (preferably 7
French), and an inner diameter, defining a primary lumen 22, of
about 1 mm. At its distal end, lumen 22 terminates at an orifice
24. A tissue-penetrating implement 48 (described below) is adapted
for movement within a distal-end region of lumen 22. A selected
agent can be passed through the main lumen directly, i.e., in
contact with the main lumen's interior walls, and/or indirectly,
for example, using one or more additional lumens (for example,
sub-lumens) extending coextensively and/or coaxially with the main
lumen. An embodiment of the latter construction is also
illustrated, in part, in FIGS. 3 and 4. For example, FIGS. 1, 3,
and 4 each depict different aspects of an elongate, flexible
agent-delivery conduit 30 is disposed substantially coaxially
within catheter accessing device 16, extending from control
structure (hand unit) 14 to a distal region of lumen 22. Conduit 30
can be formed, for example, of a substantially inert polymeric
material that resists collapse during bending or twisting, such as
braided polyimide, braided PEBAX, or the like. Conduit 30 defines a
hollow, axial lumen or passage 32, having a diameter within a range
of from about 0.25 mm to about 1 mm (for example, about 0.5 mm), or
from about 0.010" to about 0.040" (for example, about 0.020"), that
communicates at its proximal end with an agent-supply reservoir
disposed in control structure (hand unit) 14, and terminates at its
distal end at an exit or infusion port 34, through which a selected
therapeutic and/or diagnostic agent can pass. As described below,
conduit 30 is adapted for reciprocal sliding movement within
catheter accessing device 16 and, thus, is provided with an outer
diameter less than the inner diameter of catheter accessing device
16, for example, about 1 mm or less in certain constructions.
[0054] At this point, certain details of the hand unit relating to
agent storage and dispensing will be described, bearing in mind
that additional details are set forth in co-pending U.S.
Provisional Patent Application Ser. No. 09/080,175 filed May 16,
1998, entitled, "Drug Delivery Module," to Glines et al.,
incorporated herein by reference. In one preferred embodiment
depicted in FIG. 1, control structure (hand unit) 14 is provided
with a fixed drug-delivery reservoir for holding a supply of a
selected agent to be dispensed. In this embodiment, a supply
vessel, such as syringe 36, can communicate with the drug-delivery
reservoir via a connector provided in the unit's outer housing 38.
The connector is preferably a substantially sterile connector, such
as a standard Luer-type fitting or other known standard or
proprietary connector. In another embodiment, the supply reservoir
comprises a syringe, pre-loaded with a selected agent, that can be
removably fit into a holding area inside the housing. In both such
embodiments, a dosage volume adjustment thumbscrew 40 can be
mounted in the housing 38 so as to be externally accessible for
accurate, local and rapid dosage volume adjustment. Also, a dosage
volume scale or indicator, as at 42, can be provided in the housing
38. Upon depressing a trigger mechanism 44 along one side of
control structure (hand unit) 14, manually or otherwise, the agent
stored in the drug-delivery reservoir moves into conduit 30. It
should also be noted that trigger mechanism 44 is coupled to the
proximal end of conduit 30 such that, upon being depressed, the
conduit is pushed forward (advanced) within catheter accessing
device 16 from a normal, retracted condition, depicted in FIG. 1,
to a dispensing condition, shown in FIG. 4, whereat conduit orifice
34 can be positioned closely adjacent a selected tissue, such as
46, against which catheter-accessing device orifice 24 has been
placed. Upon releasing the trigger mechanism, conduit 30 shifts
back to its normal condition. The distance traversed by conduit 30,
in each direction, is from about 2 to about 10 mm, and preferably
about 5 mm.
[0055] A tissue-penetrating implement, indicated generally as 48,
is also longitudinally movable within catheter accessing device 16,
between a retracted condition, within a distal region of lumen 22
(FIG. 1), and an extended (advanced) condition, passed through and
extending out of orifice 24 (FIG. 4), over a stroke of about 4-6
mm, and preferably about 5 mm. Movement of implement 48 is effected
by way of an elongate actuation line 50, depicted in cross-section
in FIG. 3, operatively coupled at one end to trigger mechanism 44
(FIG. 1) and extending axially through conduit 30 from control
structure (hand unit) 14 to a proximal end of implement 48.
Preferred materials for forming the actuation line are laterally
flexible, permitting movement through tortuous pathways, and
sufficiently incompressible along the longitudinal direction to
provide for the efficient transmission of motion from the proximal
end to the distal end. Suitable materials include, for example,
stainless steel or a braided composite. In operation, upon the
depressing trigger mechanism, implement 48 is shifted from its
normal, retracted condition to its extended condition, and upon
release of the trigger mechanism, implement 48 returns to its
retracted condition.
[0056] For reasons that will become apparent below, it should be
noted that the above-described advancement of both conduit 30 and
cutting implement 48 takes place substantially simultaneously
(i.e., these motions are coupled) with a single depression of
trigger mechanism 44. In addition, optionally, with the same
trigger depression, an agent held in a reservoir in the hand unit
is dispensed from conduit 30. Preferably, such dispensing is
effected immediately after (not before) the conduit and cutting
implement have reached their respective extended conditions. For
example, the initial depression can actuate axial movement of the
conduit and cutting implement, and the latter member of the
depression can effect dispensing. Similarly, both conduit 30 and
cutting implement 48 are retracted together with release of the
trigger mechanism, and the dispensing of the selected agent is
stopped.
[0057] With further regard to the tissue-penetrating implement 48,
its distal end includes a cutting or slicing tip, denoted as 52. In
the illustrated arrangement, tip 52 takes the form of a narrow,
three-sided pyramid-like structure that tapers to a sharp point.
Alternatively, tip 52 could taper to a two-sided knife edge or
blade, or any other suitable cutting or slicing structure.
Preferred cutting or slicing structures are configured to
substantially avoid the removal of tissue beyond the cellular
injury inherent in cutting.
[0058] Implement 48 further includes an expandable member, proximal
of tip 52, comprised of one or more resiliently flexible expandable
elements or expandable members, three of which are visible (out of
a total of four) at 54 in the embodiment of FIGS. 1 and 4. The
expandable members are arranged at spaced positions about the
implement's longitudinal axis, and configured to flex outwardly,
away from such axis, to collectively form a three dimensional
support skeleton or cage. The expandable members can be, for
example, narrow, elongate wires, filaments or ribbons, formed of a
substantially inert, resiliently flexible material, such as a metal
or metal alloy (for example, stainless steel, nickel-titanium, or
similar material) or from an injection molded plastic. The distal
end of each expander is turned inward and attached to the proximal
side of tip 52. When the expandable member is disposed at its
retracted condition (FIG. 1), the expandable members are compressed
toward the implement's longitudinal axis; and when advanced to its
extended condition (FIG. 4), the expandable members are allowed to
flex outward, so that, overall, the expandable member achieves a
maximum diameter of about 1-3 mm, and preferably from about 1.75 mm
to about 2 mm.
[0059] According to one preferred construction of the expandable
member, between about 3-10 nickel-titanium (for example, as
available commercially under the name "Nintinol") filaments, each
between about 4-5 mm in length and from about 0.003" to about
0.005" in diameter are employed as expandable members. The
particular number, dimensions, and material composition of the
expandable members are not critical, provided only that the
expandable members are capable of forming a cavity when inserted
into a selected tissue (i.e., they have sufficient strength and
spring capabilities), and, when in the expanded condition, a drug
or other agent delivered into the region within the expandable
members can move outwardly into the tissue about the cavity, with
very little interference presented by the expandable members
themselves, as shown in FIG. 4 with agent 58 in cavity 60.
Regarding the latter, the expandable members preferably occupy no
more than about 10%, and more preferably less than about 3%, of the
region defining the boundary between the cavity and the target
tissue thereabout. In this way, the vast majority of the tissue
boarding a cavity can be directly exposed to an agent delivered
into the cavity.
[0060] An exemplary method of using the above catheter assembly
will now be described, wherein the catheter assembly is used for
intra-myocardial delivery of a selected therapeutic and/or
diagnostic agent. Initially, catheter accessing device 16 is
percutaneously introduced via femoral or radial artery access. This
can be accomplished, for example, by way of the Seldinger technique
(Acta Radiologica,38, [1953], 368-376; incorporated herein by
reference), a variation thereof, or other conventional technique.
Optionally, a conventional guiding or shielding catheter (not
shown) can be employed to assist in tracking the catheter tool
through the patient's vasculature and into targeted regions of the
heart. Once arterial access is established, the catheter accessing
device 16 is slid across the aortic valve and into the left
ventricle chamber. The distal end of the catheter accessing device
16 is maneuvered so as to be substantially perpendicular to the
endocardial wall 46 (FIG. 4), using fluoroscopic visualization
and/or ultrasound guidance, and pressed thereagainst. Trigger
mechanism 44 is next depressed, causing cutting tip 52 to advance
into the myocardial tissue, in the direction of arrow 64, to a
pre-set or adjustable depth. Expandable members 54 follow cutting
tip 52 into the myocardium and expand radially (for example, in the
direction of arrows 66), creating a cavity about the axis of
penetration (i.e., the axis of cutting or slicing). Once the cavity
has been created, the expandable members serve to maintain the
cavity by resisting heart contractile forces. The same trigger
depression serves to deliver a selected agent through conduit 30
into the cavity 60. After allowing the agent to enter into the
surrounding tissue for appropriate period of time, for example,
typically less than about 2 minutes, the tissue-penetrating
implement is withdrawn, at which point the cavity can close.
[0061] Healthy myocardial tissue is illustrated in FIG. 5A. As
shown, healthy tissue contains capillaries 70, interstitial tissue
72, and heart muscle cells 74 (See, for example, "Gray's Anatomy"
(1959) at page 597). FIG. 5B shows how a temporary cavity 60 can be
created to directly access, for example, along the direction of
arrows 68, more capillaries 70, more heart muscle cells 74, and
tissue surface area 76. It should be appreciated that the creation
of temporary cavities, as taught therein, provides direct access to
a greater number of capillaries than has been possible by the prior
techniques. As a result, the performance of the infusate tool is
greatly enhanced.
[0062] It is believed that abrasion to the wall of the cavities may
aid in absorption of the agent. Accordingly, it may be desirable to
configure the cutting tip and/or cavity expandable members of the
invention so as to allow selective abrasion. This can also be
accomplished, for example, by RF, thermal, acidic and/or ultrasonic
means acting on the cutting tip and/or cavity expandable
members.
[0063] It is noted that the above-described method is exemplary in
nature. Those skilled in the art will appreciate that the present
invention provides for the delivery of selected agents to a wide
variety of body organs and regions.
[0064] Another embodiment of the drug-delivery tool of the present
invention is shown in FIG. 6, wherein the tool is embodied in an
endoscope-type tool, shown generally at 80. As described next, the
drug-delivery tool of this embodiment is configured for
intraoperative use, to be introduced thoracoscopically or through a
thoracotomy, to form temporary cavities in a selected tissue. The
tool includes a proximal handpiece 82 (similar to the
previously-described control structure (hand unit) 14) adapted to
accommodate an drug-delivery reservoir syringe 84, and a
depressible trigger mechanism 86. This particular surgical tool
incorporates a reusable 5 mm thoracoscopic camera 88 axially
mounted to provide an operator with a field of view 90 through lens
92. This allows the operator to work through a common Trocar access
port 94 placed, for example, through a patient's chest wall 96. In
an exemplary use, upon traversing the epicardial surface 98 of the
heart, a tissue-penetrating implement 48, substantially as
described above, can create a temporary cavity for receiving a
selected agent. As with the catheter assembly, the tool is adapted
to permit a user to both extend the tissue-penetrating implement
and dispense a drug or other agent, with a single depression of the
trigger mechanism 86. Additional details of the handpiece are
presented in co-pending U.S. Provisional Patent Application Ser.
No. 09/080,175 filed May 16, 1998, entitled, "Drug Delivery
Module," to Glines et al., incorporated herein by reference. One
skilled in the art would recognize that the above mentioned
endoscopic embodiment may further be adapted for use without an
endoscopic port, for example, such as in open surgery. Such an
embodiment may be guided with or without visualization aids such as
an optical endoscope or other optical enhancement device.
[0065] It should be noted that, especially when used in open
surgery, the tissue-penetrating implement need not retract. Thus,
movement of the implement between its retracted and advanced
conditions, in such cases, need only involve movement of the
implement move from its retracted to its advanced condition.
[0066] In another embodiment of the present invention, a selected
therapeutic and/or diagnostic agent comprising a charged species
(for example, DNA) is held within the distal-end region of an
accessing device and delivered into a cavity formed by in a
selected tissue via an electrical field. An exemplary
cavity-forming and delivery implement, which can be incorporated in
a catheter-type tool or an endoscope-type, such as previously
described, is shown in FIGS. 7A-7C. Here, the implement includes
drug-delivery reservoir or storage vessel 114 which opens into the
region between a plurality of expandable members 116 via short
passage 118 through a neck member 120. First and second lead wires,
denoted as 122 and 124 respectively, extend through a flexible
actuation accessing device 126 and terminate at respective
terminals, or electrodes, fixed in the implement. The first
terminal, indicated as 123, being placed at a rearward (proximal)
region of the vessel 114, and the second terminal, denoted as 125,
being placed at a forward (distal) region of the implement's
cutting/slicing tip 128. In an exemplary operation, whereby DNA,
indicated as 130, is delivered into myocardial tissue 132 of a
subject, the catheter accessing device 134 is introduced into a
subject body and placed against an endocardial or epicardial wall
136 of the heart's left ventricle (FIG. 7A). During such
introduction and placement, the vessel terminal 123 is made
positive (+) and the tip terminal 125 is made negative (-), thereby
establishing an electrical field that maintains the negatively
charged DNA in the vessel 114. It should be noted that the lead
wires 122, 124 and regions about the terminals 123, 125 are
shielded, using conventional materials, to limit the field's reach
into the surrounding heart tissue. Such shielding about the forward
(distal) region of the implement is indicated by back-hatching in
the drawings. After placement of the catheter, actuation accessing
device 126 is advanced, via a remote shifting mechanism (such as
previously described), to push the slicing tip 128 through the wall
136 and into a region of myocardium 132, with the expandable
members 116 following the tip therein. Once a cavity has been
formed in the myocardium, the polarity is reversed, so that the tip
terminal 128 is positive (+) and the vessel terminal 123 is
negative (-) (FIG. 7B), thereby establishing an electrical field
effective to draw the negatively charged DNA 130 toward the tip
128. After a short time, with at least a substantial member of the
DNA drawn out of the vessel 114, the electrical field is
discontinued (FIG. 7C), so that the DNA can move outwardly into the
surrounding tissue and capillaries of the myocardium.
[0067] In another embodiment, a selected therapeutic and/or
diagnostic agent is held within the distal-end region of an
accessing device and placed in a cavity formed in a selected
tissue. An exemplary cavity-forming and placement implement, which
can be incorporated in a catheter-type tool or an endoscope-type,
such as previously described, is shown in FIGS. 8A-8C. Here, the
implement includes a plurality of expandable members 142 attached
at their rearward (proximal) ends to a flexible actuation accessing
device 144, and at their forward (distal) ends to a cutting/slicing
tip 146. The expandable members 142 are arranged to serve as a cage
or skeleton for containing a selected agent 148, in solid or
semi-solid form, as the catheter accessing device 150 is placed
against a selected organ wall, as at 152 (FIG. 8A). Actuation
accessing device 144 is then advanced, via a remote shifting
mechanism, to push the slicing tip 146 of the implement through the
wall 152 and into a selected layer of tissue 154, with the
expandable members 142 following the tip 146 therein (FIG. 8B).
Once a cavity has been formed in this manner, the agent 148 is
allowed to move outward into the surrounding tissue and capillaries
(FIGS. 8B-8C). The agent can be configured to for controlled
release after placement, for example, via swelling and sloughing
over a period of several minutes. In one embodiment, wherein the
agent is DNA, controlled-release preparations are formulated
through the use of polymers to complex or absorb the selected gene
sequence (with or without an associated carrier, for example,
liposomes, etc.). The agents can be formulated according to known
methods to prepare pharmaceutically useful compositions, whereby
these materials, or their functional derivatives, are combined in
admixture with a pharmaceutically acceptable carrier vehicle.
Suitable vehicles and their formulation, are described, for
example, in Nicolau, C. et al. (Crit. Rev. Ther. Drug Carrier Syst
6:239-271 (1989)), which is incorporated herein by reference. In
order to form a pharmaceutically acceptable composition suitable
for effective administration, such compositions will contain an
effective amount of the desired gene sequence together with a
suitable amount of carrier vehicle.
[0068] FIG. 9a depicts a preferred embodiment of the invention
where accessing device 900 further comprises force contact
transducer 902 mounted on distal end 904 of accessing device 900.
As accessing device 900 is urged toward tissue 906, as shown in
FIG. 9b, force contact transducer 902 contacts tissue 906 causing
detectable contact pressure to develop between force contact
transducer 902 and tissue 906. Such detectable pressure, detected
by force contact transducer 902 is communicated back to the end
user who then can further manipulate accessing device 900 to
achieve perpendicularity between the thrust axis of accessing
device 900 and tissue 906. Upon achieving perpendicularity and
contact force, tissue-penetrating implement 908, with cutting tip
908a, may be advanced to an extended condition, from a retracted
position, thus causing the formation of cavity 910 in tissue 906.
Because accessing device 900 is urged against tissue 906 in a
perpendicular manner, distal end 904 of accessing device 900
develops a seal for sealing in later delivered drug into cavity
910. FIG. 9c depicts accessing device 900 without force contact
transducer 902. FIG. 9c suggests how a non-perpendicular
orientation of accessing device 900 with respect to tissue 906
could result in seepage of delivered drug 912 from cavity 910. FIG.
9d further depicts accessing device 900 without force contact
transducer 902 urged against tissue 900. Tissue 900 is further
depicted in two states, diastolic state tissue 906a and systolic
state tissue 906b correlating to the movement of myocardial tissue
in a beating heart. As shown in FIG. 9d, diastolic position tissue
906a provides a seal between tissue 906 and accessing device 900.
However, upon systolic movement, tissue 906 moves away from
accessing device 900 unless sufficient contact force exists between
accessing device 900 and tissue 906. Force contact transducer 902
provides information to the user to enable the user to apply
sufficient and perpendicular force to the accessing device to
create a seal between accessing device 900 and tissue 906 during
the movements of beating heart between tissue 900a and 900b states.
Moreover, FIG. 9d depicts how delivered drug 912 may be further
ejected or pumped out of cavity 910 by the contractile actions
between heart tissue 900a and 900b states.
[0069] FIG. 10 depicts another embodiment of the invention
utilizing corkscrew shaped tissue-penetrating implement 1000.
Accessing device 1002 houses tissue-penetrating implement 1000 that
may be rotated within accessing device in either a retracted
condition or an extended condition. FIG. 10a depicts
tissue-penetrating implement 1000 secured into tissue 1004 by
screwing. As tissue-penetrating implement 1000 is withdrawn back
towards a retracted condition, tissue 1004 is likewise pulled into
lumen 1006 of accessing device 1002 thus creating seal 1006 between
accessing device 1002 and tissue 1004. Such pulling further creates
cavity 1008 at distal end 1010 of tissue-penetrating implement
1000. Cavity 1008 may then be filled with delivered-drug, not
shown, delivered through lumen orifice 1012 to treat the walls of
cavity 1008 with such drug.
[0070] FIG. 11 depicts another embodiment of the invention where
the expandable members comprise a balloon structure with
drug-delivery lumen orifices distributed along the surface of the
expandable members. FIGS. 11a and 11b depicts a tissue-penetrating
implement 1101 comprising four radially distributed expandable
members 1100 defining lumens 1102 with exit ports 1104 outwardly
situated on balloon 1106. Penetrating tip 1108 is situated on the
end of the balloon distal from accessing device 1110, not shown. As
balloon 1106 is inflated, expandable members 1100 are urged outward
against the tissue of a cavity, not shown. FIG. 11c further shows
yet another embodiment using a balloon as an expandable member and
drug-delivery channel. Accessing tool 1110 is urged against tissue
1112, whereby tissue-penetrating implement 1101 comprises a balloon
expandable member 1106 with distally situated exit ports 1104 and
penetrating or cutting tip 1108.
[0071] FIG. 12 depicts a preferred embodiment of the invention
where tissue penetrating implement 1200 comprises at least one
first expandable member 1202 made from a shape memory material
composition having a first remembered arc shape and a second,
stress induced, straight shape. First expandable member 1202
assumes a stress induced straight shape when housed within lumen
1204 of accessing tool 1206, but returns to its remembered shape
upon extension beyond lumen 1204. As first expandable member 1202
extends from lumen 1202, it cuts an arc shaped path through tissue
1210 as first expandable member 1202 regains its remembered shape.
Tissue-penetrating implement 1200 has cutting tip 1208 situated
distal to accessing tool 1206 for cutting tissue 1210 as
tissue-penetrating implement 1200 is advanced into tissue 1210 when
advanced from a retracted condition to an extended condition out of
lumen 1204. Second expandable member 1211 extends from lumen 1204
coaxial to first expandable member 1202. Adjacent
tissue-penetration implement's distal end, first and second
expandable members are positioned together either fixedly or
slidably. When fixedly positioned, both expandable members 1202 and
1211 extend together, but expand longitudinally from one another to
form cavity 1212. When first and second expandable members 1202 and
1211 are slidably positioned, the user may either extend one
expandable member, preferably the first expandable member 1202
having cutting tip 1208, and then extend second expandable member
1211 to follow along cut path 1216 created by previously extended
first expandable member 1202, expanding longitudinally away from
first expandable member 1202 to create cavity 1212 where a drug may
be infused from a drug-delivery reservoir, not shown, in fluid
communication through a conduit with the distal region of accessing
device 1222. FIG. 12b depicts a variation where second expandable
member further comprises construction from shape memory tube 1218,
such as nitinol or NiTi tubing, defining a longitudinal lumen in
fluid communication with a drug-delivery reservoir, not shown, and
terminating with exit ports 1220 adjacent to the distal end of
second expandable member. During or after the formation of cavity
1212, drug may be delivered from the drug-delivery reservoir, not
shown, to the cavity 1212 through the lumen and exit ports 1220 of
second expandable member 1211. FIG. 12c depicts a variation where
first and second expandable members 1202 and 1211 are spaced-apart
from one another by, for example, having two lumens, not shown,
defined within accessing device 1222. Force contact transducer 1224
is located on the distal end of accessing device 1222 to assist a
user in achieving the sufficient and perpendicular contact force
with respect to tissue 1210 to create a seal between tissue 1210
and the distal end of accessing device 1222. One skilled in the art
would readily recognize the benefits of the above mentioned
embodiment. In particular, the presence of second expandable member
1211 made from a shape memory material that assumes a stress
induced straight shape when housed within lumen 1204 of accessing
tool 1206, but returns to its remembered shape upon extension
beyond lumen 1204, when configured as shown in FIG. 12, provides
the ability to shepherd first expandable member 1202 further in its
arc shape cutting path by applying lateral force to cutting tip
1208 as it cuts through tissue 1210. This further prevents cutting
tip from accidentally cutting too deep through a wall like tissue
and thus perforating the wall and turning a cavity into a
passage.
[0072] Additional pharmaceutical methods may be employed to control
the duration of action. Controlled delivery may be exercised by
selecting appropriate macromolecules (for example polyesters,
polyamino acids, polyvinyl, pyrrolidone, ethylenevinylacetate,
methylcellulose, carboxymethylcellulose, or protamine, sulfate) and
the concentration of macromolecules as well as the methods of
incorporation in order to control release. Another method to
control the duration of action by controlled release preparations
is to incorporate the agent into particles of a polymeric material
such as polyesters, polyamino acids, hydrogels, poly(lactic acid)
or ethylene vinyl acetate copolymers. Alternatively, instead of
incorporating these agents into polymeric particles, it is possible
to entrap these materials in microcapsules prepared, for example,
by coacervation techniques or by interfacial polymerization, for
example, hydroxymethylcellulose or gelatin microcapsules and
poly(methylmethacylate) microcapsules, respectively, or in
colloidal drug delivery systems, for example, liposomes, albumin
microspheres, microemulsions, nanoparticles, and nanocapsules or in
macroemulsions.
[0073] The drug-delivery tool and method of the present invention
may employ a wide variety of agents, for example, ranging from
active compounds to markers to gene therapy compounds. Exemplary
agents, contemplated for use herein, are set forth in U.S. Pat.
Nos. 5,840,059; 5,861,397; 5,846,946; 5,703,055; 5,693,622;
5,589,466; and 5,580,859, each expressly incorporated herein by
reference. In one embodiment, for example, the invention is
employed to deliver one or more genes (for example, as so-called
"naked DNA") into cavities formed in the myocardium of a
subject.
[0074] In appropriate situations, the agent can be delivered in a
form that keeps the agent associated with the target tissue for a
useful period of time, such as with a viscosity-enhancer to produce
a thixotropic gel. In certain embodiments, the therapeutic or
diagnostic agent is mixed with a viscous biocompatible polyol to
maintain prolonged, high concentration of the agent in the channels
and affect the kinetics of the agent-target region interaction.
[0075] Alternatively, a catheter could be employed to deliver an
agent incorporated in a biocompatible polymer matrix. Suitable
polymeric materials are known in the art, for example, as set forth
in U.S. Pat. No. 5,840,059, incorporated herein by reference. For
example, non-biodegradable polymers can be employed as hollow
reservoirs or other structures. Additionally, conventional
pharmacologically inert fillers may be employed to tailor the time
release characteristics of the agent. Certain embodiments
contemplate the use of biodegradable polymers, such as collagen,
polylactic-polyglycolic acid, and polyanhydride. For example, the
agent can be dispersed in a polymer which is configured to degrade
over a useful period of time, releasing the agent. In one
embodiment, the agent is released by swelling and sloughing of the
biodegradable polymer. Various means for employing polymer
compounds to secure a therapeutic agent are disclosed, for example,
in Levy et al., WO 94/21237 and in U.S. application Ser. No.
08/033,307, filed Mar. 15, 1993, which is hereby incorporated by
reference. In still other embodiments, a biocompatible material is
delivered to seal and retain the agent within the cavity. For
example, a delivery lumen could be employed to deliver a sealing
agent after delivery of the agent.
[0076] Those skilled in the art can now appreciate from the
foregoing description that the broad teachings of the present
invention can be implemented in a variety of forms. Therefore,
while this invention has been described in connection with
particular embodiments and examples thereof, the true scope of the
invention should not be so limited. Various changes and
modification may be made without departing from the scope of the
invention, as defined by the appended claims. For example, the
expandable members of the tissue-penetrating implement can be
configured not to expand, but rather to maintain a substantially
constant configuration as it is moved between its retracted and
advanced conditions. By this construction, the cage or skeleton
structure defined by the expandable members can serve, when
inserted into a tissue, to help form a temporary cavity, and
maintain the cavity as one or more selected agents are delivered
and/or drawn therein. Thus, while an expandable member (as
described above) is advantageous for many purposes, a
non-expandable cage or skeleton in place of the previously
described expandable member can provide useful advantages, as
well.
* * * * *