U.S. patent application number 13/289490 was filed with the patent office on 2012-03-01 for balloon catheter devices with sheath covering.
This patent application is currently assigned to BOSTON SCIENTIFIC SCIMED, INC.. Invention is credited to Ben Arcand, John Chen, Ruth Cheng, Tracee Eidenschink, Kent Harrison, Daniel Horn, Gordon Kocur, Colm McGuiness, Wendy Naimark, Jay Rassat, Raed Rizq, Derek Sutermeister.
Application Number | 20120053517 13/289490 |
Document ID | / |
Family ID | 40578099 |
Filed Date | 2012-03-01 |
United States Patent
Application |
20120053517 |
Kind Code |
A1 |
Chen; John ; et al. |
March 1, 2012 |
BALLOON CATHETER DEVICES WITH SHEATH COVERING
Abstract
Catheter devices having an expandable balloon for delivering a
therapeutic agent to a body site. In one aspect, one or more
sheaths are disposed around the balloon with the therapeutic agent
being disposed within the sheath, being disposed over the sheath,
being contained in the space between the sheath and the balloon, or
being otherwise associated with the sheath. In another aspect, the
balloon includes a micro-electromechanical system (MEMS) for drug
delivery.
Inventors: |
Chen; John; (US) ;
Rizq; Raed; (US) ; Harrison; Kent; (US)
; Horn; Daniel; (US) ; Kocur; Gordon;
(US) ; Eidenschink; Tracee; (US) ; Arcand;
Ben; (Minneapolis, MN) ; Sutermeister; Derek;
(Eden Prairie, MN) ; Rassat; Jay; (Buffalo,
MN) ; McGuiness; Colm; (US) ; Naimark;
Wendy; (US) ; Cheng; Ruth; (US) |
Assignee: |
BOSTON SCIENTIFIC SCIMED,
INC.
Maple Grove
MN
|
Family ID: |
40578099 |
Appl. No.: |
13/289490 |
Filed: |
November 4, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13179054 |
Jul 8, 2011 |
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13289490 |
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12399386 |
Mar 6, 2009 |
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13179054 |
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61034328 |
Mar 6, 2008 |
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Current U.S.
Class: |
604/103.02 |
Current CPC
Class: |
A61L 29/085 20130101;
A61M 2025/1031 20130101; A61M 25/10 20130101; A61M 25/1029
20130101; A61M 2025/0056 20130101; B29L 2009/005 20130101; A61M
25/0045 20130101; A61L 29/085 20130101; A61M 2025/105 20130101;
A61L 2300/416 20130101; A61L 29/16 20130101; C08L 53/02
20130101 |
Class at
Publication: |
604/103.02 |
International
Class: |
A61M 25/10 20060101
A61M025/10 |
Claims
1. A medical device comprising: a catheter; a balloon mounted on
the catheter; a sheath disposed around the balloon, wherein the
sheath comprises a body and a plurality of reservoirs that are in
communication with the external surface of the body of the sheath,
wherein the reservoirs are elongated channels within the body of
the sheath; and a therapeutic agent contained in the
reservoirs.
2. The medical device of claim 1, wherein expansion of the balloon
applies pressure to the reservoirs and causes the release of the
therapeutic agent.
3. The medical device of claim 1, wherein the sheath has a
non-linear compliance curve.
4. The medical device of claim 1, wherein the sheath comprises an
elastomeric mesh.
5. The medical device of claim 1, wherein the channels are
longitudinally-extending.
6. The medical device of claim 1, wherein the reservoirs
communicate with the external surface of the body of the sheath via
a plurality of pores.
7. The medical device of claim 1, wherein the sheath comprises a
material having a porous cell structure.
8. The medical device of claim 7, wherein the material is
ePTFE.
9. The medical device of claim 1, wherein the therapeutic agent is
an anti-proliferative agent or an anti-restenosis agent.
10. The medical device of claim 9, wherein the therapeutic agent is
paclitaxel, sirolimus, tacrolimus, everolimus, or zotarolimus.
Description
RELATED APPLICATIONS
[0001] This application is a divisional of Application Serial
Number No. 13/179,054 filed Jul. 8, 2011, which is a divisional of
Application Serial Number No. 12/399,386 filed Mar. 6, 2009, which
claims the benefit of provisional application Ser. No. 61/034,328
filed Mar. 6, 2008, all of which are incorporated by reference
herein.
TECHNICAL FIELD
[0002] The present invention relates to medical devices, more
particularly, to catheter devices.
BACKGROUND
[0003] Catheters are used in a wide variety of minimally-invasive
or percutaneous medical procedures. Balloon catheters having drug
coatings may be used to treat diseased portions of blood vessels.
Typically, the balloon is inserted through a peripheral blood
vessel and then guided via a catheter through the vascular system
to the target intravascular site. However, as the balloon travels
through the vascular system, the flow of blood may wash away some
of the drug coating. In addition, the control of the timing,
location, and/or duration of the drug release can be an issue.
Therefore, there is a need for improved catheter-based devices for
drug delivery to an intravascular site.
SUMMARY
[0004] In one embodiment, the present invention provides a medical
device comprising: a catheter; a balloon mounted on the catheter;
one or more sheaths disposed around the balloon, wherein the one or
more sheaths are slidable over the balloon; and a therapeutic agent
disposed between the surface of the balloon and the one or more
sheaths. The therapeutic agent may be formulated to include a
pharmaceutically-acceptable lubricant material.
[0005] In another embodiment, the present invention provides a
medical device comprising: a catheter; a balloon mounted on the
catheter; a sheath disposed around the balloon, wherein the sheath
has a weakened portion, and wherein the sheath is disrupted at the
weakened portion when the balloon is expanded; and a therapeutic
agent disposed between the surface of the balloon and the
sheath.
[0006] In another embodiment, the present invention provides a
medical device comprising: a catheter; a balloon mounted on the
catheter; a sheath disposed around the balloon, wherein the sheath
comprises nanofibers; and a therapeutic agent retained on the
medical device by the sheath.
[0007] In another embodiment, the present invention provides a
medical device comprising: a catheter; a balloon mounted on the
catheter; a sheath disposed around the balloon, wherein the sheath
comprises a body and a plurality of reservoirs that are in
communication with the external surface of the body of the sheath,
wherein the reservoirs are longitudinally-extending channels within
the body of the sheath; and a therapeutic agent contained in the
reservoirs.
[0008] In another embodiment, the present invention provides a
method for making a medical device, comprising: providing a
balloon; disposing over the surface of the balloon, a layer of
therapeutic agent; embossing a pattern onto the layer of
therapeutic agent; and disposing a sheath over the layer of
therapeutic agent.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 shows a cross-section side view of a portion of a
sheath according to an embodiment. It is to be noted that certain
features in these drawings have been exaggerated to more clearly
show details thereof. For example, in FIG. 1, the size of the
fibers and therapeutic agents are exaggerated relative to the
thickness of the sheath.
[0010] FIG. 2 shows a magnified side view of a surface of a sheath
according to another embodiment.
[0011] FIG. 3 shows a magnified side view of a surface of a sheath
according to another embodiment.
[0012] FIGS. 4A and 4B show a catheter device according to another
embodiment. FIG. 4A shows the catheter device with the balloon in a
deflated stated. FIG. 4B shows the catheter device with the balloon
inflated.
[0013] FIGS. 5A-5C show a catheter device according to another
embodiment. FIG. 5A shows the catheter device with the balloon in a
deflated state. FIG. 5B shows a transverse cross-section view of
the balloon taken at arrow A in FIG. 5A. FIG. 5C shows a transverse
cross-section view of the balloon taken at arrow A in FIG. 5A with
the balloon inflated.
[0014] FIGS. 6A-6D show a catheter device according to another
embodiment. FIGS. 6A and 6B (transverse cross-section view) show
the catheter device with the balloon in a deflated state.
[0015] FIGS. 6C and 6D (transverse cross-section view) show the
catheter device with the balloon inflated.
[0016] FIGS. 7A-7D show a catheter device according to another
embodiment. FIGS. 7A and 7B (enlarged view of the elastomeric mesh)
show the catheter device with the balloon in a deflated state.
FIGS. 7C and 7D (enlarged view of the elastomeric mesh) show the
catheter device with the balloon inflated.
[0017] FIGS. 8A and 8B show side views of a catheter device
according to another embodiment.
[0018] FIGS. 9A and 9B show side views of a catheter device
according to another embodiment.
[0019] FIGS. 10A and 10B show side views of a catheter device
according to another embodiment.
[0020] FIGS. 11A and 11B show side views of a catheter device
according to another embodiment.
[0021] FIGS. 12A-12C show transverse cross-sections of a portion of
a balloon according to an embodiment.
[0022] FIGS. 13A-13C show images of a nanofiber sheath wrapped
around a balloon in its folded configuration.
[0023] FIGS. 14A and 14B show images of a nanofiber sheath wrapped
around a balloon in its inflated configuration.
[0024] FIGS. 15A-15C show the wall of a balloon according to yet
another embodiment. FIG. 15A shows a cross-section perspective view
of a fragment of the balloon wall. FIG. 15B shows a cross-sectional
side view of the balloon wall shown in FIG. 15A. FIG. 15C shows the
balloon wall of FIG. 15B after the caps have been actuated to
open.
[0025] It is to be noted that certain features in these drawings
have been exaggerated to more clearly show details thereof. For
example, the diameter of an uninflated balloon relative to the
thickness of the catheter shaft may be smaller than what is
depicted in the drawings.
DETAILED DESCRIPTION
[0026] Catheter devices of the present invention use an expandable
balloon for delivering a therapeutic agent to a target site in the
body. The balloon is designed to be insertable in the body via a
catheter. The therapeutic agent can be associated with the balloon
in any of various ways, as further described below. Any of various
mechanisms conventionally used for the delivery, actuation, or
expansion (e.g., by inflation) of balloon catheter devices may be
used in the present invention. The balloon catheter may be designed
similar to those that have been known in the art, including but not
limited to angioplasty catheters, stent delivery catheters,
inflation catheters, and/or perfusion catheters. The catheter
devices of the present invention may be used in conjunction with
other drug delivery devices, such as stents.
[0027] In one aspect of the present invention, one or more sheaths
are disposed around the balloon. The sheath may be made of various
types of materials, and in some cases, the sheath may be formed of
a permeable or semi-permeable material to allow the passage of the
therapeutic agent through the sheath. For example, the sheath may
be made of expanded polytetrafluoro-ethylene (ePTFE), which can be
made by expanding PTFE tubing under controlled conditions during
the manufacturing process. This expansion process alters the
physical properties of the PTFE tubing such that microscopic pores
are created in the tube. The sheath can also be made from various
other types of polymeric materials, such as polyolefin copolymers,
fluoropolymers, noncompliant polyethylene terephthalate (PET),
polyimide, nylon, polyethylene, PEBAX, or the like. The sheath may
have varying degrees of compliance depending upon the type of
balloon being used and the particular application. The sheath may
be attached to the surface of the balloon (e.g., at one or more
points or continuously) or the sheath may be free of any
attachments to the surface of the balloon (e.g., the sheath is
"free-floating" over the balloon surface).
[0028] Further, a therapeutic agent can be disposed over the
sheath, within the sheath, or between the balloon and the sheath.
The therapeutic agent can be associated with the sheath in various
ways. For example, referring to FIG. 1, a sheath 100 has a fibrous
structure (e.g., a fibrous mat-like structure) containing a network
of fibers 102, and therapeutic agent 104 is dispersed within the
network of fibers 102. In another example, referring to the
magnified side view shown in FIG. 2, the surface 110 of a sheath is
rough-textured and therapeutic agent 114 is dispersed in the
interstices 112 of the rough-textured surface. In another example,
referring to the magnified side view shown in FIG. 3, a surface 120
of a sheath has numerous pili 122 (e.g., hair-like projections)
extending from surface 120, and therapeutic agent 124 is dispersed
between pili 122.
[0029] In certain embodiments, the sheath is designed to retract
away from the balloon as the balloon is expanded. For example,
referring to the embodiment shown in FIGS. 4A and 4B, a catheter
device 80 comprises a balloon 84 mounted on an elongate shaft 82
(note that balloon 84 may have a smaller unexpanded profile
relative to the shaft 82 than that illustrated in FIG. 4A). Balloon
84 is coated with a therapeutic agent 18 which is formulated to
include a pharmaceutically-acceptable lubricant material. The
pharmaceutically-acceptable lubricant material can either be
incorporated into a matrix comprising the therapeutic agent or the
therapeutic agent can be directly disposed on the outer surface of
balloon 84 and the lubricant can be placed over the therapeutic
agent as a top coat. The proximal half of balloon 84 is covered by
a proximally located sheath 85 and the distal half of balloon 84 is
covered by a distally located sheath 86. The edges of proximal
sheath 85 and distal sheath 86 meet or overlap near the middle, for
example, of balloon 84 so that therapeutic agent 18 on balloon 84
is enclosed within the sheaths. Of course, the edges of proximal
sheath 85 and distal sheath 86 can meet or overlap at another
portion of balloon 84. In addition, as an alternate embodiment, the
edges of the proximal sheath 85 and the distal sheath 86 may be
separated, in which case it may be desirable to have the
therapeutic agent only on those portions of the balloon covered by
the sheaths.
[0030] In operation, balloon 84 is inserted into the body via a
catheter, with the balloon in an unexpanded condition as shown in
FIG. 4A. Because therapeutic agent 18 is covered by sheaths 85 and
86, therapeutic agent 18 is protected while balloon 84 is being
guided to the target site. At the target site, as shown in FIG. 4B,
balloon 84 is inflated. Expansion of balloon 84 causes sheaths 85
and 86 to slip across the surface of balloon 84 and be pulled
proximally and distally, respectively, thus exposing therapeutic
agent 18 for release at the target site. In an alternate
embodiment, therapeutic agent 18 is applied to the inner surface of
sheaths 85 and 86 so that therapeutic agent 18 is smeared onto the
surface of balloon 84 as the sheaths retract.
[0031] In certain embodiments, the sheath comprises a body and a
plurality of reservoirs for containing a therapeutic agent. The
reservoirs can be, for example, longitudinally-extending channels
within the body of the sheath. As the balloon is expanded within
the sheath, the expanding balloon applies pressure against the
reservoirs to push the therapeutic agent out of the reservoirs. In
some cases, two or more of the reservoirs may be in communication
with each other.
[0032] For example, referring to the embodiment shown in FIGS.
5A-5C, a catheter device 40 comprises a balloon 48 mounted on an
elongate shaft 43 (note that balloon 48 may have a smaller
uninflated profile relative to shaft 43 than what is depicted in
FIG. 5A). Balloon 48 is enclosed in a sheath 42 that is shaped and
dimensioned to allow balloon 48 to expand within sheath 42. Sheath
42 has a plurality of longitudinally extending channels 44 which
contain a therapeutic agent 18. Each channel 44 is in communication
with a plurality of pores 47 on the external surface of sheath 42
via openings 46. As shown in FIG. 5B, when balloon 48 (shown with
inflation chamber 49) is in a deflated state, channels 44 are in a
relaxed condition. FIG. 5B shows a space between channels 44 and
balloon 48 which is for illustration purposes only. This space is
not necessary and channels 44 may be in contact with un-inflated
balloon 48. The sheath 42 may be fitted snugly around the
un-inflated balloon 48.
[0033] In operation, catheter device 40 is inserted into the body
via a catheter. At the target site, as shown in FIG. 5C, balloon 48
is inflated, causing it to press against channels 44. Internal
pressure in channels 44 causes therapeutic agent 18 to be forced
through openings 46 and out of pores 47 of sheath 42.
[0034] In certain embodiments, the sheath has a non-linear
compliance curve. Balloons having high compliance at smaller
inflation diameters and low compliance at larger inflation
diameters (i.e., a non-linear or hybrid compliance curve) are
described in U.S. Pat. No. 5,348,538 (Wang et al.), which is
incorporated by reference herein. Such balloons can be made using
the shrunken balloon technique described in Wang et al., which is
incorporated by reference herein. In general, a high compliance
balloon will undergo a relatively large increase in diameter in
response to an increase in inflation pressure, whereas a low
compliance balloon will undergo a relatively small increase in
diameter in response to an increase in inflation pressure. As such,
a sheath of the present invention can be made in the same or
similar manner, such that it has high compliance at smaller
expansion diameters and low compliance at larger expansion
diameters. In some cases, such a sheath can be formed of ePTFE
having a porous cell structure. As the sheath expands in diameter
with inflation of the balloon, the size of the pores in the sheath
increase, making it more permeable to the therapeutic agent.
[0035] For example, referring to the embodiment shown in FIGS.
6A-6D, a catheter device 150 comprises a balloon 156 mounted on an
elongate shaft 152. Balloon 156 has an inflation chamber 155.
Balloon 156 is covered with a sheath 154 formed of ePTFE having a
porous cell structure. Sheath 154 has a non-linear compliance
curve, such that it has high compliance at smaller expansion
diameters and low compliance at larger expansion diameters.
Disposed between the outer surface of balloon 156 and sheath 154 is
a therapeutic agent 18.
[0036] In operation, balloon 156 is inserted into the body via a
catheter. Because therapeutic agent 18 is covered by sheath 154,
therapeutic agent 18 is protected while balloon 156 is being guided
to the target site. At the target site, as shown in FIGS. 6C and
6D, balloon 156 is inflated. With the inflation of balloon 156,
sheath 154 also expands. Initially, sheath 154 expands with
relatively high compliance. Also, as sheath 154 expands, the pores
in sheath 154 increase in size, allowing the release of therapeutic
agent 18 through sheath 154. With further inflation of balloon 156
and expansion of sheath 154, sheath 154 becomes less compliant as
it reaches its predetermined maximum diameter.
[0037] In certain embodiments, it may be desirable to apply the
sheath (e.g., of ePTFE) over a balloon that has been inflated and
then deflated. This deflation or shrinking process can allow
subsequent over-expansion of the sheath or ePTFE layer to create a
larger cell size to allow for burst release of the therapeutic
agent. When a relatively non-compliant balloon is used, the
shrinking process facilitates the use of higher inflation
pressures.
[0038] In certain embodiments, the sheath may be elastomeric and
expands upon inflation of the balloon. In some cases, the
elastomeric sheath may be an elastomeric mesh. With expansion, the
widened spaces of the mesh allow for the release of the therapeutic
agent. In some cases, the elastomeric mesh may comprise a
biodegradable material (e.g., polyglycolic acid, polylactic acid,
polyanhydride, etc.). In some cases, the medical device may further
include a biodegradable stent (e.g., made of a biodegradable
polymer or bioresorbable metal, such as magnesium) disposed over
the balloon, with the biodegradable stent being covered by the
elastomeric mesh.
[0039] For example, referring to the embodiment shown in FIGS.
7A-7D, a catheter device 160 comprises a balloon 166 mounted on an
elongate shaft 162. Balloon 166 has an inflation chamber 165.
Balloon 166 is covered with an expandable sheath 164 formed of an
elastomeric mesh 168 having interstices 169 (see FIG. 7B). Disposed
between the outer surface of balloon 166 and sheath 164 is a
therapeutic agent 18. With balloon 166 in a deflated state and
sheath 154 unexpanded, intersticial openings 169 are sufficiently
small such that therapeutic agent 18 is trapped by elastomeric mesh
168 of sheath 164 (e.g., less than 25 .mu.m, or less than 10 .mu.m
in size, or another suitable size depending upon the particular
application).
[0040] In operation, balloon 166 is inserted into the body via a
catheter. Because therapeutic agent 18 is covered by sheath 164,
therapeutic agent 18 is protected while balloon 166 is being guided
to the target site. At the target site, as shown in FIG. 7C,
balloon 166 is inflated. With the inflation of balloon 166, sheath
164 also expands. Expansion of sheath 164 causes the widening of
intersticial openings 169 (see FIG. 7D), which allows for the
release of therapeutic agent 18.
[0041] In some cases, sheath 164 may further have numerous pili as
shown in FIG. 3. In such cases, therapeutic agent 18 that passes
through the wall of sheath 164 may then be "smeared" onto the inner
wall of the blood vessel when the balloon is retracted through the
blood vessel. In such cases, the therapeutic agent may be
formulated with a biocompatible adhesive substance.
[0042] In certain embodiments, the sheath is designed to tear,
break, or otherwise become disrupted at one or more points when the
sheath expands as a result of balloon inflation. The sheath is
provided with one or more weakened portions where the tearing,
breaking, or disruption occurs. The weakened portions are areas
where the sheath has a different structure or composition than
other areas of the sheath, wherein the different structure or
composition at the weakened portions cause the area to be
structurally weaker than the other areas of the sheath. For
example, the weakened portions may be slots, slits, grooves, or
perforations in the sheath. The weakened portions may have any of
various orientations or configurations relative to the balloon,
including radial, longitudinal, grid-like, or random. The tearing,
breaking, or disruption of the sheath allows the release of the
therapeutic agent. In some cases, the weakened portions may be
areas where the sheath is attached to the balloon such that
disruption of the sheath preferentially occurs at the attachment
points. Such attachments can be made by, for example, spot welding
of the sheath to the balloon.
[0043] Referring to the embodiment shown in FIGS. 8A and 8B, a
catheter device 200 comprises a balloon 204 mounted on an elongate
shaft 202. Balloon 204 is coated with a therapeutic agent 18 (not
shown in FIG. 8A). Balloon 204 is enclosed within a sheath 206 such
that therapeutic agent 18 is covered by sheath 206. Sheath 206 has
a plurality of longitudinally extending perforation lines 208,
along which sheath 206 is designed to tear.
[0044] In operation, balloon 204 (enclosed within sheath 206) is
inserted into the body via a catheter. Because therapeutic agent 18
is covered by sheath 206, therapeutic agent 18 is protected while
balloon 204 is being guided to the target site. At the target site,
as shown in FIG. 8B, balloon 204 is inflated, causing sheath 206 to
also expand. Expansion of sheath 206 causes tearing of sheath 206
along perforation lines 208 to form tears 209. Tears 209 expose
therapeutic agent 18 on the surface of balloon 204 such that
therapeutic agent 18 is released.
[0045] Referring to the embodiment shown in FIGS. 9A and 9B, a
catheter device 210 comprises a balloon 214 (not shown in FIG. 9A)
mounted on an elongate shaft 212. Balloon 214 is coated with a
therapeutic agent 18 (not shown in FIG. 9A). Balloon 214 is
enclosed within a sheath 216 such that therapeutic agent 18 is
covered by sheath 216. Sheath 216 has a plurality of radially
extending perforation lines 218, along which sheath 216 is designed
to tear.
[0046] In operation, balloon 214 enclosed within sheath 216 is
inserted into the body via a catheter. Because therapeutic agent 18
is covered by sheath 216, therapeutic agent 18 is protected while
balloon 214 is being guided to the target site. At the target site,
as shown in FIG. 9B, balloon 214 is inflated, causing sheath 216 to
also expand. Expansion of sheath 216 causes tearing of sheath 216
along perforation lines 218 to form tears 219. Tears 219 expose
therapeutic agent 18 on the surface of balloon 214 such that
therapeutic agent 18 is released.
[0047] Referring to the embodiment shown in FIGS. 10A and 10B, a
catheter device 220 comprises a balloon 224 (not shown in FIG. 10A)
mounted on an elongate shaft 222. Balloon 224 is coated with a
therapeutic agent 18 (not shown in FIG. 10A). Balloon 224 is
enclosed within a sheath 226 such that therapeutic agent 18 is
covered by sheath 226. At its midportion, sheath 226 has a
circumferentially extending perforation line 228, along which
sheath 226 is designed to tear.
[0048] In operation, balloon 224 enclosed within sheath 226 is
inserted into the body via a catheter. Because therapeutic agent 18
is covered by sheath 226, therapeutic agent 18 is protected while
balloon 224 is being guided to the target site. At the target site,
as shown in FIG. 10B, balloon 224 is inflated, causing sheath 226
to also expand. Expansion of sheath 226 causes tearing of sheath
226 at perforation line 228 (creating sheath edges 229) as proximal
portion 226' and distal portion 226'' of sheath 226 are pulled in
opposite directions. This tearing of sheath 226 exposes therapeutic
agent 18 on the surface of balloon 224 such that therapeutic agent
18 is released.
[0049] Referring to the embodiment shown in FIGS. 11A and 11B, a
catheter device 230 comprises a balloon 234 (not shown in FIG. 11A)
mounted on an elongate shaft 232. Balloon 234 is coated with a
therapeutic agent 18 (not shown in FIG. 11A). Balloon 234 is
enclosed within a sheath 236 such that therapeutic agent 18 is
covered by sheath 236. Sheath 236 has a plurality of perforation
lines 238 oriented in a grid-like pattern, along which sheath 236
is designed to tear. The size of at least some of the individual
grid units may be in the micron range (e.g., less than 100 .mu.m,
or less than 10 .mu.m) such that the fragments would not cause an
embolism.
[0050] In operation, balloon 234 enclosed within sheath 236 is
inserted into the body via a catheter. Because therapeutic agent 18
is covered by sheath 236, therapeutic agent 18 is protected while
balloon 234 is being guided to the target site. At the target site,
as shown in FIG. 11B, balloon 234 is inflated, causing sheath 236
to also expand. Expansion of sheath 236 causes tearing of sheath
236 at perforation lines 238, which results in the fragmentation of
sheath 236 into fragments 239. The size of fragments 239 may be in
the micron range (e.g., less than 100 .mu.m, or less than 10
.mu.m). This fragmentation of sheath 236 exposes therapeutic agent
18 on the surface of the balloon 234 such that therapeutic agent 18
is released.
[0051] Referring to the embodiment shown in FIGS. 12A-12C, a
catheter device comprises a balloon having a surface 240. As shown
in FIG. 12A, a layer of therapeutic agent 18 is deposited onto
surface 240 of the balloon. As shown in FIG. 12B, the layer of
therapeutic agent 18 is then embossed with a pattern (e.g., by
stamping) to create ridges 242 and depressions 244 in the layer of
therapeutic agent 18. The layer of therapeutic agent 18 can be
formulated in any suitable way to allow this type of patterning
(e.g., by including a binder material, such as
polyvinylpyrrolidone).
[0052] As shown in FIG. 12C, a sheath is provided by depositing a
film 246 (representing a sheath) of brittle material, such as low
molecular weight poly(lactic-co-glycolic acid) (PLGA) or low
molecular weight poly(lactic acid) (PLA), onto the patterned layer
of therapeutic agent 18. Film 246 may also be made of a
non-polymeric material, such as salts of moderate to high molecular
weight. Film 246 that is located over ridges 242 is thinner (at
regions 247) relative to film 246 that is located over depressions
244 (at regions 249). Thus, a pattern of thin regions 247 in film
246 allows film 246 to fragment upon expansion of the balloon. In
some cases, thin regions 247 may be attached to the surface 240 of
the balloon (e.g., by spot welding), which can enhance
fragmentation of film 246.
[0053] In certain embodiments, the sheath comprises nanofibers. The
nanofibers are formed of any suitable polymer material, including
polymers that are elastic. The nanofibers may have diameters
(thickness) that are less than 1 .mu.m (e.g., in the range of 200
nm-1 .mu.m). The nanofibers may comprise biodegradable polymers,
such as poly(lactic-co-glycolic acid) (PLGA), poly(lactic acid)
(PLA), or uncured poly(ethylene oxide) (PEO). The nanofibers may
also comprise non-biodegradable polymers, such as
poly(styrene-isobutylene-styrene) (SIBS) block copolymers,
polyamides (e.g., nylon), polyesters, polyethylene, polyurethane,
or carbon fiber.
[0054] The nanofibers may be disposed over the balloon in any of
various ways. In some cases, the nanofibers are wound
circumferentially around the body of the balloon. The nanofibers
may be wound around the balloon loosely or under elastic tension.
Where the nanofibers are wound around the balloon under elastic
tension, the elastic tension may restrain the balloon in its
unexpanded or folded configuration.
[0055] For example, FIGS. 13A-13C show PLGA nanofibers wrapped
circumferentially around a balloon in its folded configuration.
FIG. 13A shows a side view of the balloon; FIG. 13B shows a
close-up view of a portion of the balloon, with the nanofibers
being more visible; and FIG. 13C shows a scanning-electron
micrograph of the nanofiber sheath showing the individual
nanofibers. In another example, FIGS. 14A and 14B show PLGA
nanofibers wrapped circumferentially around a balloon in its
inflated configuration. FIG. 14A shows a side view of the balloon;
and FIG. 14B shows a close-up view of a portion of the balloon,
with the nanofibers being more visible.
[0056] In some cases, the nanofibers are deposited as a tangled mat
on the balloon. In some of such cases, additional nanofibers may be
wound circumferentially around the tangled mat of nanofibers (e.g.,
to encase the tangled mat of nanofibers).
[0057] The nanofibers may be disposed over the balloon with the
balloon in any suitable configuration (e.g., inflated or
uninflated, folded or unfolded). The nanofibers may be disposed
over the entire balloon or over only a portion of the balloon
(e.g., between the cones).
[0058] The therapeutic agent may be associated with the nanofiber
sheath in any of various ways. The therapeutic agent may be
provided in any suitable form, including as a liquid, a gel, or a
solid. In some cases, the therapeutic agent is contained between
the nanofiber sheath and the balloon (i.e., the sheath covers over
the therapeutic agent). For example, the therapeutic agent can be
deposited on the balloon and the nanofibers are spun (e.g., by
electro-spinning) over the therapeutic agent to encase and protect
it. Where the sheath comprises a tangled mat of nanofibers, the
therapeutic agent may be dispersed within the network of
nanofibers. In some cases, the therapeutic agent may be dispersed
in the spaces between the nanofibers. In some cases, where the
nanofibers are biodegradable (e.g., made of partially cured PEO),
the therapeutic agent may constitute part of the composition of the
nanofibers and be released upon degradation of the nanofibers. For
example, the therapeutic agent may be contained in the nanofiber
solution and spun with the nanofibers.
[0059] Upon delivery of the balloon to the target site, the
therapeutic agent may be released through any of various
mechanisms. Where the nanofiber sheath covers over the therapeutic
agent, the therapeutic agent may be released through gaps or
openings between the nanofibers. For example, as the balloon
expands, the therapeutic agent may be squeezed through such gaps or
openings. In some cases, stretching of the nanofibers as the
balloon expands causes thinning of the nanofibers. This thinning of
the nanofibers increases the spacing between the nanofibers,
providing openings for the release of the therapeutic agent.
[0060] In addition to their role in delivery of the therapeutic
agent, the nanofibers may also serve other functions. For example,
elastic nanofibers may serve to control the folding or re-folding
of the balloon or control the shape or dimensions of the expanded
balloon.
[0061] In another aspect of the present invention, the balloon
includes a micro-electromechanical system (MEMS) for drug delivery.
Various types of drug delivery systems using MEMS are known in the
art, such as microfluidic devices that incorporate micropumps,
valves, or flow channels; microfabricated porous membranes for drug
encapsulation; microparticles for carrying drugs; and the microchip
devices for drug delivery described in U.S. Pat. No. 6,656,162
(Santini et al.).
[0062] Referring to FIGS. 15A-15C, in this embodiment, a catheter
device comprises a balloon having a substrate layer 52 on the
surface of the balloon wall 50. Substrate layer 52 has a plurality
of micro-sized reservoirs 54 which contain a therapeutic agent 18.
Reservoirs 54 are formed using any of various microfabrication
techniques, including lithographic etching, molding, or
micromachining (e.g., laser drilling). As such, substrate layer 52
is made of a material which can be shaped by microfabrication
techniques, including for example, ceramics, metal oxides,
semiconductor materials, and polymers. Reservoirs 54 have openings
55 through which therapeutic agent 18 may be released. To contain
therapeutic agent 18 within the reservoirs 54 until the appropriate
time for release, reservoirs 54 are covered by reservoir caps 56
formed of a shape memory material. Various types of shape memory
material are suitable for use in reservoir caps 56, including shape
memory polymers and shape memory alloys (e.g., nitinol).
[0063] In operation, the balloon is inserted into the body via a
catheter. At the target site, as shown in FIG. 15C, the balloon is
inflated and reservoir caps 56 are actuated to open (e.g., by
bending), allowing therapeutic agent 18 contained in reservoirs 54
to be released. Reservoir caps 56 may be actuated in any of various
ways, including temperature change or application of an electric
current.
[0064] In certain embodiments of the invention, as described above,
the configuration of the balloon and the sheath can be controlled
such as to allow release of the therapeutic agent only at the
desired time. For example, the device may be designed such that a
certain pressure within the balloon is required for the sheath to
release the therapeutic agent (e.g., by retracting, fracturing,
fragmenting, opening pores, etc.). In this way, the therapeutic
agent can be held in the folds while the device is delivered
through the blood vessel to the target site. Then, at the target
site, the balloon is inflated to the pressure and/or diameter at
which the sheaths are designed to release the therapeutic agent. In
this way, for example, the therapeutic agent release can be
controlled such that it is released only if the balloon is in
contact with or in close proximity to the vessel wall. This helps
to prevent loss of the therapeutic agent during catheter placement
and balloon inflation. Also, because deflation of the balloon can,
in some instances, stop or substantially reduce therapeutic agent
release, certain embodiments of the invention can control the
duration of release after the initial release of therapeutic
agent.
[0065] Medical devices of the present invention may also include a
vascular stent mounted on the balloon. The vascular stent may be
any of those known in the art, including those with or without
coatings that elute a therapeutic agent. The stent may also be
biostable, bioerodible, or biodegradable.
[0066] The balloons of the present invention may also be coated
with a low-molecular weight carbohydrate, such as mannitol. The
carbohydrate may be a separate coating or be blended with the
therapeutic agent. The balloons of the present invention may also
be coated with a radiocontrast agent (ionic or non-ionic), such as
iopromide. The contrast agent may be a separate coating or be
blended with the therapeutic agent.
[0067] The therapeutic agent used in the present invention may be
any pharmaceutically-acceptable agent such as a drug, a non-genetic
therapeutic agent, a biomolecule, a small molecule, or cells.
Example drugs include anti-proliferative agents or anti-restenosis
agents such as paclitaxel, sirolimus (rapamycin), tacrolimus,
everolimus, and zotarolimus.
[0068] Exemplary non-genetic therapeutic agents include
anti-thrombogenic agents such heparin, heparin derivatives,
prostaglandin (including micellar prostaglandin E1), urokinase, and
PPack (dextrophenylalanine proline arginine chloromethylketone);
anti-proliferative agents such as enoxaparin, angiopeptin,
sirolimus (rapamycin), tacrolimus, everolimus, zotarolimus,
monoclonal antibodies capable of blocking smooth muscle cell
proliferation, hirudin, and acetylsalicylic acid; anti-inflammatory
agents such as dexamethasone, rosiglitazone, prednisolone,
corticosterone, budesonide, estrogen, estrodiol, sulfasalazine,
acetylsalicylic acid, mycophenolic acid, and mesalamine;
anti-neoplastic/anti-proliferative/anti-mitotic agents such as
paclitaxel, epothilone, cladribine, 5-fluorouracil, methotrexate,
doxorubicin, daunorubicin, cyclosporine, cisplatin, vinblastine,
vincristine, epothilones, endostatin, trapidil, halofuginone, and
angiostatin; anti-cancer agents such as antisense inhibitors of
c-myc oncogene; anti-microbial agents such as triclosan,
cephalosporins, aminoglycosides, nitrofurantoin, silver ions,
compounds, or salts; biofilm synthesis inhibitors such as
non-steroidal anti-inflammatory agents and chelating agents such as
ethylenediaminetetraacetic acid, O,O'-bis (2-aminoethyl)
ethyleneglycol-N,N,N',N'-tetraacetic acid and mixtures thereof;
antibiotics such as gentamycin, rifampin, minocyclin, and
ciprofloxacin; antibodies including chimeric antibodies and
antibody fragments; anesthetic agents such as lidocaine,
bupivacaine, and ropivacaine; nitric oxide; nitric oxide (NO)
donors such as linsidomine, molsidomine, L-arginine,
NO-carbohydrate adducts, polymeric or oligomeric NO adducts;
anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, an RGD
peptide-containing compound, heparin, antithrombin compounds,
platelet receptor antagonists, anti-thrombin antibodies,
anti-platelet receptor antibodies, enoxaparin, hirudin, warfarin
sodium, Dicumarol, aspirin, prostaglandin inhibitors, platelet
aggregation inhibitors such as cilostazol and tick antiplatelet
factors; vascular cell growth promoters such as growth factors,
transcriptional activators, and translational promoters; vascular
cell growth inhibitors such as growth factor inhibitors, growth
factor receptor antagonists, transcriptional repressors,
translational repressors, replication inhibitors, inhibitory
antibodies, antibodies directed against growth factors,
bifunctional molecules consisting of a growth factor and a
cytotoxin, bifunctional molecules consisting of an antibody and a
cytotoxin; cholesterol-lowering agents; vasodilating agents; agents
which interfere with endogenous vascoactive mechanisms; inhibitors
of heat shock proteins such as geldanamycin; angiotensin converting
enzyme (ACE) inhibitors; beta-blockers; .beta.AR kinase (.beta.ARK)
inhibitors; phospholamban inhibitors; protein-bound particle drugs
such as ABRAXANE.TM.; structural protein (e.g., collagen)
cross-link breakers such as alagebrium (ALT-711); any combinations
and prodrugs of the above.
[0069] Exemplary biomolecules include peptides, polypeptides and
proteins; oligonucleotides; nucleic acids such as double or single
stranded DNA (including naked and cDNA), RNA, antisense nucleic
acids such as antisense DNA and RNA, small interfering RNA (siRNA),
and ribozymes; genes; carbohydrates; angiogenic factors including
growth factors; cell cycle inhibitors; and anti-restenosis agents.
Nucleic acids may be incorporated into delivery systems such as,
for example, vectors (including viral vectors), plasmids or
liposomes.
[0070] Non-limiting examples of proteins include serca-2 protein,
monocyte chemoattractant proteins (MCP-1) and bone morphogenic
proteins ("BMP's"), such as, for example, BMP-2, BMP-3, BMP-4,
BMP-5, BMP-6 (VGR-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11,
BMP-12, BMP-13, BMP-14, BMP-15. Preferred BMP's are any of BMP-2,
BMP-3, BMP-4, BMP-5, BMP-6, and BMP-7. These BMPs can be provided
as homodimers, heterodimers, or combinations thereof, alone or
together with other molecules. Alternatively, or in addition,
molecules capable of inducing an upstream or downstream effect of a
BMP can be provided. Such molecules include any of the "hedgehog"
proteins, or the DNA's encoding them. Non-limiting examples of
genes include survival genes that protect against cell death, such
as anti-apoptotic Bcl-2 family factors and Akt kinase; serca 2
gene; and combinations thereof. Non-limiting examples of angiogenic
factors include acidic and basic fibroblast growth factors,
vascular endothelial growth factor, epidermal growth factor,
transforming growth factors .alpha. and .beta., platelet-derived
endothelial growth factor, platelet-derived growth factor, tumor
necrosis factor .alpha., hepatocyte growth factor, and insulin-like
growth factor. A non-limiting example of a cell cycle inhibitor is
a cathespin D (CD) inhibitor. Non-limiting examples of
anti-restenosis agents include p15, p16, p18, p19, p21, p2'7, p53,
p57, Rb, nFkB and E2F decoys, thymidine kinase and combinations
thereof and other agents useful for interfering with cell
proliferation.
[0071] Exemplary small molecules include hormones, nucleotides,
amino acids, sugars, and lipids and compounds have a molecular
weight of less than 100 kD.
[0072] Exemplary cells include stem cells, progenitor cells,
endothelial cells, adult cardiomyocytes, and smooth muscle cells.
Cells can be of human origin (autologous or allogenic) or from an
animal source (xenogenic), or genetically engineered. Non-limiting
examples of cells include side population (SP) cells, lineage
negative (Lin.sup.-) cells including Lin.sup.- CD34.sup.-,
Lin.sup.-CD34.sup.+, Lin.sup.-cKit.sup.+, mesenchymal stem cells
including mesenchymal stem cells with 5-aza, cord blood cells,
cardiac or other tissue derived stem cells, whole bone marrow, bone
marrow mononuclear cells, endothelial progenitor cells, skeletal
myoblasts or satellite cells, muscle derived cells, go cells,
endothelial cells, adult cardiomyocytes, fibroblasts, smooth muscle
cells, adult cardiac fibroblasts+5-aza, genetically modified cells,
tissue engineered grafts, MyoD scar fibroblasts, pacing cells,
embryonic stem cell clones, embryonic stem cells, fetal or neonatal
cells, immunologically masked cells, and teratoma derived cells.
Any of the therapeutic agents may be combined to the extent such
combination is biologically compatible.
[0073] The foregoing description and examples have been set forth
merely to illustrate the invention and are not intended to be
limiting. Each of the disclosed aspects and embodiments of the
present invention may be considered individually or in combination
with other aspects, embodiments, and variations of the invention.
Modifications of the disclosed embodiments incorporating the spirit
and substance of the invention may occur to persons skilled in the
art and such modifications are within the scope of the present
invention.
* * * * *