U.S. patent application number 10/705108 was filed with the patent office on 2004-05-20 for methods for embolizing vascular sites with an embolizing composition.
Invention is credited to Greff, Richard J., Hayman, Douglas Ray, Moret, Jacques, Roth, Noah Michael, Tran, Chinh Ngoc, Whalen, Thomas J. II.
Application Number | 20040097901 10/705108 |
Document ID | / |
Family ID | 46203862 |
Filed Date | 2004-05-20 |
United States Patent
Application |
20040097901 |
Kind Code |
A1 |
Whalen, Thomas J. II ; et
al. |
May 20, 2004 |
Methods for embolizing vascular sites with an embolizing
composition
Abstract
Disclosed are novel techniques for embolizing blood vessels
which are particularly suited for treating vascular lesions via
catheter delivery of an embolic composition.
Inventors: |
Whalen, Thomas J. II;
(Encinitas, CA) ; Tran, Chinh Ngoc; (Mission
Viejo, CA) ; Hayman, Douglas Ray; (Mission Viejo,
CA) ; Roth, Noah Michael; (Highland Park, NJ)
; Moret, Jacques; (Les Bordes, FR) ; Greff,
Richard J.; (St. Pete Beach, FL) |
Correspondence
Address: |
SWISS LAW GROUP
3000 PAGE MILL ROAD, BUILDING # 3
SUITE 100
PALO ALTO
CA
94306
US
|
Family ID: |
46203862 |
Appl. No.: |
10/705108 |
Filed: |
November 10, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10705108 |
Nov 10, 2003 |
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09574500 |
May 19, 2000 |
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6645167 |
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60135222 |
May 21, 1999 |
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60135289 |
May 21, 1999 |
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Current U.S.
Class: |
604/509 ;
604/96.01 |
Current CPC
Class: |
A61L 24/08 20130101;
A61L 2430/36 20130101; A61M 5/31586 20130101; C08J 3/091 20130101;
C08L 29/04 20130101; A61K 9/0024 20130101; A61K 49/0419 20130101;
A61L 24/06 20130101; A61L 24/046 20130101; A61L 24/001 20130101;
A61L 24/06 20130101; A61M 2025/1052 20130101 |
Class at
Publication: |
604/509 ;
604/096.01 |
International
Class: |
A61M 031/00 |
Claims
What is claimed is:
1. A method for embolizing a vascular site comprising an opening
that is in communication with a vascular vessel by delivering via a
catheter to said vascular site a composition comprising (1) a
biocompatible polymer; (2) a biocompatible water insoluble contrast
agent; and (3) a biocompatible solvent, said method includes: (a)
positioning the distal end of a delivery catheter in said vascular
site wherein the delivery catheter is connected to a source of said
composition and whereby said composition can be injected into the
vascular site through the delivery catheter; (b) positioning a flow
arresting device (e.g., balloon) at the vascular site to be
embolized; (c) activating the flow arresting device at the vascular
site to be embolized such that the activated device substantially
arrests blood flow through the vascular site; and (d) injecting
said composition into the vascular site; (e) deactivating said flow
arresting device to permit sufficient blood flow through said
vascular site to be embolized such that removal of the
biocompatible solvent is facilitated and oxygenated blood is
delivered to the tissue distal to said flow arresting device; and
(f) repeating procedures (c)-(e) at least once and as necessary to
effect embolization of said vascular site.
2. The method according to claim 1 wherein procedure (c) comprises
inflating a balloon so that the inflated balloon has a diameter
that is greater than the inner diameter of the vascular vessel.
3. The method according to claim 2 wherein the balloon is inflated
to a diameter that is about 100% to 130% of the inner diameter of
the vascular vessel.
4. The method according to claim 1 wherein in procedure (e), the
balloon is deflated until its diameter is about 10% to 90% of the
diameter of the vascular vessel and allowing at least some of the
biocompatible solvent to be removed from the vascular site by
entrainment in bodily fluid and
5. A method for embolizing a vascular site comprising an opening
that is in communication with a vascular vessel by delivering via a
catheter into said vascular site a first embolic composition and
then a second embolic composition wherein each embolic composition
comprises (1) a biocompatible polymer; (2) a biocompatible water
insoluble contrast agent; and (3) a biocompatible solvent, said
method includes: (a) positioning the distal end of a delivery
catheter in said vascular site wherein the delivery catheter
defines a channel that contains first embolic composition and the
second embolic composition wherein the first embolic composition is
situated adjacent the distal end and the second embolic composition
is situated adjacent to the first embolic composition and whereby
said first and second embolic compositions can be injected into the
vascular site through the delivery catheter and wherein the first
embolic composition has a higher concentration or viscosity of
biocompatible polymer than the second embolic composition; (b)
injecting the first embolic composition in said vascular site
whereby substantially no axial mixing of the first and second
embolic compositions occurs in the channel and, thereafter, (c)
injecting the second embolic composition into the vascular
site.
6. The method according to claim 5 wherein procedure (b) comprises
applying a first force into the channel to inject said first
embolic composition into the vascular site and, procedure (c)
comprises applying a second force into the channel to inject said
second embolic composition into the vascular site wherein the first
force is greater than the second force.
7. The method according to claim 5 wherein, following procedure
(b), the first embolic composition forms a nidus (kernel) in the
vascular site and following procedure (c) the second embolic forms
a precipitate that emanates from the nidus, wherein the precipitate
embolizes the vascular site.
8. A method for embolizing a vascular site comprising an opening
that is in communication with said site by delivering via a
catheter into said site a composition comprising (1) a
biocompatible polymer; (2) a biocompatible water insoluble contrast
agent; and (3) a biocompatible solvent, said method includes: (a)
positioning the distal end of a delivery catheter into the vascular
site wherein the delivery catheter is connected to a source of said
composition and whereby said composition can be injected into the
vascular site through the delivery catheter; (b) positioning a flow
arresting device at the vascular site to be embolized; (c)
injecting DMSO into the catheter to fill the lumen of said catheter
followed by injecting a first amount of said composition into said
catheter thereby at least a portion of said DMSO is ejected from
said catheter into the vascular site and washed downstream
therefrom; (d) activating a flow arresting device at the vascular
site so that the activated device substantially seals the opening;
(e) injecting the first amount of said composition from said
catheter into the vascular site to form a nidus (kemal) of the
embolizing composition; (f) inactivating the flow arresting device;
(g) determining the volume of the vascular site that has been
embolized; and (h) repeating procedures (e), (f), and (g) as needed
to embolize the vascular site.
9. The method according to claim 8 wherein, prior to procedure (c)
said method further comprises: (i) inflating a balloon to a first
size in the vascular vessel so that the opening is substantially
sealed; and, before procedure (e) (j) deflating the balloon.
10. The method according to claim 8 wherein procedure (c)
comprises: (1) filling the catheter with biocompatible solvent
(e.g., DMSO); (2) connecting the catheter to the source of the
embolic composition; and (3) injecting the first amount of
composition into the vascular vessel.
11. A method for embolizing a vascular site comprising an opening
that is in communication with a vascular vessel by delivering via a
catheter to said vascular site a composition comprising (1) a
biocompatible polymer; (2) a biocompatible water insoluble contrast
agent; and (3) a biocompatible solvent, said method includes: (a)
positioning the distal end of a delivery catheter in said vascular
site wherein the delivery catheter is connected to a source of said
composition and whereby said composition can be injected into the
vascular site through the delivery catheter; (b) activating a flow
arresting device in the vascular vessel so that the activated
device substantially seals the opening and does not occlude the
delivery catheter; and (c) injecting a single mass (bulk) of said
composition into the vascular site wherein the single mass is
sufficient to substantially fill the vascular site.
12. The method according to claim 11 wherein the volume of the
vascular site to be embolized is measured prior to injecting the
single mass in said site.
13. A method for embolizing a vascular site comprising an opening
that is in communication with a vascular vessel by delivering via a
catheter into said vascular site an embolizing composition
including (1) a biocompatible polymer; (2) a biocompatible water
insoluble contrast agent; and (3) a biocompatible solvent, said
method includes: (a) positioning the distal end of a delivery
catheter into the vascular site wherein the delivery catheter is
connected to a source of a first embolizing composition and second
embolizing composition and whereby said first and second embolizing
compositions can be injected into the vascular site through the
delivery catheter and wherein the first embolizing composition has
a higher concentration or concentration of biocompatible polymer
than the second embolizing composition; (b) injecting said first
embolizing composition into said vascular site to form a nidus
(kernel) of the first embolizing compositon; and, thereafter, (c)
injecting said second embolizing composition into said vascular
site to form a precipitate emanating from the nidus that embolizes
the vascular site.
14. The method according to claim 13 wherien, prior to procedure
(a) the balloon is inflated in the vascular vessel so that the
balloon when inflated seals the opening and does not occlude the
delivery catheter, and/or (2) the balloon when inflated has a
diameter that is greater than the inner diameter of the vascular
vessel.
15. The method according to claim 1 wherein the viscosity of the
composition is at least 150 cSt at 40.degree. C.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Patent Application Serial No. 60/135,222 filed May 21, 1999 which
application is incorporated herein by reference in its
entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention is directed to novel methods for embolizing
blood vessels which are particularly suited for treating aneurysms,
AVM and high flow fistulas. In one embodiment, the compositions
employed in the methods of this invention comprise a biocompatible
polymer, a biocompatible solvent and a biocompatible contrast agent
wherein the viscosity of this composition is at least about 150 cSt
at 40.degree. C. and, preferably, at least 200 cSt at 40.degree.
C.
REFERENCES
[0004] The following publications are cited in this application as
superscript numbers:
[0005] .sup.1 Mandai, et al., "Direct Thrombosis of Aneurysms with
Cellulose Acetate Polymer", J. Neurosurg., 12:497-500 (1992)
[0006] .sup.2 Kinugasa, et al., "Direct Thrombosis of Aneurysms
with Cellulose Acetate Polymer", J. Neurosurg., 77:501-507
(1992)
[0007] .sup.3 Casarett and Doull's Toxicology, Amdur et al.,
Editors, Pergamon Press, New York, pp. 661-66.sup.4 (1975)
[0008] .sup.4 Greff, et al., U.S. patent application Ser. No.
08/507,863 for "Novel Compositions for Use in Embolizing Blood
Vessels", filed Jul. 27, 1995
[0009] .sup.5 Greff, et al., U.S. patent application Ser. No.
08/508,248 for "Cellulose Diacetate Compositions for Use in
Embolizing Blood Vessels", filed Jul. 27, 1995
[0010] .sup.5 Kinugasa, et al., "Early Treatment of Subarachnoid
Hemorrhage After Preventing Rerupture of an Aneurysm", J.
Neurosurg., 83:34-41 (1995)
[0011] .sup.6 Kinugasa, et al., "Prophylactic Thrombosis to Prevent
New Bleeding and to Delay Aneurysm Surgery", Neurosurg., 36:661
(1995)
[0012] .sup.8 Taki, et al., "Selection and Combination of Various
Endovascular Techniques in the Treatment of Giant Aneurysms", J.
Neurosurg., 21:37-42 (1992)
[0013] .sup.9 Evans, et al., U.S. patent application Ser. No.
08/655,822 for "Novel Compositions for Use in Embolizing Blood
Vessels", filed May 31, 1996
[0014] .sup.10 Dunn, et al., U.S. Pat. No. 4,938,763 for
"Biodegradable In-Situ Forming Implants and Methods of Producing
Same", issued Jul. 3, 1990
[0015] .sup.11 Greff, et al., U.S. Pat. No. 5,695,480 for "Novel
Embolizing Compositions", issued Dec. 9, 1997
[0016] .sup.12 Greff, et al., U.S. Pat. No. 5,830,178 for "Novel
Methods for Embolizing Vascular Sites with an Embolizing
Composition Comprising Dimethylsulfoxide, issued Nov. 3, 1998.
[0017] All of the above references are herein incorporated by
reference in their entirety to the same extent as if each
individual reference was specifically and individually indicated to
be incorporated herein by reference in its entirety.
[0018] State of the Art
[0019] Embolization of blood vessels is conducted for a variety of
purposes including the treatment of tumors, the treatment of
lesions such as aneurysms, uncontrolled bleeding and the like.
[0020] Embolization of blood vessels is preferably accomplished via
catheter techniques which permit the selective placement of the
catheter at the vascular site to be embolized. In this regard,
recent advancements in catheter technology as well as in
angiography now permit neuroendovascular intervention including the
treatment of otherwise inoperable lesions. Specifically,
development of microcatheters and guide wires capable of providing
access to vessels as small as 1 mm in diameter allows for the
endovascular treatment of many lesions.
[0021] Embolizing compositions heretofore disclosed in the art
include those comprising a biocompatible polymer, a biocompatible
solvent and a contrast agent which allowed visualization of the in
vivo delivery of the composition via fluoroscopy..sup.1-8 Such
compositions typically contain no more than about 8 weight percent
of biocompatible polymer based on the weight of the total
composition.
[0022] Endovascular treatment regimens preferably include the use
of a water insoluble, radiopaque contrast agent in the embolizing
compositions in order that the physician can visualize delivery of
the composition to the vascular site via conventional techniques
such as fluoroscopy..sup.1-8 Additionally, the use of water
insoluble contrast agents is beneficial during post treatment
procedures to visualize the embolized mass during, for example,
surgery or to monitor the disease condition and/or for retreatment
purposes. Visualization is particularly necessary when using
catheter delivery techniques in order to ensure both that the
composition is being delivered to the intended vascular site and
that the requisite amount of composition is delivered. The latter
requirement is particularly critical in the treatment of aneurysms
where only the aneurysm sac is intended to be filled while leaving
the adjoining blood vessel unaffected. Accordingly, in such
treatments, the amount of embolic composition delivered is selected
to substantially fill but not overflow the aneurysm sac. If less
than this amount of embolic composition is delivered to the
aneurysm sac, the patient will be left with an active aneurysm
which, in some cases, may grow or enlarge. If more than this amount
of embolic composition is delivered, the composition will overflow
into the adjoining blood vessel which can then embolize this blood
vessel as well as the aneurysm. In the case where the affected
blood vessel is in or leads to a critical body organ e.g., the
brain, permanent damage due to ischemia will result.
[0023] When delivered by catheter, the embolic compositions
preferably comprise a biocompatible solvent, a biocompatible
polymer and the water insoluble contrast agent. The biocompatible
solvent is miscible or soluble in blood or other body fluid and
also solubilizes the biocompatible polymer during delivery. The
biocompatible polymer is selected to be soluble in the
biocompatible solvent but insoluble in blood or other body fluid.
The water insoluble contrast agent is suspended in the composition
and, as above, permits the physician to fluoroscopically visualize
catheter delivery of this composition. Upon contact with the blood
or other body fluid, the biocompatible solvent dissipates from the
embolic composition whereupon the biocompatible polymer
precipitates in the presence of the water insoluble contrast agent
and embolizes the blood vessel.
[0024] In practice, complications in this procedure have hindered
the delivery of the embolic composition into vascular sites. For
example, the use of a flow arresting device to limit blood flow
during aneurysm treatment by injection of an embolic composition
from a catheter has been heretofore suggested..sup.11 However,
there are severe limitations placed on the use of such devices in
combination with embolic compositions delivered via catheters. For
example, in situ solidification of these composition is facilitated
by blood transport of the biocompatible solvent away from the
growing precipitate. However, a flow arresting device limits the
amount of blood flow in the area adjacent the precipitate which, in
turn, hinders further precipitate formation. Moreover, blood flow
can be arrested for only a short period of time prior to the onset
of tissue damage due to ischemia.
[0025] In addition, reproducible formation and control of
precipitate formed from the embolic composition at the desired
vascular site is critical to effectively treat vascular disorders.
While techniques heretofore disclosed in the art provide an
adequate level of reproducibility.sup.12, new methods which enhance
the reproducibility of these techniques would be of great
value.
[0026] In view of the above, the art is in search of improved
embolization techniques.
SUMMARY OF THE INVENTION
[0027] This invention is directed to novel methods for embolizing
blood vessels which are particularly suited for treating aneurysms,
AVM's and high flow fistulas. These methods, either singularly or
in combination, permit the facile delivery of liquid embolic
compositions to vascular sites while overcoming one or more of the
problems heretofore associated with vascular embolization by use of
these compositions. These methods, either singularly or in
combination, further permit the controlled, reproducible formation
of an embolic precipitate at the vascular site.
[0028] In one aspect, the invention is directed to a method for
embolizing a vascular site comprising an opening that is in
communication with a vascular vessel by delivering via a catheter
to said vascular site a composition comprising (1) a biocompatible
polymer; (2) a biocompatible water insoluble contrast agent; and
(3) a biocompatible solvent, said method includes:
[0029] (a) positioning the distal end of a delivery catheter in
said vascular site wherein the delivery catheter is connected to a
source of said composition and whereby said composition can be
injected into the vascular site through the delivery catheter;
[0030] (b) positioning a flow arresting device (e.g., balloon) at
the vascular site to be embolized;
[0031] (c) activating the flow arresting device (i.e., a device
that either controls or reduces blood flow through a vessel) at the
vascular site to be embolized such that the activated device
substantially arrests blood flow through the vascular site; and
[0032] (d) injecting said composition into the vascular site;
[0033] (e) deactivating said flow arresting device to permit
sufficient blood flow through said vascular site to be embolized
such that removal of the biocompatible solvent is facilitated and
oxygenated blood is delivered to the tissue distal to said flow
arresting device; and
[0034] (f) repeating procedures (c)-(e) at least once and as
necessary to effect embolization of said vascular site.
[0035] Preferably, step (c) comprises inflating a balloon so that
the inflated balloon has a diameter that is greater than the inner
diameter of the vascular vessel. In one embodiment, the balloon is
inflated to a diameter that is about 100% to 130% of the inner
diameter of the vascular vessel, and more preferably about
115%.
[0036] In another embodiment, after procedure (d), the balloon is
deflated until its diameter is about 10% to 90% of the inner
diameter of the vascular vessel and allowing at least some of the
biocompatible solvent to be removed from the vascular site by
entrainment in bodily fluid, e.g., blood. Preferably the diameter
is reduced to about 20-25% of the diameter of the vascular
vessel.
[0037] In another aspect the invention is directed to a method for
embolizing a vascular site comprising an opening that is in
communication with a vascular vessel by delivering via a catheter
into said vascular site a first embolic composition and then a
second embolic composition wherein each embolic composition
comprises (1) a biocompatible polymer; (2) a biocompatible water
insoluble contrast agent; and (3) a biocompatible solvent, said
method includes:
[0038] (a) positioning the distal end of a delivery catheter in
said vascular site wherein the delivery catheter defines a channel
that contains first embolic composition and the second embolic
composition wherein the first embolic composition is situated
adjacent the distal end and the second embolic composition is
situated adjacent to the first embolic composition and whereby said
first and second embolic compositions can be injected into the
vascular site through the delivery catheter and wherein the first
embolic composition has a higher concentration or viscosity of
biocompatible polymer than the second embolic composition;
[0039] (b) injecting the first embolic composition in said vascular
site whereby substantially no axial mixing of the first and second
embolic compositions occurs in the channel and, thereafter,
[0040] (c) injecting the second embolic composition into the
vascular site.
[0041] As is apparent, the technique is applicable to injecting two
or more formulations.
[0042] In one embodiment, procedure (b) comprises applying a first
force into the channel to inject said first embolic composition
into the vascular site and, procedure (c) comprises applying a
second force into the channel to inject said second embolic
composition into the vascular site wherein the first force is
greater than the second force.
[0043] In another embodiment, following procedure (b) the first
embolic composition forms a nidus (kernel) in the vascular site and
following procedure (c) the second embolic forms a precipitate that
emanates from the nidus, wherein the precipitate embolizes the
vascular site.
[0044] In a further aspect, the invention is directed to a method
for embolizing a vascular site comprising an opening that is in
communication with said site by delivering via a catheter into said
site a composition comprising (1) a biocompatible polymer; (2) a
biocompatible water insoluble contrast agent; and (3) a
biocompatible solvent, said method includes:
[0045] (a) positioning the distal end of a delivery catheter into
the vascular site wherein the delivery catheter is connected to a
source of said composition and whereby said composition can be
injected into the vascular site through the delivery catheter;
[0046] (b) positioning a flow arresting device at the vascular site
to be embolized;
[0047] (c) injecting the biocompatible solvent (e.g., DMSO) into
the catheter to fill the lumen of said catheter followed by
injecting a first amount of said composition into said catheter
thereby at least a portion of said biocompatible solvent is ejected
from said catheter into the vascular site and washed downstream
therefrom;
[0048] (d) activating a flow arresting device at the vascular site
so that the activated device substantially seals the opening;
[0049] (e) injecting the first amount of said composition from said
catheter into the vascular site to form a nidus (kernal) of the
embolizing composition;
[0050] (f) inactivating the flow arresting device;
[0051] (g) determining the volume of the vascular site that has
been embolized; and
[0052] (h) repeating procedures (e), (f), and (g) as needed to
embolize the vascular site.
[0053] In the above method, repeating procedure (e), (f) and (g) is
preferably done at least one.
[0054] In one embodiment, prior to procedure (c) said method
further comprises:
[0055] (i) inflating a balloon to a first size in the vascular
vessel so that the opening is substantially sealed; and, before
procedure (e)
[0056] (j) deflating the balloon.
[0057] In another embodiment, procedure (c) comprises:
[0058] (1) filling the catheter with biocompatible solvent (e.g.,
DMSO);
[0059] (2) connecting the catheter to the source of the embolic
composition; and
[0060] (3) injecting the first amount of composition into the
vascular vessel.
[0061] In other preferred embodiments: (1) the vascular site has an
upper surface (findus) and a base at the opening wherein the base
and fundus are spaced apart by a distance D and procedure (a)
comprises positioning the distal end of the catheter a distance of
about one-third D from the upper surface, (2) procedure (c) takes
place while the flow arresting device is deactivated and comprises
injecting an amount of the embolic composition into the vascular
site and wherein following procedure (c), the method comprises
allowing the biocompatible solvent to be flushed out of the
vascular site, (3) procedure (e) comprises injecting an amount of
the embolic composition and procedure (f) comprises deactivating
the device to allow perfusion, and/or (4) procedure (e) comprises
injecting for a time period to permit perfusion and procedure (f)
comprises deactivating the device to allow perfusion.
[0062] In yet another aspect, the invention is directed to a method
for embolizing a vascular site comprising an opening that is in
communication with a vascular vessel by delivering via a catheter
to said vascular site a composition comprising (1) a biocompatible
polymer; (2) a biocompatible water insoluble contrast agent; and
(3) a biocompatible solvent, said method includes:
[0063] (a) positioning the distal end of a delivery catheter in
said vascular site wherein the delivery catheter is connected to a
source of said composition and whereby said composition can be
injected into the vascular site through the delivery catheter;
[0064] (b) activating a flow arresting device in the vascular
vessel so that the activated device substantially seals the opening
and does not occlude the delivery catheter; and
[0065] (c) injecting a single mass (bulk) of said composition into
the vascular site wherein the single mass is sufficient to
substantially fill the vascular site.
[0066] In one embodiment, the method further comprises the
procedure of measuring the volume of the vascular site before
injecting the single mass in said site.
[0067] In other embodiments (1) the volume of the single mass that
is injected is substantially equal to that of the vascular site,
and/or (2) the activated device is kept inflated for a sufficient
amount of time until the biocompatible polymer has formed a
precipitate at the vascular site.
[0068] In yet another aspect the invention is directed to a method
for embolizing a vascular site comprising an opening that is in
communication with a vascular vessel by delivering via a catheter
into said vascular site an embolizing composition including (1) a
biocompatible polymer; (2) a biocompatible water insoluble contrast
agent; and (3) a biocompatible solvent, said method includes:
[0069] (a) positioning the distal end of a delivery catheter into
the vascular site wherein the delivery catheter is connected to a
source of a first embolizing composition and second embolizing
composition and whereby said first and second embolizing
compositions can be injected into the vascular site through the
delivery catheter and wherein the first embolizing composition has
a higher concentration or concentration of biocompatible polymer
than the second embolizing composition;
[0070] (b) injecting said first embolizing composition into said
vascular site to form a nidus (kernel) of the first embolizing
compositon; and, thereafter,
[0071] (c) injecting said second embolizing composition into said
vascular site to form a precipitate emanating from the nidus that
embolizes the vascular site.
[0072] In other embodiments (1) the method prior to procedure (a)
further comprises inflating a balloon in the vascular vessel so
that the balloon when inflated seals the opening and does not
occlude the delivery catheter, and/or (2) the balloon when inflated
has a diameter that is greater than the inner diameter of the
vascular vessel.
[0073] Preferably, the methods employ a device to connect the
delivery system (e.g., catheter liner) and the injector (e.g.,
syringe) to create a blunt interface between delivered liquids.
[0074] Preferably, and as noted above, when treating aneurysms, the
distal end of the catheter is placed approximately 1/3 from the top
of aneurysm.
BRIEF DESCRIPTION OF THE DRAWINGS
[0075] The invention will now be described in greater detail with
reference to the preferred embodiments illustrated "in the
accompanying drawings, in which like elements bear like reference
numerals, and wherein:
[0076] FIG. 1 is an exploded side view of a side view of a
catheter, interface needle, and syringe system;
[0077] FIG. 2 is a cross sectional view of the interface needle,
taken along line 2-2 of FIG. 1;
[0078] FIG. 3 is a side view of the interface needle;
[0079] FIG. 4 is a side view of the syringe according to the
present invention;
[0080] FIG. 5 is an exploded side view of the syringe of FIG.
4;
[0081] FIG. 6A is an end view of the proximal end of the syringe
barrel;
[0082] FIG. 6B is an enlarged cross sectional view of the plunger
shaft;
[0083] FIG. 7 is a is a top view of a sliding end member of the
syringe;
[0084] FIG. 8 is a side view of the sliding end member of FIG.
8;
[0085] FIG. 9 is an enlarged side view of the spring element;
and
[0086] FIG. 10 is a cross-sectioned view of a side-wall
aneurysm.
DETAILED DESCRIPTION OF THE INVENTION
[0087] This invention is directed to novel compositions for
embolizing blood vessels which are particularly suited for treating
vascular lesions via catheter delivery of the composition.
[0088] However, prior to discussing this invention in further
detail, the following terms will first be defined:
[0089] The term "embolizing" refers to a process wherein a material
is injected into a blood vessel which, in the case of, for example,
aneurysms, fills or plugs the aneurysm sac and/or encourages clot
formation so that blood flow into the aneurysm ceases, in the case
of high flow AVM's forms a plug or clot to control/reroute blood
flow to permit proper tissue perfusion, and, in the case of a
vascular site, fills the vascular site to prevent blood flow there
through. Embolization of the blood vessel is, therefore, important
in preventing/controlling bleeding due to lesions (e.g., organ
bleeding, gastrointestinal bleeding, vascular bleeding as well as
bleeding associated with an aneurysm). In addition, embolization
can be used to ablate diseased tissue (e.g., tumors, etc.) by
cutting off its blood supply.
[0090] The term "biocompatible polymer" refers to polymers which,
in the amounts employed, are non-toxic and substantially
non-immunogenic when used internally in the patient and which are
substantially insoluble in the body fluid of the mammal. The
biocompatible polymer can be either biodegradable or, preferably,
non-biodegradable.
[0091] Biodegradable polymers are disclosed in the art. For
example, Dunn, et al..sup.10 discloses the following examples of
biodegradable polymers: linear-chain polymers such as polylactides,
polyglycolides, polycaprolactones, polyanhydrides, polyarnides,
polyurethanes, polyesteramides, polyorthoesters, polydioxanones,
polyacetals, polyketals, polycarbonates, polyorthocarbonates,
polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates,
polyalkylene oxalates, polyalkylene succinates, poly(malic acid),
poly(amino acids), polyvinylpyrrolidone, polyethylene glycol,
polyhydroxycellulose, chitin, chitosan, and copolymers, terpolymers
and combinations thereof. Other biodegradable polymers include, for
example, gelatin, collagen, etc.
[0092] Suitable non-biodegradable biocompatible polymers include,
by way of example, cellulose acetates.sup.2,6-7 (including
cellulose diacetate.sup.5), ethylene vinyl alcohol
copolymers.sup.4,8, hydrogels (e.g., acrylics), polyacrylonitrile,
polyvinylacetate, cellulose acetate butyrate, nitrocellulose,
copolymers of urethane/carbonate, copolymers of styrene/maleic
acid, and mixtures thereof.
[0093] Preferably, the biocompatible polymer employed does not
cause an adverse inflammatory reaction when employed in vivo. The
particular biocompatible polymer employed is selected relative to
the viscosity of the resulting polymer solution, the solubility of
the biocompatible polymer in the biocompatible solvent, and the
like. For example, the selected biocompatible polymer should be
soluble in the amounts employed in the selected biocompatible
solvent and the resulting composition should have a viscosity
suitable for in vivo delivery by. e.g., injection. Such factors are
well within the skill of the art.
[0094] Preferred biocompatible polymers include cellulose diacetate
and ethylene vinyl alcohol copolymer. Cellulose diacetate polymers
are either commercially available or can be prepared by art
recognized procedures. In a preferred embodiment, the number
average molecular weight, as determined by gel permeation
chromatography, of the cellulose diacetate composition is from
about 25,000 to about 100,000 more preferably from about 50,000 to
about 75,000 and still more preferably from about 58,000 to 64,000.
The weight average molecular weight of the cellulose diacetate
composition, as determined by gel permeation chromatography, is
preferably from about 50,000 to 200,000 and more preferably from
about 100,000 to about 180,000. As is apparent to one skilled in
the art, with all other factors being equal, cellulose diacetate
polymers having a lower molecular weight will impart a lower
viscosity to the composition as compared to higher molecular weight
polymers. Accordingly, adjustment of the viscosity of the
composition can be readily achieved by merely adjusting the
molecular weight of the polymer composition.
[0095] Ethylene vinyl alcohol copolymers comprise residues of both
ethylene and vinyl alcohol monomers. Small amounts (e.g., less than
5 mole percent) of additional monomers can be included in the
polymer structure or grafted thereon provided such additional
monomers do not alter the properties of the composition. Such
additional monomers include, by way of example only, maleic
anhydride, styrene, propylene, acrylic acid, vinyl acetate and the
like.
[0096] Ethylene vinyl alcohol copolymers are either commercially
available or can be prepared by art recognized procedures.
Preferably, the ethylene vinyl alcohol copolymer composition is
selected such that a solution of 5 weight percent of the ethylene
vinyl alcohol copolymer, 20 weight percent of a tantalum contrast
agent in DMSO has a viscosity equal to or less than 60 centipoise
at 20.degree. C. As is apparent to one skilled in the art, with all
other facts being equal, copolymers having a lower molecular weight
will impart a lower viscosity to the composition as compared to
higher molecular weight copolymers. Accordingly, adjustment of the
viscosity of the composition as necessary for catheter delivery can
be readily achieved by merely adjusting the molecular weight of the
copolymer composition.
[0097] As is also apparent, the ratio of ethylene to vinyl alcohol
in the copolymer affects the overall hydrophobicity/hydrophilicity
of the composition which, in turn, affects the relative water
solubility/insolubility of the composition as well as the rate of
precipitation of the copolymer in an aqueous environment (e.g.,
blood or tissue). In a particularly preferred embodiment, the
copolymers employed herein comprise a mole percent of ethylene of
from about 25 to about 60 and a mole percent of vinyl alcohol of
from about 40 to about 75. These compositions provide for requisite
precipitation rates suitable for use in the methods described
therein.
[0098] The term "contrast agent" refers to a biocompatible
radiopaque material capable of being monitored during injection
into a mammalian subject by, for example, radiography. The contrast
agent can be either water soluble or water insoluble.
[0099] Examples of water soluble contrast agents include
metrizamide, iopamidol, iothalamate sodium, iodomide sodium, and
meglumine. Examples of water insoluble contrast agents include
tantalum, tantalum oxide, and barium sulfate, each of which is
commercially available in the proper form for in vivo use including
a preferred particle size of about 10 .mu.m or less. Other water
insoluble contrast agents include gold, tungsten, and platinum
powders.
[0100] Preferably, the contrast agent is water insoluble (i.e., has
a water solubility of less than 0.01 mg/ml at 20.degree. C.).
[0101] The term "biocompatible solvent" refers to an organic
material liquid at least at body temperature of the mammal in which
the biocompatible polymer is soluble and, in the amounts used, is
substantially non-toxic. Suitable biocompatible solvents include,
by way of example, ethyl lactate, dimethylsulfoxide,
analogues/homologues of dimethylsulfoxide, ethanol, acetone, and
the like. Aqueous mixtures with the biocompatible solvent can also
be employed provided that the amount of water employed is
sufficiently small that the dissolved polymer precipitates upon
contact with the blood. Preferably, the biocompatible solvent is
dimethylsulfoxide.
[0102] The term "encapsulation" as used relative to the contrast
agent being encapsulated in the polymer precipitate is not meant to
infer any physical entrapment of the contrast agent within the
precipitate much as a capsule encapsulates a medicament. Rather,
this term is used to mean that an integral coherent precipitate
forms which does not separate into individual components.
[0103] Compositions
[0104] The polymer compositions employed in this invention are
prepared by conventional methods whereby each of the components is
added and the resulting composition mixed together until the
overall composition is substantially homogeneous.
[0105] For example, these compositions can be prepared by adding
sufficient amounts of the biocompatible polymer to the
biocompatible solvent to achieve the effective concentration for
the polymer composition. Preferably, the polymer composition will
comprise from about 2 to about 50 weight percent of the
biocompatible polymer composition based on the total weight of the
polymer composition and more preferably from about 12 to about 50
weight percent. If necessary, gentle heating and stirring can be
used to effect dissolution of the biocompatible polymer into the
biocompatible solvent, e.g., 12 hours at 50.degree. C. for EVOH in
DMSO.
[0106] Sufficient amounts of the contrast agent are then added to
the biocompatible solvent to achieve the effective concentration
for the complete composition. Preferably, the composition will
comprise from about 10 to about 40 weight percent of the contrast
agent and more preferably from about 20 to about 40 weight percent
and even more preferably about 30 weight percent. Insofar as water
insoluble contrast agents are not soluble in the biocompatible
solvent, stirring is employed to effect homogeneity of the
resulting suspension for compositions employing such constrast
agents.
[0107] In order to enhance formation of the suspension, the
particle size of water insoluble contrast agents is preferably
maintained at about 10 .mu.m or less and more preferably at from
about 1 to about 5 .mu.m (e.g., an average size of about 2 .mu.m).
In one preferred embodiment, the appropriate particle size of the
contrast agent is prepared, for example, by fractionation. In such
an embodiment, a water insoluble contrast agent such as tantalum
having an average particle size of less than about 20 microns is
added to an organic liquid such as ethanol (absolute) preferably in
a clean environment. Agitation of the resulting suspension followed
by settling for approximately 40 seconds permits the larger
particles to settle faster. Removal of the upper portion of the
organic liquid followed by separation of the liquid from the
particles results in a reduction of the particle size which is
confirmed under an optical microscope. The process is optionally
repeated until a desired average particle size is reached.
[0108] The particular order of addition of components to the
biocompatible solvent is not critical and stirring of the resulting
solution or suspension is conducted as necessary to achieve
homogeneity of the composition. Preferably, mixing/stirring of the
composition is conducted under an anhydrous atmosphere at ambient
pressure. The resulting composition is heat sterilized and then
stored preferably in sealed bottles or vials until needed.
[0109] Each of the polymers recited herein is commercially
available but can also be prepared by methods well known in the
art. For example, polymers are typically prepared by conventional
techniques such as radical, thermal, UV, .gamma. irradiation, or
electron beam induced polymerization employing, as necessary, a
polymerization catalyst or polymerization initiator to provide for
the polymer composition. The specific manner of polymerization is
not critical and the polymerization techniques employed do not form
a part of this invention.
[0110] In order to maintain solubility in the biocompatible
solvent, the polymers described herein are preferably not
cross-linked.
[0111] The embolic compositions used in the methods of this
invention preferably are high viscosity compositions having a
viscosity of at least 150 cSt at 40.degree. C., more preferably, at
least 200 cSt at 40.degree. C. and even more preferably, at least
500 cSt at 40.degree. C.
[0112] In specific preferred embodiments, the embolic compositions
used in the methods of this invention have a viscosity which ranges
from about 200 to 40,000 cSt at 40.degree. C., more preferably from
about 500 to 40,000 cSt at 40.degree. C. In another embodiment, the
viscosity ranges from about 500 to 5000 cSt at 40.degree. C.
Examples of such high viscosity compositions are set forth in U.S.
Patent Application Serial No. ______, concurrently filed herewith
as Attorney Docket No. 018413-257, entitled "Novel High Viscosity
Embolizing Compositions" which application is incorporated herein
by reference in its entirety.
[0113] One preferred embolizing composition for use in the methods
of this invention comprises, for example, a biocompatible polymer
at a concentration of from about 12 to about 50 weight percent; a
biocompatible contrast agent at a concentration of from about 10 to
about 40 weight percent; and a biocompatible solvent from about 10
to 78 weight percent wherein the weight percent of the
biocompatible polymer, contrast agent and biocompatible solvent is
based on the total weight of the complete composition and further
wherein the composition has a viscosity of at least about 150 cSt
at 40.degree. C. and preferably at least 200 cSt at 40.degree.
C.
[0114] Another preferred embolizing composition for use in the
methods of this invention comprises a biocompatible polymer at a
concentration of from about 2 to 50 weight percent; a biocompatible
contrast agent at a concentration of from about 10 to about 40
weight percent; and a biocompatible solvent from about 10 to 88
weight percent wherein the weight percent of the biocompatible
polymer, contrast agent and biocompatible solvent is based on the
total weight of the complete composition and further wherein the
composition has a viscosity of at least about 150 cSt at.
40.degree. C. and preferably at least 200 cSt at 40.degree. C.
[0115] Preferably in this particular composition, the concentration
of the polymer ranges from 6 to 50 weight percent and more
preferably 8 to 30 weight percent.
[0116] Methods
[0117] The compositions described above can then be employed in
methods for the catheter assisted embolization of mammalian blood
vessels. In such methods, a sufficient amount of this composition
is introduced into the selected blood vessel via a catheter
delivery means under fluoroscopy so that upon precipitation of the
polymer, the blood vessel is embolized. The particular amount of
embolizing composition employed is dictated by the total volume of
the vasculature to be embolized, the concentration of polymer in
the composition, the rate of precipitation (solids formation) of
the polymer, etc. Such factors are well within the skill of the
art.
[0118] One particularly preferred method for catheter delivery of
the embolizing compositions of this invention to the selected
vascular site is via a small diameter medical catheter. The
particular catheter employed is not critical provided that
polymeric catheter components are compatible with the embolizing
composition (i.e., the catheter components will not readily degrade
in the embolizing composition). In this regard, it is preferred to
use polyethylene in the catheter components because of its
inertness in the presence of the embolizing composition described
herein. Other materials compatible with the embolizing compositions
can be readily determined by the skilled artisan and include, for
example, other polyolefins, fluoropolymers (e.g., Teflon.TM.),
silicone, etc.
[0119] In a preferred embodiment, the microcatheter is employed in
combination with a threaded syringe which has a threaded plunger
which is operable as a conventional syringe for aspiration of the
embolic composition and then is used in a threaded manner for
delivery of the embolic composition. The threaded syringe may also
include a tactile or audible indication of delivery which allows
clinician to monitor delivery of the embolic composition without
looking at the syringe. The catheter for delivery of the embolic
compositions preferably has a burst strength of 100 psi or greater,
and more preferably 200 psi or greater, and still more preferably
1000 psi or greater. In order to prevent catheter burst, the
threaded syringe may be provided with a force release mechanism
which prevents the clinician from applying pressures above the
catheter burst strength. As an alternative delivery means to the
threaded syringe, a syringe pump may be used.
[0120] When a water insoluble contrast agent is employed, the
composition delivered in vivo should have this agent uniformly
suspended therein. Preferably, such a uniform suspension is
achieved by heating/mixing the composition at a temperature of
above 40.degree. C. which ensures formation of a uniform suspension
and then this heated/mixed composition is transferred while
maintaining its temperature above room temperature and preferably
above 40.degree. C. into the catheter for in vivo delivery.
[0121] Specifically, a uniform suspension is achieved by mixing the
compositions at a temperature above about 40.degree. C., preferably
from above about 40.degree. C. to about 90.degree. C., and more
preferably from about 50.degree. C. to about 70.degree. C. The
particular temperature employed should be sufficiently high to
ensure adequate mixing of the composition.
[0122] In a particularly preferred embodiment, the composition is
heated for a period of time from at least about 3 to about 20
minutes and preferably from about 5-10 minutes to facilitate
formation of a uniform suspension. In some cases, the formation of
a uniform suspension requires that the heated composition be placed
in a suitable mixer, e.g., vortex mixer, and is mixed until the
suspension is homogeneous. In this case, after formation of the
homogenous suspension via the mixer, the composition is preferably
reheated to a temperature of from above about 40.degree. C. to
about 90.degree. C. and preferably from about 50.degree. C. to
about 70.degree. C. The specific temperature employed for heating
is selected relative to the biocompatible solvent and biocompatible
polymer employed. Such selections are well within the skill of the
art.
[0123] In either case, the heated composition is then transferred
preferably via a syringe and delivered into the catheter under
conditions wherein the temperature of the composition is above room
temperature and preferably above about 40.degree. C. In one
preferred embodiment, the conditions which effect such transfer are
rapid transfer (e.g., transfer occurs within 2 minutes of heating
cessation) of the composition to the catheter.
[0124] Surprisingly, the heated composition maintains both a
uniform suspension and ease of delivery during catheter injection
into a vascular site in a mammal and, when ejected at the distal
end of the catheter, there is no evidence of trauma to this site.
See, for example, U.S. patent application Ser. No. ______ filed
concurrently herewith as Attorney Docket No.018413-195 and entitled
"Methods for Delivering In Vivo Uniform Dispersed Embolic
Compositions of High Viscosity" which application is incorporated
herein by reference in its entirety.
[0125] The preferred delivery techniques will be described in
treating aneurysm but it is understood that the techniques are
applicable treating vascular sites in general. As shown in FIG. 10,
vascular vessel 3 has an opening 5 that is connected to a vascular
sac that forms the aneurysm. The top of the sac is typically
referred as the fundus 4 and the base of the sac at the opening is
the neck.
[0126] Standard procedures can be employed to position the distal
(i.e., tip) of delivery catheter 1 into the sac. One method of
securing the delivery catheter 1 in place is during the
embolization procedure is to employ a occluding or flow arresting
devices such as inflatable balloon 2.
[0127] The proximal end of the delivery catheter is connected to
one or more syringes. Multiple syringes each containing different
embolizing compositions can be employed to load the compositions
into the channel of the delivery catheter. For example, in the
"stack" method two compositions comprising different polymer
concentrations are used. The first formulation to be injected into
the vascular site preferably has a higher polymer concentration
than that of the second although, it is contemplated that the
concentration of the first polymer can be less than the
concentration of the second polymer. Given the length of the
delivery catheter, a preferred method of injecting both the first
and second compositions is load the compositions in the catheter in
tandem or series thereby forming a "stack" in the channel of the
catheter. Thereafter, force is applied to inject the
compositions.
[0128] Preferably an interface needle, which is described herein,
is employed to connect the luer of the catheter to the syringe.
This interface needle creates a blunt flow pattern so that the
embolizing composition entering into the catheter channel from the
syringe remain uniform, that is, the compositions do not mix but
remain as discrete volumes.
[0129] A. Pulse Injection
[0130] This technique is suited for delivering "stack" compositions
wherein two or more different formulations are injected. In
particular, it can be employed to deliver a high viscosity
embolizing formulation at the distal tip of a delivery system and
the formation of an initial nidus within the aneurysm during a
balloon assisted embolization technique.
[0131] In one embodiment, a small quantity of a high viscosity
solution of the composition (e.g., 0.025 cc of an embolic
composition comprising 30% polymer) is injected into the delivery
system followed by a lower viscosity material (e.g., a similar
composition comprising only 12% to 14% of the same polymer). A hard
pulse (1-3 lbs.) methodology is used to provide a sufficient
pressure head to advance the high viscosity material to the tip of
the delivery system followed by the lower viscosity material. Once
the high viscosity material has reached the tip of the delivery
system as visualized by fluoroscopy, a soft pulse action (0.1-0.5
lbs.) is used to produce an initial nidus of the composition.
[0132] This procedure allows for reproducible precipitate formation
at the vascular site thereby reducing the likelihood of precipitate
formation at unintended sites.
[0133] B. Controlled Embolization of an Aneurysm
[0134] This technique comprises a procedure for injecting an
embolic composition into a vascular site in a controlled manner.
The method allows for nidus formation and delivery of a controlled
amount the composition to specific location to complete the
embolization. This technique is particularly suited for use of an
interface needle and a threaded syringe both of which are described
herein.
[0135] The method as described in the following protocol for
treating a representative aneurysm having a vascular volume of
about 1 cc. As is apparent, the volume of materials used herein can
be adjusted accordingly, for instance, to different size aneurysms.
Further, the time periods involved will range depending on the site
of the aneurysm, e.g, brain, and the patient's condition.
Aneurysm Procedure
[0136] 1. Place balloon catheter at the vascular site.
[0137] 2. Place distal tip of the delivery catheter tip just below
top 1/3 of fundus.
[0138] 3. Inflate the balloon until the inflated balloon
substantially seals or bridges the opening of the aneurysm.
[0139] 4. Record inflation volume.
[0140] 5. Flush delivery catheter with about saline, e.g., 5
cc.
[0141] 6. Fill dead space of delivery catheter with DMSO, e.g.,
0.25 cc.
[0142] 7. Inject a desired amount of embolizing composition, e.g,
0.20 cc into the delivery catheter channel while balloon is
deflated. This may take about 40 seconds.
[0143] 8. Stop injection and wait until the DMSO has been
sufficiently flushed from the site, e.g., 1 minute.
[0144] 9. Inflate balloon preferably to the volume determined in
procedure 3.
[0145] 10. Slowly inject the embolizing composition until a nidus
is formed in the sac of the aneurysm as visualized by
fluoroscopy.
[0146] 11. Injection of the composition should take place within a
safe period of time (e.g., for no more than 2 minutes or 0.2 cc).
This time period will depend on the location of the aneurysm (e.g.,
brain) and other factors.
[0147] 12. The balloon also should not be inflated for extensive
periods of time for similar reasons. For instance, the inflation
period should be no longer than 5 minutes.
[0148] 13. Completely deflate balloon and wait for sufficient
amount of time to allow for perfusion, e.g., blood flow. This may
be for example 1-2 minutes.
[0149] 14. A contrasting agent can be used during the procedure as
needed to determine percent of aneurysm or vascular fill.
[0150] 15. Repeat procedures 12-16 until embolization is
complete.
[0151] 16. Following treatment, the delivery catheter is
detached:
[0152] 17.1 Leave balloon deflated for a sufficient amount of time,
e.g, 10 minutes, to permit solidification of the embolizing
compositon.
[0153] 17.2 Aspirate the syringe (e.g., 0.20 cc).
[0154] 17.3 Remove slack from the delivery catheter. Detach with
quick pull (with balloon inflated). Catheter will detach.
[0155] C. Embolization "Stack" Method
[0156] This technique enables the repeatable formation of a nidus
of embolizing composition within an aneurysm followed by uniform
embolization to create a dense packing.
[0157] In one embodiment, this method permits the selective
delivery of various formulations of embolizing composition into an
aneurysm within one procedure and same delivery system. By this
method, it is possible to fill the aneurysm with embolizing
composition while minimizing the presence of crevices and/or voids
within the cast.
[0158] The "stack" method first injects a more viscous solution of
embolizing composition as the primary injection formulation which
allows for quicker solidification and thus a nidus formation. Once
the nidus has formed the reminder of the aneurysm can be filed with
a lower viscosity material. The second and any subsequent injection
are of a higher volume. The primary indication of use is in
conjunction with a balloon assisted embolization technique.
[0159] In a preferred embodiment, a 0.025 cc injection of an
embolizing composition of either a 30% or 40% EVOH was followed by
an injection of a 12% composition appears to obtain good
results.
[0160] In another embodiment, a pulse injection of 30% embolizing
composition followed by 14% composition appears to facilitate the
formation of a nidus within the aneurysm.
[0161] D. Solitary Embolization Injection
[0162] This technique applies a quick, safe, and uniform force to
delivery an embolization composition. An important result is the
improvement in the morphology of the embolization (i.e., the cross
sectional structure and capacity to fill small crevasses.)
[0163] With this procedure, the distal tip of a delivery system is
placed within and aneurysm and the neck (i.e., opening) of the
aneurysm is sealed using an inflation balloon. Thereafter a single
bulk (mass) injection of embolizing composition, preferably equal
in volume to the internal space of the aneurysm, is injected into
the aneurysm. The balloon remains inflated for a time sufficient to
cause partial and/or complete solidification of the embolizing
composition such that no protrusion and/or migration results. Next
the delivery system is detached from the mass and the embolization
procedure is complete.
[0164] E. Balloon Inflation/Deflation During Embolization
[0165] This technique enables the containment of an embolic
material within an aneurysm during solidification or set-up and
facilitates the extraction of any solvent and/or the interaction
between the embolic agent located at the neck (i.e., opening) of
the aneurysm and blood. A flow arresting device such as a balloon
is employed to facilitate the extraction of a solvent and/or the
interaction between the embolic agent and blood. In addition, the
interaction between the balloon and the delivery system is
important. Namely, the delivery system may have a tendency to
become closed due to over inflation of the balloon. This
methodology sets limits on the inflation of the balloon to guard
against closure of the delivery system while still completely
sealing the neck of the aneurysm.
[0166] Without being limited to any theory, it is believed that
this technique seals the neck of the aneurysm while an embolic
composition is delivered and facilitates the solidification of the
agent by the creation of a high speed laminar type flow around the
balloon to extract any solvent and/or induce contact with
blood.
[0167] Testing revealed that a balloon diameter about 15% greater
than arterial diameter (e.g., per compliant balloon) results in the
substantially complete seal of the neck of the aneurysm while still
being able to maneuver a guidewire and inject an embolic agent
through the delivery system. It is expected that the diameter of
the inflated balloon can typically range from about 100 to 130% of
the inner diameter of the vessel. Secondly, testing revealed that a
balloon diameter 85% of the parent artery inner diameter
significantly increases the extraction of solvent injected into the
aneurysm by washing the solvent downstream. It is expected that the
diameter of the deflated balloon can typically range from about 10
to 90%. Hence the methodology results in an adequate seal of the
neck of the aneurysm embolization and a method by which to
facilitate the solidification of the embolic material at the neck
of the aneurysm (the material most prone to protrusion and/or
migration out of the aneurysm.)
[0168] Interface Needle
[0169] The interface needle addresses a problem of mixing between
two liquids delivered through a catheter. The interface needle is
particularly useful for creating a blunt interface between a
biocompatible solvent and a liquid embolic composition which are
delivered to the body for treating aneurysms, arterial venus
malformations, head and neck tumors, tumors and peripheral
applications.
[0170] Although the device is particularly suitable for creating a
blunt liquid interface between the biocompatible solvent
(dimethylsulfoxide (DMSO)) and a biocompatible polymer composition,
it should be understood that the systems and methods of the present
invention may be used for creating a blunt liquid interface between
any two liquids delivered sequentially through a delivery
system.
[0171] The blunt liquid interface between the DMSO and a liquid
embolic composition improves the delivery of the liquid embolic
composition by allowing the formation of a small kernel or ball of
polymer material during the initial injection, and preventing the
formation of strands of polymer material which can be carried away
in the bloodstream.
[0172] As shown in FIG. 1, the system for liquid delivery with a
blunt liquid interface includes a catheter 10, an interface needle
12, and a syringe 14. The interface needle 12 includes a proximal
end with a female luer fitting 18 for connection to a male luer
fitting 20 of the syringe 14. A distal end of the interface needle
12 includes a male luer fitting 22 for connection to a female luer
fitting 24 of a catheter hub 28.
[0173] As shown most clearly in the cross-sectional view of FIG. 2,
the interface needle 12 includes a lumen 30 with a tapered portion
32. The tapered portion 32 tapers from a largest proximal dimension
to a smallest distal dimension. The taper is provided at an angle A
which is between about 10 and about 60 degrees, preferably between
about 20 and about 40 degrees, and most preferably approximately 30
degrees. A hypo tube 36 is fitted within the lumen 30 and extends
from the distal end of the male luer fitting 22. The hypo tube 36
may be overmolded, press fit, crimped in place, or otherwise
secured inside the lumen 30 of the interface needle 12. The body of
the interface needle 12 is preferably formed of a polymer material
which is compatible with DMSO such as polypropylene, polyethylene,
polyester, and the like. The hypo tube 36 extends from the distal
end of the male luer fitting 22 a distance sufficient to allow the
hypo tube to bypass a reservoir 36 in the catheter hub 28 and
delivers the liquid directly into the catheter lumen. The length of
the hypo tube 36 may vary depending on the type of catheter hub 28
used. For example, the hypo tube 36 may have a total length of
about 0.2 to about 0.5 inches and a length extending from the
distal end of the male luer 22 of about 0.05 to about 0.3 inches.
The hypo tube 36 is dimensioned to fit within the lumen of the
catheter 10 forming a seal between the interface needle and the
catheter lumen and bypassing any liquid in the reservoir 36 of the
catheter hub 28.
[0174] One procedure for delivering two liquids and achieving a
blunt liquid interface is as follows. Initially, a first liquid is
delivered directly to the catheter 10 with a syringe. The second
liquid is then provided in a second syringe and the interface
needle 12 is connected to the second syringe. Air is expelled from
the interface needle 12 and liquid is preferably cleared from the
distal tip of the hypo tube 36. The male luer fitting 22 of the
interface needle 12 is then connected to the catheter hub 28 such
that a blunt liquid interface is formed between a first liquid in
the catheter and a second liquid in the hypo tube 36.
[0175] When the present invention is used to deliver a liquid
embolic composition with a blunt or even interface between a
biocompatible solvent and a liquid embolic composition, the
procedure employed is as follows. The syringe 14 is filled with the
quid embolic composition and the interface needle 12 is attached to
the syringe. Air is expelled from the interface needle 12 by
injection of liquid embolic composition and the exterior of the
interface needle is preferably cleaned. The interface needle is
then attached to the catheter hub 28 of a catheter which has been
previously flushed with DMSO or other biocompatible solvent. The
liquid embolic composition is injected slowly to create a blunt
liquid interface between the DMSO and liquid embolic composition
and prevent dilution of the two fluids. The blunt liquid interface
created by the interface needle travels down the length of the
catheter to a delivery site with minimal mixing between the two
liquids.
[0176] Other suitable interface needles are disclosed in U.S.
patent application Ser. No. ______ filed concurrently herewith as
Attorney Docket No. 018413-265 which application is entitled
"Interface Needle and Method for Creating a Blunt Interface between
Delivered Liquids.
[0177] This application is incorporated herein by reference in its
entirety.
[0178] Threaded Syringe
[0179] A preferred syringe that provides a mechanism by which a
clinician can deliver a viscous fluid through relatively small
lumens and can obtain tactile or audible feedback of delivery is
preferred. The syringe can be used either as a conventional syringe
or as a threaded syringe. The threaded syringe allows for delivery
of more viscous fluids with less force and/or allows for more
controlled delivery.
[0180] FIG. 4 shows a syringe assembly 10 according to the present
invention which includes a syringe barrel 12, a sliding member 14,
and a threaded plunger 16. The syringe barrel 12, as shown most
clearly in FIG. 5, includes a distal delivery orifice 18 having a
male luer fitting 20 to facilitate connection to a catheter hub. A
proximal end of the syringe barrel 12 is provided with a flange 22.
An end view of the of the flange 22 is illustrated in FIG. 6A.
[0181] The sliding member 14 is shown in further detail in FIGS. 7
and 8. The sliding member 14 includes a threaded through bore 28
and a second unthreaded bore 30 having a diameter slightly larger
than that of the threaded bore 28. The sliding member 14 also
includes side rails 34 and an end stop or tab 36. The sliding
member 14 is received on the flange 22 of the syringe barrel 12
such that the flange is received between the side rails 34 of the
sliding member and the sliding member can slide back and forth
along the flange. The ability of the sliding member 14 to slide
with respect to the barrel 12 allows either the threaded bore 28 or
the unthreaded bore 30 to be axially aligned with the syringe
barrel 12. Accordingly, the syringe can be used as a conventional
syringe when the unthreaded bore 30 is aligned with the syringe
barrel and can be used as a threaded syringe for a more precisely
controlled fluid delivery when the threaded bore 28 is aligned with
the syringe barrel 12.
[0182] The sliding member 14 also includes a spring element 40
shown in FIG. 9 which is threaded into a side bore 42 in the
sliding member. The side bore 42 is positioned at an angle A from a
line which is transfers to the direction of sliding. The angle A is
between about 10 and about 60 degrees, preferably between about 20
and about 40 degrees, and most preferably about 30 degrees. The
spring element 40 includes a threaded casing which contains a
spring and a movable ball element 44.
[0183] The threaded plunger 16 as shown in FIG. 5, includes a
plunger handle 48 connected to a shaft 50. The shaft 50 includes a
threaded portion 52 and an unthreaded portion 54. A distal end of
the plunger 16 includes a resilient fluid tight member 56. The
threaded portion 52 of the plunger is provided with a longitudinal
groove 60 which cuts through the plunger threads as shown in FIG.
6. The longitudinal groove 60 is preferably a V-shaped groove which
encompasses an angle B of about 30 to about 60 degrees, preferably
approximately 90 degrees. The ball element 44 of the spring element
40 is configured to be received in the groove 60 of the threaded
plunger 44. The inter-engagement of the spring element 40 and the
longitudinal groove 60 provide a tactile and/or audible indication
to the clinician. With the longitudinal groove 60 as shown in the
drawings, the clinician will feel and/or hear a click of the
syringe plunger 16 for each rotation of the plunger 16. Other
arrangements of the groove 60 may be provided to provide a tactile
or audible indication at frequencies other than one click per
rotation. For example, every other thread may be provided with a
transverse notch to provide tactile indications for every two
rotations.
[0184] The syringe assembly 10 according to the present invention
provides a mechanism by which the syringe can be filled with fluid
in the normal fashion with the plunger shaft 50 positioned in the
unthreaded bore 30 of the sliding member 14. After filling, the
sliding member 14 can be slid to a second position at which the
plunger shaft 50 is positioned in the threaded bore 28 and the
threaded plunger is used for slow, controlled injection of fluid by
rotation of the plunger. In order to slide the sliding member 14
from the first position to the second position, the plunger 16
should be positioned with the unthreaded portion 54 of the plunger
shaft 50 located at the intersection of the bores 28, 30 in the
sliding member 14. The groove 60 and spring element 40 provide a
tactile and/or audible indication or click upon each revolution of
the threaded plunger 16. This allows the clinician to determine the
amount of fluid injected without looking at the syringe graduation
lines.
[0185] U.S. Provisional Patent Application Serial Nos. 60/135,289
and 60/135,287, entitled "THREADED SYRINGE" and entitled "SCREW
SYRINGE WITH FORCE RELEASE MECHANISM" provide a further description
of these devices. Both of these applications are incorporated
herein by reference in their entirety.
[0186] The methods, devices, and compositions described herein are
useful in embolizing mammalian blood vessels which, in turn, can be
used to prevent/control bleeding (e.g., organ bleeding,
gastrointestinal bleeding, vascular bleeding, bleeding associated
with an aneurysm) or to ablate diseased tissue (e.g., tumors,
etc.). Accordingly, the invention finds use in human and other
mammalian subjects requiring embolization of blood vessels.
[0187] It is contemplated that the compositions can be employed as
a carrier for a compatible pharmaceutically active compound wherein
this compound is delivered in vivo for subsequent release. Such
compounds include by way of example only antibiotics,
anti-inflammatory agents, chemotherapeutic agents, and the
like.
[0188] The following example is set forth to illustrate the claimed
invention and are not to be construed as a limitation thereof.
EXAMPLE
[0189] The following example illustrates one method for delivery of
an embolic composition as per this invention. In this example, the
following composition is employed:
[0190] approximately 17.5 weight % EVOH
[0191] 30 weight % micronized tantalum
[0192] approximately 52.5 weight % DMSO
[0193] Viscosity=approximately 1100 cSt at 40.degree. C.
[0194] The composition is prepared by dissolution of the polymer at
50.degree. C. in DMSO with stirring. Afterwards, micronized
tantalum (average size 3 .mu.m) is then added. The resulting
composition is heated for about 5 minutes at 70.degree. C. then
shaken in a vortex mixer for approximately 20 minutes at room
temperature to obtain a uniform suspension of the insoluble
tantalum in the composition.
[0195] 1.5 mL of the composition described above is employed in a
sterile vial in conjunction with a 1 mL delivery syringe, one
threaded syringe device with an interface device, a Rebar
microcatheter available from Micro Therapeutics Inc., Irvine Calif.
(105-5080), and an Equinox Balloon catheter available Micro
Therapeutics Inc., Irvine Calif. The composition must be used with
appropriately designed DMSO compatible microcatheters and balloon
catheters.
[0196] The composition is injected into an aneurysm as follows:
[0197] 1. The vial comprising the embolic composition is heated dry
at 70.degree. C. for 5 minutes then shaken for 20 minutes on a
suitable mixer. The mixing is continued with intermittent heating
per step 6 until ready to be injected into the catheter.
[0198] 2. Confirm microcatheter placement in upper third (1/3) of
aneurysm sac with injection of contrast agent.
[0199] 3. Confirm balloon placement, inflation volume and neck
coverage by inflating balloon. Record volume of balloon inflation
for use during this embolization. Balloon inflation should be
carefully conducted since over inflation of balloon catheter may
cause occlusion of delivery catheter leading to over
pressurization.
[0200] 4. With the balloon deflated, flush contrast from
microcatheter with 5 ml of saline. Leave the syringe connected.
[0201] 5. Fill microcatheter deadspace: aspirate approximately 0.8
mL of sterile DMSO into a 1 mL syringe. Inject the DMSO into the
delivery microcatheter in sufficient volume to just fill the
catheter deadspace at a rate not greater than 0.3 mL/min and
preferably not greater than 0.1 mL/min.
[0202] 6. Ensure that the embolic composition is mixed per step 1.
Fill a 1 mL threaded syringe with the mixed embolic composition
through a 16 or 18 gauge needle. Activate the syringe device to
deliver 0.2 mL of the embolic composition to the catheter. Connect
an interface device to the syringe. Turn syringe knob to inject
embolic composition through the interface device and to remove air.
As soon as the DMSO is injected into the catheter deadspace, remove
the DMSO syringe and overfill and wash the luer hub with the
balance of the DMSO. NOTE: The threaded syringe generates a tactile
click for each full revolution. Each full revolution is equal to
0.02 ml.
[0203] 7. Immediately connect the embolic composition threaded
syringe/interface device to the microcatheter hub, making sure
there is no air in the hub during the connection. Failure to
continuously mix embolic composition for the required time may
result in inadequate fluoroscopic visualization during
delivery.
[0204] 8. Inject 0.2 ml maximum of the embolic composition into the
microcatheter at a steady rate not to exceed 0.1 ml/min. (Balloon
deflated). Rapid injection of DMSO into the vasculature may lead to
vasospasm and/or undesired angionecrosis.
[0205] 9. Wait one minute for DMSO to disperse from aneurysm
sac.
[0206] 10. Inflate balloon to same volume as determined in step
3.
[0207] 11. Inject embolic composition through the microcatheter at
a rate of 0.1 ml/min. Continue until up to 0.2 ml maximum has been
injected, but for no longer than two minutes. If the embolic
composition does not appear after 2 full revolutions of the syringe
handle, stop injection and replace catheter. Excessive pressure may
result in catheter rupture. Maximum quantity and time of injection
of the embolic composition should be reduced to be proportional to
amount of fill desired in each injection. Aneurysm size should be
considered for each injection.
[0208] 12. Allow the balloon to stay inflated for a total of five
minutes. (To allow for solidification of the embolic composition).
Then completely deflate balloon to reestablish perfusion.
[0209] 13. Repeat steps 10-12 until fill is completed.
[0210] 14. Upon completion of injection allow ten (10) minutes for
solidification (Balloon deflated). Aspirate syringe at least 0.25
ml during ten minute solidification period. Aspirating will allow
for pressure in column to dissipate and prevent inadvertent
injection of the embolic composition during separation.
[0211] 15. Remove slack from catheter and quickly pull the catheter
to separate the catheter from the precipitated mass.
[0212] 16. Remove balloon system.
[0213] From the foregoing description, various modifications and
changes in the above described methods will occur to those skilled
in the art. All such modifications coming within the scope of the
appended claims are intended to be included therein.
* * * * *