U.S. patent application number 10/262639 was filed with the patent office on 2003-08-28 for multi layer radiation delivery balloon.
Invention is credited to Tam, Lisa A., Trauthen, Brett A..
Application Number | 20030163017 10/262639 |
Document ID | / |
Family ID | 27761621 |
Filed Date | 2003-08-28 |
United States Patent
Application |
20030163017 |
Kind Code |
A1 |
Tam, Lisa A. ; et
al. |
August 28, 2003 |
Multi layer radiation delivery balloon
Abstract
Disclosed is a sealed radiation source, which may be used to
deliver a radioactive dose to a site in a body lumen. The source
comprises a thin flexible substrate, and a layer of radioisotope
attached thereto. The source may further comprise additional layers
such as one or more tie layers disposed between the substrate and
the radioisotope layer and one or more outer coating layers. In one
embodiment, the source is wrapped around an inflatable balloon.
Inflation of the balloon at a treatment site positions the source
directly adjacent to the vessel wall, and allows irradiation of the
site following or simultaneously with a balloon angioplasty, stent
implantation, or stent sizing procedure.
Inventors: |
Tam, Lisa A.; (Lake Forest,
CA) ; Trauthen, Brett A.; (Newport Beach,
CA) |
Correspondence
Address: |
KNOBBE MARTENS OLSON & BEAR LLP
2040 MAIN STREET
FOURTEENTH FLOOR
IRVINE
CA
92614
US
|
Family ID: |
27761621 |
Appl. No.: |
10/262639 |
Filed: |
October 1, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10262639 |
Oct 1, 2002 |
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09382302 |
Aug 24, 1999 |
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6458069 |
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09382302 |
Aug 24, 1999 |
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09253433 |
Feb 19, 1999 |
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09382302 |
Aug 24, 1999 |
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09256337 |
Feb 19, 1999 |
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6287249 |
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09256337 |
Feb 19, 1999 |
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09025921 |
Feb 19, 1998 |
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10262639 |
Oct 1, 2002 |
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09040172 |
Mar 17, 1998 |
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6149574 |
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Current U.S.
Class: |
600/3 ;
977/949 |
Current CPC
Class: |
G21G 4/06 20130101; A61F
2/82 20130101; A61K 51/1282 20130101; A61N 2005/1005 20130101; G03C
5/02 20130101; Y10S 977/949 20130101; A61K 9/1641 20130101; A61M
2025/1075 20130101; A61K 51/1279 20130101; A61N 2005/1004 20130101;
A61N 5/1002 20130101 |
Class at
Publication: |
600/3 |
International
Class: |
A61N 005/00 |
Claims
What is claimed is:
1. A multilayer radiation delivery source, comprising: a first
bonding layer, having a first side; a second bonding layer, having
a second side which faces toward the first side; and an isotope
layer in between the first side and the second side; wherein the
first side and the second side are secured together through the
isotope layer to produce a multilayer radiation delivery
source.
2. The source of claim 1, wherein said isotope is a gamma emitting
isotope or a beta emitting isotope.
3. The source of claim 1, wherein the isotope is selected from the
group consisting of P-32, I-125, Pd-103, W/Re-188, As-73, Gd-153,
and combinations thereof.
4. The source of claim 1, further comprising a structural layer on
at least one of the first and second bonding layers.
5. The source of claim 1, wherein the source comprises a sheet
having a total thickness of no more than about 0.003 inches.
6. The source of claim 1, wherein the source comprises a tube
having a total wall thickness of no more than about 0.003
inches.
7. The source of claim 1, further comprising a first structural
layer on the first bonding layer and a second structural layer on
the second bonding layer.
8. The source of claim 7, wherein the first and second bonding
layers are fused together to provide a continuous seal from
proximally of to distally of the isotope layer.
9. The source of claim 7, further comprising a coating layer on the
isotope layer.
10. The source of claim 9, wherein the coating layer comprises a
material selected from the group consisting of cyanoacrylates,
acrylics, acrylates, acrylic acid, urethanes, polybutyl vinyl
chloride, polyvinylidene chloride, polyethylene and combinations
thereof.
11. The source of claim 7, wherein at least one of the first and
second structural layers comprises a material selected from the
group consisting of polyamide, polyethylene, polyester,
polyethylene terephthalate, polyvinyl chloride and combinations
thereof.
12. The source of claim 11, wherein the first and second bonding
layers comprise ethylene methyl acrylate.
13. The source of claim 12, wherein the first and second structural
layers comprise polyethylene.
14. The source of claim 12, wherein the first and second bonding
layers are sufficiently adhered together that they can not be
manually delaminated from each other without tearing.
15. The source of claim 12, comprising at least one co-extrusion of
EMA and PE, or EMA and polyurethane.
16. A radiation delivery balloon catheter, comprising: an elongate
flexible tubular body, having a proximal end and a distal end; an
inflatable balloon on the tubular body near the distal end thereof,
said balloon in fluid communication with an inflation lumen
extending axially through the tubular body; a balloon bonding
surface carried by the outer surface of the balloon; a radiation
source on the balloon bonding surface; and an encapsulant
surrounding the radiation source, the encapsulant having at least
an encapsulant bonding surface on its radially inwardly facing
surface for fusing with the balloon bonding surface at least
proximally and distally of the radiation source.
17. A radiation delivery balloon catheter as in claim 16, wherein
the balloon bonding surface comprises ethylene methyl acrylate.
18. A radiation delivery balloon catheter as in claim 17, wherein
the encapsulant bonding surface comprises ethylene methyl
acrylate.
19. A radiation delivery balloon catheter as in claim 16, wherein
the encapsulant comprises an outer polyethylene layer and an inner
ethylene methyl acrylate layer.
20. A radiation delivery balloon catheter as in claim 16, wherein
all bonding surfaces comprise the same material.
21. A radiation delivery balloon catheter as in claim 16, wherein
the radiation source comprises a metal salt or oxide, and at least
one isotope.
22. A radiation delivery balloon catheter as in claim 21 wherein
the source further comprises a tie layer for binding with an
isotope.
23. A radiation delivery balloon catheter as in claim 16, wherein
the source comprises at least one source bonding layer to permit a
continuous bond between the source and at least one of the
encapsulent and the balloon bonding surface from proximally of the
source to distally of the source.
24. A radiation delivery balloon catheter as in claim 16, further
comprising a guide wire lumen extending axially throughout at least
a distal portion of the tubular body.
25. A radiation delivery balloon catheter as in claim 24 further
comprising a proximal guide wire access port on the tubular body,
positioned within about 35 cm of the distal end of the tubular
body.
26. A radiation delivery balloon catheter as in claim 16, further
comprising a perfusion conduit extending through the tubular body
from a proximal side of the inflatable balloon to a distal side of
the inflatable balloon, at least a first perfusion port on the
tubular body on the proximal side of the balloon and at least a
second perfusion port on the distal side of the balloon.
27. A radiation delivery balloon catheter as in claim 26, wherein
the perfusion conduit comprises a distal portion of a guidewire
lumen.
28. A method of treating a site within a vessel, comprising the
steps of: identifying a site in a vessel to be treated; providing a
radiation delivery catheter having an expandable balloon with a
thin film radiation source thereon, said thin film comprising a
substrate layer having an isotope thereon, said isotope
encapsulated by an outer encapsulant layer fused to the substrate
throughout the length of the source; positioning the balloon within
the treatment site; inflating the balloon within the treatment
site; delivering a dose of radiation from the delivery balloon to
the treatment site; and thereafter deflating the balloon and
removing the balloon from the treatment site.
29. The method of claim 28, wherein said catheter has an isotope
loss of no more than 5 nCi throughout the period between the
positioning step and the removing step.
30. A method of treating a site within a vessel as in claim 28,
wherein said source comprises a metal salt or a metal oxide, and at
least one isotope.
31. A method of treating a site within a vessel as in claim 28,
wherein said site comprises a previously implanted prosthesis, and
the positioning the balloon step comprises positioning the balloon
at least partially within the prosthesis.
32. A method of treating a site within a vessel as in claim 31,
wherein the prosthesis comprises a stent.
33. A method of treating a site within a vessel as in claim 31,
wherein the prosthesis comprises a graft.
34. A method of treating a site within a vessel as in claim 28,
wherein the radiation delivery catheter further comprises an
expandable stent on the balloon, and wherein the inflating the
balloon step comprises inflating the balloon within the treatment
site to implant the stent at the treatment site and simultaneously
delivering radiation from the thin film into the vessel wall.
35. A method of treating a site within a vessel as in claim 28,
further comprising the step of perfusing blood from a first side of
the balloon to a second side of the balloon during the delivering a
dose of radiation step.
36. A method of simultaneously performing balloon dilatation of a
stenosis in a body lumen and delivering radiation to the body
lumen, comprising the steps of: identifying a stenosis in a body
lumen; providing a treatment catheter having an elongate flexible
tubular body with an inflatable balloon near the distal end
thereof, a cylindrical thin film radiation delivery layer on the
balloon, an encapsulant layer over the radiation delivery layer, a
continuous seal between the encapsulant, the delivery layer and the
balloon along at least the length of the radiation delivery layer;
transluminally advancing the balloon through the lumen; positioning
the balloon within the stenosis; inflating the balloon to radially
expand the lumen in the area of the stenosis; and simultaneously
delivering radiation from the thin film into the lumen wall.
37. A method of simultaneously performing balloon dilatation of a
stenosis in a body lumen, delivering a stent, and delivering
radiation to the body lumen, comprising the steps of: identifying a
stenosis in a vessel; providing a treatment catheter having an
elongate flexible tubular body with an inflatable balloon carrying
an expandable stent near the distal end thereof, and a cylindrical
thin film radiation delivery layer on the balloon, an encapsulant
layer over the radiation delivery layer, a continuous seal between
the encapsulant, the delivery layer and the balloon along at least
the length of the radiation delivery layer; transluminally
advancing the balloon through the vessel; positioning the balloon
within the stenosis; inflating the balloon to radially expand the
vessel in the area of the stenosis; and simultaneously expand and
deliver the stent; and delivering radiation from the thin film to
the vessel wall.
38. A method of manufacturing a sealed source radiation delivery
balloon catheter, comprising the steps of: extruding a tube for
producing a balloon, having a bonding layer on a radially outwardly
facing surface thereof; positioning an annular radiation delivery
source on the balloon bonding layer; extruding a tubular
encapsulant having a sealing layer on a radially inwardly directed
surface thereof; positioning the encapsulant concentrically around
the radiation source and the balloon to produce a
balloon-source-encapsulant stack; exposing the
balloon-source-encapsulant stack to elevated temperature to bond at
least one of the balloon and the encapsulant to the source thereby
producing a sealed source.
39. The method of claim 38, wherein the encapsulant is coextruded
to have a radially inwardly directed sealing surface and an outer
structural surface.
40. The method of claim 39, wherein the structural surface
comprises polyethylene and the sealing surface comprises ethylene
methyl acrylate.
41. The method of claim 38, wherein the exposing step fuses the
encapsulent to the balloon through the source.
42. The method of claim 38, further comprising the step of
inflating the balloon prior to the exposing step.
43. The method of claim 38, wherein the extruding a tube step
comprises coextruding a tube having at least an inner structural
layer and an outer bonding layer.
44. The method of claim 38, wherein the radiation delivery source
comprises a bonding layer and an isotope layer.
45. The method of claim 44, wherein the isotope layer comprises a
metal salt or oxide, and at least one isotope.
46. The method of claim 45, wherein the isotope layer further
comprises a tie layer.
47. The method of claim 44, wherein the radiation delivery source
further comprises a structural surface on the bonding layer.
48. The method of claim 44, wherein the radiation delivery source
further comprises a coating layer on the isotope layer.
49. A multilayer radiation delivery source, comprising: a first
portion comprising a first support layer having a first bonding
layer thereon; a second portion comprising a second support layer
having a second bonding layer thereon; and a third portion
comprising an isotope; wherein the third portion lies between the
first and second bonding layers and the first and second bonding
layers begin to melt at a different temperature than the first and
second support layers.
50. The multilayer radiation delivery source of claim 49, wherein
the first and second bonding layers begin to melt at a lower
temperature than the first and second support layers.
Description
RELATED APPLICATION DATA
[0001] This application is a continuation in part of Ser. No.
09/253,433, filed Feb. 19, 1999, which is a continuation-in-part of
Ser. No. 09/025,921, filed Feb. 19, 1998.
FIELD OF THE INVENTION
[0002] This invention relates to catheters used to deliver
radiation to prevent or slow restenosis of an artery traumatized
such as by percutaneous transluminal angioplasty (PTA).
BACKGROUND OF THE INVENTION
[0003] PTA treatment of the coronary arteries, percutaneous
transluminal coronary angioplasty (PTCA), also known as balloon
angioplasty, is the predominant treatment for coronary vessel
stenosis. Approximately 300,000 procedures were performed in the
United States in 1990 and nearly one million procedures worldwide
in 1997. The U.S. market constitutes roughly half of the total
market for this procedure. The increasing popularity of the PTCA
procedure is attributable to its relatively high success rate, and
its minimal invasiveness compared with coronary by-pass surgery.
Patients treated by PTCA, however, suffer from a high incidence of
restenosis, with about 35% or more of all patients requiring repeat
PTCA procedures or by-pass surgery, with attendant high cost and
added patient risk.
[0004] Recent attempts to prevent restenosis by use of drugs,
mechanical devices, and other experimental procedures have had
limited long term success. Stents, for example, dramatically reduce
acute reclosure, and slow the clinical effects of smooth muscle
cell proliferation by enlarging the minimum luminal diameter, but
otherwise do nothing to prevent the proliferative response to the
angioplasty induced injury.
[0005] Restenosis is now believed to occur at least in part as a
result of injury to the arterial wall during the lumen opening
angioplasty procedure. In some patients, the injury initiates a
repair response that is characterized by hyperplastic growth of
vascular cells in the region traumatized by the angioplasty which
is termed neointimal hyperplasia. Neointimal hyperplasia narrows
the lumen that was opened by the angioplasty, regardless of the
presence of a stent, thereby necessitating a repeat PTCA or other
procedure to alleviate the restenosis.
[0006] Preliminary studies indicate that intravascular radiotherapy
(IVRT) has promise in the prevention or long-term control of
restenosis following angioplasty. IVRT may also be used to prevent
or delay stenosis following cardiovascular graft procedures or
other trauma to the vessel wall. Proper control of the radiation
dosage, however, appears to be important to inhibit or arrest
hyperplasia without causing excessive damage to healthy tissue.
Overdosing of a section of blood vessel can cause arterial
necrosis, inflammation, hemorrhaging, and other risks discussed
below. Underdosing will result in inadequate inhibition of smooth
muscle cell hyperplasia, or even exacerbation of hyperplasia and
resulting restenosis.
[0007] The prior art contains many examples of catheter based
radiation delivery systems. The simplest systems disclose seed
train type sources inside closed end tubes. An example of this type
of system can be found in U.S. Pat. No. 5,199,939 to Dake. In order
to separate the radiation source from the catheter and allow re-use
of the source, a delivery system is disclosed by U.S. Pat. No.
5,683,345 to Waksman et al. where radioactive source seeds are
hydraulically driven into the lumen of a closed end catheter where
they remain for the duration of the treatment, after which they are
pumped back into the container. Later disclosures integrated the
source wire into catheters more like the type common in
interventional cardiology. In this type of device, a closed end
lumen, through which is deployed a radioactive source wire, is
added to a conventional catheter construction. A balloon is
incorporated to help center the source wire in the lumen. It is
supposed that the radioactive source wire would be delivered
through the catheter with a commercial type afterloader system
produced by a manufacturer such as Nucletron, BV. These types of
systems are disclosed in Liprie U.S. Pat. No. 5,618,266, Weinberger
U.S. Pat. No. 5,503,613, and Bradshaw U.S. Pat. No. 5,662,580.
[0008] In the systems disclosed by Dake and Waksman, the source
resides in or very near the center of the catheter during
treatment. However, it does not necessarily reside in the center of
the artery. The systems disclosed by Weinberger and Bradshaw
further include a centering mechanism, such as an inflatable
balloon, to overcome this shortcoming. In either case, the source
activity and energy must be high enough to overcome absorption loss
encountered as the particles traverse the lumen of the blood vessel
to get to the target tissue site in the vessel wall. Higher
activity and energy sources, however, can have undesirable
consequences. First, the likelihood of radiation inadvertently
affecting untargeted tissue is higher because the absorption factor
per unit tissue length is lower. Second, the higher activity and
energy sources are more hazardous to the medical staff and thus
require additional shielding during storage and additional
precaution during use. In addition, the source of any activity or
energy may or may not be exactly in the center of the lumen, so the
dose calculations are subject to error factors due to
non-uniformity in the radial distance from the source surface to
the target tissue. The impact of these factors is a common topic of
discussion at recent medical conferences addressing Intravascular
Radiation Therapy, such as the Trans Catheter Therapeutics
conference, the Scripps Symposium on Radiotherapy, the Advances in
Cardiovascular Radiation Therapy meeting, the American College of
Cardiology meeting, and the American Heart Association Meeting.
[0009] The impact on treatment strategy is discussed in detail in a
paper discussing a removable seed system similar to the ones
disclosed above (Tierstein et al., Catheter based Radiotherapy to
Inhibit Restenosis after Coronary Stenting, NEJM 1997;
336(24):1697-1703). Tierstein reports that Scripps Clinic
physicians inspect each vessel using ultrasonography to assess the
maximum and minimum distances from the source center to the target
tissue. To prevent a dose hazard, they will not treat vessels where
more than about a 4X differential dose factor (8-30 Gy) exists
between the near vessel target and the far vessel target.
Differential dose factors such as these are inevitable for a
catheter in a curvilinear vessel such as an artery, and will
invariably limit the use of radiation and add complexity to the
procedure. Moreover, the paper describes the need to keep the
source in a lead transport device called a "pig", as well as the
fact that the medical staff leaves the catheterization procedure
room during the treatment. Thus added complexity, time and risk is
added to the procedure caused by variability of the position of the
source within the delivery system and by the activity and energy of
the source itself.
[0010] In response to these dosimetry problems, several more
inventions have been disclosed in an attempt to overcome the
limitations of the high energy seed based systems. These systems
share a common feature in that they attempt to bring the source
closer to the target tissue. For example, U.S. Pat. No. 5,302,168
to Hess teaches the use of a radioactive source contained in a
flexible carrier with remotely manipulated windows; Fearnot
discloses a wire basket construction in U.S. Pat. No. 5,484,384
that can be introduced in a low profile state and then deployed
once in place; Hess also purports to disclose a balloon with
radioactive sources attached on the surface in U.S. Pat. No.
5,302,168; Hehrlein discloses a balloon catheter coated with an
active isotope in WO 96/22121; and Bradshaw discloses a balloon
catheter adapted for use with a liquid isotope in U.S. Pat. No.
5,662,580. The purpose of all of these inventions is to place the
source closer to the target tissue, thus improving the treatment
characteristics of dosimetry.
[0011] In a non-catheter based approach, U.S. Pat. No. 5,059,166 to
Fischell discloses an IVRT method that relies on a radioactive
stent that is permanently implanted in the blood vessel after
completion of the lumen opening procedure. Close control of the
radiation dose delivered to the patient by means of a permanently
implanted stent is difficult to maintain because the dose is
entirely determined by the activity of the stent at the particular
time it is implanted. In addition, current stents are generally not
removable without invasive procedures. The dose delivered to the
blood vessel is also non-uniform because the tissue that is in
contact with the individual struts of the stent receive a higher
dosage than the tissue between the individual struts.
[0012] Additional problems arise when conventional methods, such as
ion implantation, are used to make a radioactive source for IVRT.
Hehrlein describes the use of direct ion implantation of active
P-32 in his paper "Pure .beta.-Particle-Emitting Stents Inhibit
Neointima Formation in Rabbits" cited previously. While
successfully providing a single mode of radiation using this
method, the ion implantation process presents other limitations.
For example, ion implantation is only about 10 to 30% efficient. In
other words, only about one to three of every ten ions put into the
accelerator is implanted on the target, and the remainder remains
in the machine. Thus, the radiation level of the machine increases
steadily with consistent use. With consistent use, the machine can
become so radioactive that it must be shut down until the isotope
decays away. Therefore, the isotope used must be of a relatively
short half-life and/or the amount of radiation utilized in the
process must be very small, in order to shorten the "cooling off"
period. Moreover, the major portion of the isotope is lost to the
process, implying increased cost to the final product.
[0013] Another approach to the same set of problems is to use a
nuclide suspended in solution to inflate a balloon (Thornton '114).
This technique provides uniform nuclide distribution within the
balloon to form the source, resulting in uniform dose patterns.
Also, this configuration moves the position of the nuclide closer
to the target tissue. No special catheter is required for this type
of approach, and many nuclides are available in liquid form. Hence,
several investigators have begun clinical studies on so called
"[radioactive]liquid filled balloons."
[0014] While a seemingly adequate solution to the problems of
centering and dosimetry, the liquid filled balloon systems have an
obvious drawback known to those familiar with the design,
manufacture, or use of balloon angioplasty catheters: balloons
potentially break. If a balloon is used to contain an active
nuclide, a break poses an obvious health threat to the patient,
physician and any nearby laboratory personnel. A break or leak may
also shut down the procedure room.
[0015] In all of the foregoing designs, full containment of the
isotope remains a significant challenge. The American National
Standards Institute (ANSI) publishes a standard for sealed sources
(ANSI N44.1-1973 Integrity and Test Specifications for Selected
Brachytherapy Sources), and the US Nuclear Regulatory Commission
(NRC) defines a sealed source as containing less than 5 nanoCuries
(5.times.10.sup.-9 Curies) of removable activity. Hehrlein reported
(Scripps Conference, January 1998) a balloon coated with P-32 that
lost 0.5% of its contained activity in an animal study. Even with
only 1 mCi of contained activity, the balloon proposed by Hehrlein
would have lost 5000 nCi, well beyond NRC standards for a sealed
source, and well outside of the ANSI definition of a sealed
source.
[0016] Despite the foregoing, among many other advances in IVRT,
there remains a need for an IVRT method and apparatus that delivers
an easily controllable uniform dosage of radiation without the need
for special devices or methods to center a radiation source in the
lumen. Furthermore, a need remains for a radiation delivery device
which is similar in use to conventional angioplasty balloon
catheters, and which has a sealed source to prevent escape of
radioactive species.
SUMMARY OF THE INVENTION
[0017] There is provided in accordance with one aspect of the
present invention, a multilayer radiation delivery source. The
source comprises a first bonding layer, having a first side, a
second bonding layer, having a second side which faces toward the
first side, and an isotope layer in between the first side and the
second side. The first side and the second side are secured
together through the isotope layer to produce a multilayer
radiation delivery source. In one embodiment, the isotope layer
comprises a metal salt or oxide and at least one isotope.
[0018] In accordance with another aspect of the invention, there is
provided a radiation delivery balloon catheter. The catheter
comprises an elongate flexible tubular body, having a proximal end
and a distal end. An inflatable balloon is provided on the tubular
body near the distal end, and is in fluid communication with an
inflation lumen extending axially through the tubular body. A
balloon bonding surface is carried on the outer surface of the
balloon, and a radiation source is provided on the balloon bonding
surface. An encapsulant surrounds the radiation source. The
encapsulant has at least an encapsulant bonding surface on its
radially inwardly facing surface for fusing with the balloon
bonding surface at least proximally and distally of the radiation
source.
[0019] In accordance with another aspect of the present invention,
there is provided a method of treating a site within a vessel. The
method comprises the steps of identifying a site in a vessel to be
treated, and providing a radiation delivery catheter. The catheter
has an expandable balloon with a thin film radiation source
thereon. The thin film comprising a substrate layer having an
isotope thereon, the isotope encapsulated by an outer encapsulant
layer which is fused to the substrate throughout the length of the
source. The balloon is positioned within the treatment site and
inflated to bring the source in close proximity to the vessel wall.
A dose of radiation is delivered from the delivery balloon to the
treatment site. The balloon is thereafter deflated and removed from
the treatment site.
[0020] In accordance with another aspect of the present invention,
there is provided a method of simultaneously performing balloon
dilation of a stenosis in a body lumen and delivering radiation to
the body lumen. The method comprises the steps of identifying a
stenosis in a body lumen. A treatment catheter is provided, having
an elongate flexible tubular body with an inflatable balloon near
the distal end. A cylindrical thin film radiation delivery layer is
provided on the balloon, and an encapsulant layer is positioned
over the radiation delivery layer. A continuous seal is provided
between the encapsulant, the radiation delivery layer, and the
balloon along at least the length of the radiation delivery layer
to provide a sealed source. The balloon is inserted into the lumen,
transluminally advanced therethrough, and positioned within the
stenosis. The balloon is inflated to radially expand the vessel in
the area of the stenosis, and simultaneously deliver radiation from
the thin film to and through the vessel wall.
[0021] In accordance with another aspect of the present invention,
there is provided a method of simultaneously performing balloon
dilation of a stenosis in a body lumen, delivering a stent, and
delivering radiation to the body lumen. The method comprises the
steps of identifying a stenosis in a vessel. A treatment catheter
is provided, having an elongate flexible tubular body with an
inflatable balloon near the distal end. A cylindrical thin film
radiation delivery layer is provided on the balloon, and an
encapsulant layer is positioned over the radiation delivery layer.
A continuous seal is provided between the encapsulant, the
radiation delivery layer, and the balloon along at least the length
of the radiation delivery layer to provide a sealed source. The
balloon is inserted into the lumen, transluminally advanced
therethrough, and positioned within the stenosis. The balloon is
inflated to radially expand the vessel in the area of the stenosis,
and simultaneously deliver the stent. Radiation is also delivered
from the thin film to the vessel wall.
[0022] In accordance with a further aspect of the present
invention, there is provided a method of manufacturing a sealed
source radiation delivery balloon catheter. The method comprises
the steps of extruding a tube for producing a balloon, where the
tube has a bonding layer on a radially outwardly facing surface
thereof. An annular radiation delivery source is positioned or
attached adjacent the balloon bonding layer. A tubular encapsulant
is extruded, having a sealing layer on a radially inwardly directed
surface thereof. The encapsulant is positioned concentrically
around the radiation source and the balloon to produce a
balloon-source-encapsulant stack, and the stack is exposed to
elevated temperature to bond at least one of the balloon and the
encapsulant to the source, thereby producing a sealed source.
[0023] In accordance with yet another aspect of the present
invention, there is provided a multilayer radiation delivery
source. The source comprises first, second, and third portions. The
first portion comprises a first support layer having a first
bonding layer thereon. The second portion comprises a second
support layer having a second bonding layer thereon. The third
portion comprises an isotope, and lies between the first and second
bonding layers. The first and second bonding layers of the source
begin to melt at a lower temperature than the first and second
support layers.
[0024] Further features and advantages of the present invention
will become apparent to those of skill in the art in view of the
detailed description of preferred embodiments which follow, when
considered together with the attached drawings and claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] FIG. 1 is a schematic perspective view of a thin film
radiation source in accordance with the present invention.
[0026] FIG. 1A is a schematic perspective view of an alternate thin
film source in accordance with the present invention.
[0027] FIG. 1B is a schematic of a cross-section of one embodiment
of the radiation delivery source of the present invention having a
substrate layer, an isotope layer and a coating layer.
[0028] FIG. 1C is a schematic of a cross-section of one embodiment
of the radiation delivery source of the present invention having a
substrate layer, a tie layer, an isotope layer and a coating
layer.
[0029] FIG. 2 is a schematic side elevational view of a catheter
incorporating the thin film source of the present invention.
[0030] FIG. 3 is a schematic side elevational view of an alternate
catheter incorporating the thin film source of the present
invention.
[0031] FIG. 4 is an enlarged side elevational cross-sectional view
through a balloon incorporating the thin film source of the present
invention.
[0032] FIG. 5 is an enlarged elevational cross-sectional view of a
balloon incorporating the thin film source in accordance with
another aspect of the present invention.
[0033] FIG. 6 is an enlarged side elevational cross-sectional
detail view through a balloon incorporating the multi-layered
sealed source embodiment of the present invention.
[0034] FIG. 7 is a cross-section taken along the 7-7 in FIG. 6.
[0035] FIG. 8 is a schematic illustration of the assembly of a one
embodiment of multi-layered sealed source in which the sections are
shown in partial cross-section.
[0036] FIG. 9 is an exploded cross-sectional view through a
preferred multi-layered sealed source embodiment of the present
invention, prior to fusing the bonding layers.
[0037] FIG. 9A is a cross-sectional view of the source of FIG. 9
where the bonding layers have been completely fused.
[0038] The drawing figures are not necessarily to scale.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0039] This invention provides a novel sealed source design, new in
terms of structure, materials and production methods. The invention
can be generally described as a thin film radioactive source
intended for site specific delivery of radiation ("brachytherapy")
to an anatomical structure. As presently contemplated, one
embodiment of the source design is intended for incorporation into
the balloon segment of a vascular dilatation catheter such as that
disclosed in U.S. Pat. No. 5,782,742, Crocker, et al., the
disclosure of which is incorporated in its entirety herein by
reference.
[0040] Alternatively, the source could be incorporated into
traditional "seeds," or placed on a wire, or on a trocar, or most
any other delivery system. The thin film can be rolled up into a
cylindrical configuration for insertion and unrolled in-situ for
positioning adjacent the vessel wall either by itself or as a
laminate on a flexible metal or polymeric support sheet, such as
disclosed in U.S. patent application Ser. No. 08/965,900, entitled
Radiation Delivery Catheter, filed Nov. 7, 1997 by von Hoffmann,
the disclosure of which is incorporated in its entirety herein by
reference. However, for the sake of simplicity, the present
invention will be described herein primarily in the context of a
sealed source balloon structure for use in intravascular
procedures.
[0041] The term "thin film source" is descriptive of the
invention's structure. Referring to FIG. 1, the source 10 comprises
of a thin sheet, or "substrate" layer 12, a chemical attachment or
"tie" layer 14 for binding the isotope, and an isotope species 16.
The substrate 12 can consist of a very thin (1 microns, or from
about 0.00004 to about 0.002" thickness) sheet or tubing. At these
thicknesses, a wide variety of biologically compatible materials
are very flexible and conforming. Examples of substrates
commercially available at these thicknesses are Mylar.RTM.
(polyester), Kapton.RTM. (polyimide), polyethylene, nylon, and
polyurethane, EMA, and polyethylene terephthalate (PET), in the
form of sheet or tubing, or even metal foils.
[0042] FIGS. 1A-1C show additional embodiments of the thin film
source of the present invention. Referring to FIG. 1A, a schematic
of a cross-section of a two-layer embodiment of thin film source is
shown. The first or innermost layer is the substrate 12, and the
second or outer layer is the isotope layer 16.
[0043] Referring to FIG. 1B, a schematic of a cross-section of thin
film source, wherein the source has three layers, is shown. The
first or innermost layer is the substrate 12, the second or middle
layer is the isotope layer 16, and the outer layer is the coating
layer 17.
[0044] Referring to FIG. 1C, a schematic of a cross-section of a
four-layer embodiment of the thin film source of the present
invention is shown. The four layers are the substrate layer 12, tie
layer 14, isotope layer 16, and coating layer 17.
[0045] The thin film sources of the present invention are comprised
of two or more layers of materials. There may or may not be a clear
visual or physical distinction between the various layers in the
source 10 because each layer need not be a discrete structural
element of the thin film source 10. As the layers bond together to
form the source, they may become blended, alloyed, intermingled or
the like to form what looks and acts like a single layer having a
somewhat heterogeneous composition. For this reason, the various
layers as defined and used herein are intended to denote the
functional characteristics of the components or help denote what
process steps are used in their formation, whether through the use
of discrete structural layers or layers blended with neighboring
layers, the selection of which will be apparent to those of skill
in the art in view of the particular materials and components
used.
[0046] For example, the term tie layer as used herein is intended
to denote a functional characteristic which enables securing of the
isotope species 16 to the substrate 12, whether through the use of
a discrete structural layer (such as an adhesive or functionally
analogous component) or a surface modification to the substrate 12
(such as chemical activation), the selection of which will be
apparent to those of skill in the art in view of a particular
substrate 12 material and isotope layer 16 material. For example,
FIG. 1A schematically represents a substrate 12 having an isotope
zone 16 comprising at least one isotope.
[0047] The thin film sources of the present invention all comprise
a substrate layer or substrate 12. The thickness and composition of
the substrate layer 12 can be varied widely, depending upon the
catheter design or the design of the other medical device to which
the isotope species 16 is to be bound. For example, materials in
the thickness of conventional PTCA balloons (from about 0.0005 to
about 0.005 inches) may be utilized, such as where the balloon
itself is used as the substrate 12. Additonally, a layer of bonding
material or encapsulant may be used as the substrate 12.
[0048] A balloon substrate may be either of the compliant or
non-compliant variety, as known in the art. Thus, for a radiation
delivery balloon which is not intended to additionally accomplish
angioplasty, working pressures on the order of 1 to 5 atmospheres
may be used. At such relatively low pressures, a variety of balloon
materials may be utilized, which do not experience excessive
expansion as a function of pressure. If higher inflation pressures
are desired, more traditionally non-compliant materials such as
polyethylene terephthalate may be desirable. In general, the
radioactive source on the delivery balloon preferably does not
expand in response to pressure. The substrate 12 may be polymeric
or a metal, depending upon the desired characteristics of the
finished product.
[0049] The shape of the source is generally dictated by the
geometry of the substrate 12. When present, any of the layers
described herein, other than the substrate, are disposed over at
least one surface of the source, and may be disposed over the
entire surface of the source. All layers present in a given
embodiment need not cover the same areas of the substrate or the
entire surface of the source. In one embodiment, the tie layer and
isotope layer cover only a portion of the substrate, and the entire
substrate is coated with one or more coating layers.
[0050] The thin film sources also all comprise an isotope layer 16.
The isotope layer comprises at least one radioactive isotope. Such
isotopes are preferably either beta- or gamma-emitting. The
composition of the isotope layer may be of a wide variety of
possibilities. In one embodiment, the isotope layer comprises a
collection of individual isotope ions, atoms, or compounds attached
to the layer below, preferably in a relatively even distribution.
In another embodiment, the isotope layer comprises a metal salt
wherein same or all of one ion of the salt has been replaced by
isotope-ions (simple or complex). Such a salt-containing isotope
layer may be bound directly to the substrate layer 12 or to a tie
layer 14, if present. The isotope layer preferably has an isotope
density or nuclide density in the range of 10.sup.10-10.sup.35
atoms/cm.sup.2, more preferably about 10.sup.13-10.sup.25
atoms/cm.sup.2 more preferably about 10.sup.25 atoms/cm.sup.2 and
has a thickness of preferably 25-10,000 Angstroms thick, more
preferably about 25-100 Angstroms thick.
[0051] As used herein, the term "metal salt" refers to a compound
comprised of at least one anion and at least one cation. The anions
and cations of the metal salt may be either simple (monatomic) ions
such as Al.sup.3+, C.sup.-, Ca.sup.2+, Zn.sup.2+and Ag.sup.+, or
complex ()olyatomic) ions such as PO.sub.4.sup.3-, O.sub.3.sup.2-,
and WO.sub.4.sup.2-. At least one of the ions in the metal salt
should comprise a metal. The term "metal" as used herein means all
metals, including, for example, semimetals, alkali metals, and
alkaline earth metals. Preferably metals are selected from the
transition metals or main group of the Periodic Table of the
Elements. The term "metal salt" as used herein in its broadest
sense can encompass metal oxides.
[0052] The thin film sources of the present invention may further
comprise at least one tie layer 14. The tie layer 14 lies between
the substrate 12 and isotope layer 16 and may act to increase the
tenacity of attachment of the isotope layer 16 to the substrate 12.
The tie layer 14 may be any composition or structure which
functions to bind the isotope 16 to the substrate 12. The tie layer
14 may comprise adhesives, chemically activated surfaces,
mechanical locking structures, a chemical coating layer, or a layer
of one or more an organic or inorganic compound. Preferred tie
layer materials include metals, alloys, metal salts, alumina and
other metal oxides, polyester, polyimide and other polymers. Its
chemical composition and structure can be varied, depending on the
isotope to be attached. It can be an organic or inorganic material
or compound; it must only have the appropriate chemistry to attract
and bind the isotope or isotope layer materials. The tie layer may
be applied to one or both surfaces of the substrate, depending on
factors such as the desired activity, composition or geometry of
the finished product. In one embodiment, the tie layer 14 is a
layer of metal or metal oxide, and it is 100 to 10,000 Angstroms
thick, more preferably 200 to 1000 Angstroms thick.
[0053] The thin film sources of the present invention may further
comprise one or more coating layers 17, as is discussed in
connection with FIGS. 6-7 below. A coating layer 17, can act as a
sealing means to protect the isotope layer from mechanical abrasion
or other injury which could remove radioisotopes from the isotope
layer. Although the isotopes in the sources of the present
invention may be sufficiently adherent without the addition of a
coating layer, addition of a coating layer may aid in providing
sufficient protection for the device to be classified as a sealed
radiation source, i.e. one that has less than 5 nCi of removable
activity. The coating layer may also provide the additional
advantage of sealing or binding the layers of the source
together.
[0054] The coating may be a metal or plastic. Plastic coating
materials are preferably biocompatible, but not excessively
biodegradable. Preferred materials include cyanoacrylates,
acrylics, ethylene methyl acrylate, ethylene methyl
acrylate/acrylic acid (EMA/AA), urethanes, thermal plastic urethane
(TPU) polybutyl vinyl chloride (PBDC), polyvinylidene chloride
(PVDC, such as Saran.RTM.) polyethylene, polyethylene
terephthalate, nylon and the like. Likewise, metal coatings can be
used as well. If the coating is metal, the metal used is preferably
one which is bio-stable. For example, platinum, gold, or titanium
may be vapor deposited on the surface to encapsulate the isotope
layer.
[0055] The foregoing thin film structures offer several advantages
over existing source designs. First, the source can conform to
almost any shape, unlike conventional seed or solid wire type
sources or even a thin metal film. Thus, this type of source is
ideal for incorporation into flexible catheter-like delivery
systems.
[0056] The radioisotopes used in the thin film sources of the
present invention may be beta or gamma emitters, or both, and may
have any of a wide range of half-lives, both long and short. The
particular isotope, or combination of isotopes as well as the
concentration of isotopes in the source (which determines the
dose), can be chosen by one skilled in the art to serve the needs
of a particular application. In a recent paper presented by Howard
Amols at the January 1998 Scripps Clinic Conference on
Intravascular Radiation Therapy entitled "Choosing the Right
Isotope: What's New? Insights into Isotopes or Why Is it so Hard to
Find the Ideal Isotope?," the author states that the best isotope
choice from the perspective of both physics and dosimetry would be
a photon source with an energy greater than 3 MeV and a half-life
greater than 7 days. Shirish K. Jani, in a lecture entitled "Does
the Perfect Isotope Exist?" at the same conference states that the
perfect isotope for vascular brachytherapy would exhibit a low dose
gradient, low dose levels to surrounding body tissues, manageable
radiation exposure levels around the patient and a long half-life.
Iodine-125 (I-125, half-life 60 days) and tungsten-188/rhenium-188
(W/Re-188, half-life 70 days) are candidates to meet these
criteria, and also have long half-lives. Thus, these are two
preferred radioisotopes for use in the present invention.
Phosphorous-32 (P-32, half-life 14.3 days) is also a preferred
isotope for use in the present invention.
[0057] Preferred radioisotopes are selected from the group of gamma
emitters (or x-ray emitters) with energies less than about 300 KeV
such as I-125, Pd-103, As-73, Gd-153, or the high-energy beta
emitters (E.sub.max>1.5 meV) including P-32 and W/Re-188, or
others as may be deemed suitable for a particular use. The
selection of the isotope may be influenced by its chemical and
radiation properties, and other isotopes not mentioned herein, but
which have properties suitable for a particular application, can be
utilized in the present invention. Preferred radioisotopes used in
the thin film sources of the present invention may be purchased
from Oak Ridge National Laboratory (Oak Ridge, Tenn.), New England
Nuclear (NEN) or any other commercial suppliers of
radioisotopes.
[0058] In accordance with one isotope attachment technique, a thin
film substrate is treated with a tie layer composed of a
three-dimensional matrix with an ionic compound. The choice of the
ionic compound is made to encourage the ion desired to bond within
the tie layer. In one embodiment, the three-dimensional matrix is
polyvinyl pyrrolidone (PVP) with an ionic compound containing a Br
anion. The PVP matrix is commonly used as a carrier for I.sub.2 in
antimicrobial applications. Direct attachment of the ionic compound
would result in layers on the molecular scale. To accomplish
attachment, the treated substrate is placed in an ionic solution of
I-125 (Na.sup.125I, a commercially available form of I-125). I-125
anions exchange with Cl.sup.- Br.sup.- anions with less affinity to
PVP from the PVP, thus incorporating I-125 into the tie layer and
producing a gamma radiation source. A similar system can work
alternatively in a solution comprising .sup.32P-containing ions
such as H.sub.3.sup.32PO.sub.4 (a commercially available form of
P-32 ) to form a beta emitting source.
[0059] In one specific embodiment of the present invention, a
generally rectangular polyester sheet having a width of about 2 cm,
a length of about 3 cm and a thickness of about 12 microns was
coated with a PVP ion exchange surface and soaked in a 0.125 wt %
I-125 in Nal solution. The resulting source may thereafter be
wrapped around a balloon having an inflated diameter of about 3.0
mm and an axial length of about 30 mm. The sheet length of 3 cm
would allow the source to be wrapped around the inflated balloon
approximately 3 full revolutions. Thus, in this context, sheet
length corresponds to the circumferential direction as wrapped
around the balloon, and sheet width corresponds to the axial length
of the source along the balloon. In this embodiment, the activity
of the source would be approximately 110 milliCuries per centimeter
length of the substrate sheet. Thus, by providing three full
revolutions, a net activity of about 330 milliCuries may be
produced. This activity is similar to that disclosed by Teirstein
for the Ir-192 (gamma) source used in the Scripps study. Using the
present invention, the net activity could conveniently be doubled,
for example, by lengthening the substrate sheet to about 6 cm,
thereby enabling six revolutions of the substrate around the
balloon. This may accomplish a respective reduction in treatment
time of 50%.
[0060] In cases where adequate activity can be achieved with a
single wrap of the source, a thin tube could be used alternatively
to the sheet. For example, PET tubing can be commercially obtained
with wall thicknesses similar to the sheet material described
earlier (0.0003-0.001 inch). The tube construction may allow for
simpler assembly, but otherwise it possesses the same properties as
the rolled sheet.
[0061] In one specific embodiment of the present invention a PE/EMA
coextruded, crosslinked and expanded tube was manufactured to a
wall thickness of 0.001" to 0.0015" thick. A metal oxide tie layer
and metal salt isotope layer was placed on the sheet. The nuclide
density of P-32 on the tube was similar to that of a sheet of the
same specific surface area. A delivery system may be manufactured
in similar fashion to the sheet source with the added benefit of
sealing the entire tubular substrate to the encapsulant in addition
to the proximal and distal balloon to encapsulant seal.
[0062] There are alternative ways of taking advantage of the thin
film structural properties, however, without utilizing a chemical
attachment system for the isotopes. For example, the radioactive
isotope or a salt thereof can be attached directly to the sheet
without a distinct tie layer 14 through ion implantation, vapor
deposition, or sputtering. Thus, for some techniques, a distinct
tie layer 14 is omitted completely. See FIGS. 1A and 1B.
[0063] Other methods of direct isotope attachment to the substrate
can be considered for metal isotopes. For example, vapor deposition
and sputtering can be used to deposit metal isotopes on the
substrate. The layers in these processes can be controlled to
submicron thicknesses, such that all of the physical/mechanical
advantages described in the above paragraphs for chemical
attachment systems are maintained: flexibility, ability to adjust
activity based on multiple wraps, ability to utilize less active
isotopes.
[0064] Preferred methods of making the isotope layer of the present
invention may begin with either a substrate to be coated or a tie
layer to serve as the place of attachment. Preferred methods
comprise exposing surfaces to fluids comprising reactants or
isotopes.
[0065] Such fluids may be gaseous (including plasma and vapor) or
liquid (such as solutions), with liquid solutions being preferred.
As such, the methods below are described in terms of liquid
solutions.
[0066] Some preferred methods of making the isotope layer of thin
film sources of the present invention comprise, in part, either one
or both of the following solution processes: (1) oxidation in an
acidic solution to form a metal salt from a metal; and (2) ion
exchange wherein ions at or near the surface of the metal salt are
exchanged with those present in a solution. The first process is
based on differences in oxidation-reduction potentials, and the
second process is based on differences in solubility. These
processes will be taken in turn.
[0067] In the first process, the equilibrium is driven by
principles of oxidation-reduction (redox). A metal, in the form of
a pure metal or part of an alloy, may be converted to a metal salt
when it is placed in solution comprising an oxidizing agent. Many
metals, including those in preferred embodiments discussed below,
can be readily oxidized in solution to form metal cations, which
may then form salts with anions in solution.
[0068] Whether or not a particular reaction of an oxidizing agent
and a metal will occur spontaneously can be predicted by reference
to a standard table of half-cell potentials such as that in CRC
Handbook of Chemistry and Physics, (CRC Press). If the sum of the
potentials of the oxidation half-reaction and the reduction
half-reaction is positive, then the reaction will occur
spontaneously.
[0069] For example, it can be predicted that when silver is added
to an acid solution of sodium chlorite, the silver will be
oxidized. When added to the solution, sodium chlorite (NaClO.sub.2)
disproportionates to form hypochlorous acid and chlorine dioxide,
which is capable of oxidizing silver as shown below:
1 Ag .fwdarw. Ag.sup.+ + e.sup.- (ox) Emf = -0.80 V ClO.sub.2 +
e.sup.- .fwdarw. ClO.sub.2 (red) Emf = 1.16 V Ag + ClO.sub.2 +
e.sup.- .fwdarw. Ag.sup.+ + ClO.sub.2 Emf = 0.36 V
[0070] In addition to the reaction shown above, the hypochlorous
acid undergoes a redox reaction whereby chloride ions are produced,
which then couple with the silver cations to form silver
chloride.
[0071] The second process is a solubility-driven ion exchange.
When, for example, two anions are placed in solution with a given
cation, there is a driving force which results in the formation of
the metal salt which is less soluble/more insoluble. Because it is
difficult to compare solubilities and thus predict behavior when
the relative terms "soluble" and "insoluble" are used, solubility
is related to a type of equilibrium constant, the solubility
product (K.sub.sp), in order to quantify the degree of solubility
for a given compound. The solubility product is equal to the
concentrations of the dissociated ions of the salt at equilibrium,
that is for salt AB, K.sub.sp=[A.sup.+][B.sup.-] wherein [A.sup.+]
and [B.sup.-] are the concentrations of the A cation and the B
anion, respectively. If a salt is fairly soluble, the
concentrations of its component ions in solution will be relatively
high, leading to a relatively large K.sub.sp. On the other hand, if
a salt is fairly insoluble, most of it will be in solid form,
leading to low concentrations of the ions and a relatively small
K.sub.sp. Thus, when comparing two salts of the same metal, the
salt with the lower K.sub.sp is the more insoluble of the two.
Solubility products for most common compounds can be found in
reference texts such as the CRC Handbook of Chemistry and Physics
(CRC Press).
[0072] The salts silver chloride (AgCl,
K.sub.sp=1.77.times.10.sup.-10) and silver iodide (AgI,
K.sub.sp=8.51.times.10.sup.-17) can be used to illustrate the
principle of solubility driven ion exchange. The solubility
products for these compounds are both fairly low, but K.sub.sp for
silver iodide is lower by nearly 7 powers of ten, indicating that
it is more insoluble than silver chloride. Thus, if solid silver
chloride is placed in a solution containing iodide ions, the
equilibrium lies on the side of the silver iodide, and the chloride
ions will exchange with the iodide ions so that the more insoluble
silver iodide is formed. On the other hand, if silver iodide is
placed into a solution containing chloride ions, the ion exchange
will not take place. In this manner, chloride ions in silver
chloride coated on the surface of a substrate can be replaced by
.sup.125I anions to form a radiation source of the present
invention.
[0073] The metal salt layer which is the starting point for the
above solution ion exchange process may be formed by a redox
process such as that described above, or it may be applied directly
by means of sputtering, vapor deposition, or other techniques known
in the art. Alternatively, if a redox process described above is
performed using an oxidizing solution containing a radioisotope,
for example H.sub.3.sup.32PO.sub.4, the radioisotope-containing
metal salt layer may be obtained directly, eliminating the need for
the ion exchange.
[0074] Another preferred method for making thin film sources of the
present invention comprises oxidizing a metal, such as those bound
to or incorporated in the substrate, and then binding an isotope to
the metal oxide. The step in which the metal is oxidized preferably
occurs spontaneously in air. Thus, metals such as aluminum and
copper, which readily and spontaneously undergo oxidation to form
their respective oxides, are preferred. Oxide formation occurs when
the metal is exposed to air, but may be enhanced or increased by
exposure to oxygen-enriched atmospheres or increased temperature.
The binding of the isotope is preferably performed by immersing the
metal oxide in a solution containing isotope ions, either simple or
complex. The attraction between the metal oxide and the isotope
ions is such that the isotope ions will bind to the metal oxide
rather than existing free in solution. This binding or "plating"
process may occur either with or without displacement of ions from
the metal oxide.
[0075] There are several advantages to using the processes above to
place active isotopes on a source as opposed to the ion
implantation of radioisotopes and nuclear bombardment. One
advantage is that unwanted isotopes are not formed. As discussed
above with reference to Hehrlein '177, neutron activation of a
metal-containing source produces numerous isotopes, making it very
difficult to control the dose provided by the source.
[0076] Another advantage of the present method is that it does not
create large quantities of radioactive waste. By using the correct
quantity of radioisotope solution, very little waste is produced.
Isotopes which are not incorporated into a given source remain in
solution and may be used to form another source. Unlike radioactive
ion implantation, there is no stray isotope-filled machine chamber
that must be cleaned and safely discarded or taken out of use and
allowed to "cool."
[0077] Yet another advantage of the present method is that it
allows use of isotopes which cannot be readily obtained on a solid
source by the other means known in the art. With the proper choice
of materials and solutions and the disclosure herein, one skilled
in the art would be able to create a reaction scheme to make a salt
containing most any of the desirable therapeutic radioisotopes.
Furthermore, by using particular long-lived isotopes, a radiation
source with a longer half-life can be produced that is capable of
delivering a dose with less variation between maximum and minimum.
Use of an isotope with a longer half-life may provide for a
radiation source which is capable of lowering the amount of
radioactivity necessary to perform its function over that which
incorporates a short-lived isotope.
[0078] Another advantage of the present invention is that the
radioisotopes are held by strong atomic-level bonding interactions,
and which are highly resistant to leaching or release under
physiological conditions or during handling. Additionally, the use
of ionic bonding is especially useful for radioisotope species such
as iodine-125, as the salt form holds the normally volatile iodine
atoms in place.
[0079] Another benefit to the solution processes of the present
invention is that the density of activity of a given isotope or
multiple isotopes may be controlled by simply controlling the time
of immersion and/or the density and amount of metal salt or tie
layer on the source.
[0080] Another advantage of the thin film source is that the
structure lends itself to batch processing. The coating step can be
done in relatively large volumes using common chemical attachment
techniques found in the photographic film and semiconductor
industries. Radioactive isotopes are commonly provided in
solutions, so the final production step of adding the isotope may
be as simple as soaking the coated substrate in the isotope
solution. This can be simply performed in very small or very large
sheet sizes. The ability to perform this step in small batches is
advantageous because the amount of radiation in process can be
adjusted to suit the radiation capabilities of the
manufacturer.
[0081] The basic method, as discussed in part above, comprises
providing a substrate and forming a coating comprising an insoluble
metal salt with at least one radioactive isotope species
thereon.
[0082] One preferred embodiment of thin film source of the present
invention is that which has an isotope layer comprising the
gamma-emitting isotope .sup.125I. As mentioned previously,
.sup.125I meets the criteria of an "ideal" isotope as defined by
Amols and Jani. One method for making a thin film source having an
isotope layer comprising .sup.125I is that which uses both solution
methods discussed above. First, a substrate is provided that
comprises silver or elemental silver is attached to the surface of
the substrate using well-known methods such as ion implantation,
vapor deposition, sputtering, electroplating, or rolling. The
silver is then converted to silver chloride (AgCl) via an
oxidation-reduction solution process such as that described above
which uses an acidic solution of sodium chlorite to reduce the
silver and produce silver chloride. Then the silver chloride-coated
source is immersed in an ion exchange solution comprising sodium
iodide in the form of Na.sup.125I, wherein the AgCl is converted to
Ag.sup.125I on the surface of the source. This manufacturing
process may be performed quickly, easily and efficiently. In
addition, the I-125 with a half-life of 60 days would provide an
equivalent or lower dose of radiotherapy for a longer period of
time.
[0083] As an alternative to the above method, silver chloride could
be directly deposited to the surface of the thin film source by
means of vapor deposition or other method known in the art, and
then immersed in the ion exchange solution containing
Na.sup.125.
[0084] In one specific embodiment of the present invention, a
silver foil having a surface area of 4 cm.sup.2 was immersed in a
solution of 6M HCl and 1M NaClO.sub.2 in a 10:1 ratio. A portion of
the silver was thereby converted to silver chloride. The foil was
then immersed in a bath having about 2 ml of a solution. The
solution in the bath contained about 0.07% Na.sup.125I in NaI, and
was prepared by dissolving 0.5 mg NaI in 2ml water and adding 4.6
mCi .sup.125I into the solution. Following immersion, the resulting
activity of the foil was measured at 2mCi, which, when the amount
of carrier (non-radioactive) iodine is factored in, corresponds to
about 10.sup.18 atoms of iodine attached to the sheet. In a carrier
free solution, this number of I-125 ions would result in an
activity of 3Ci per 4cm.sup.2 of substrate.
[0085] Another preferred embodiment of thin film source of the
present invention is that which has an isotope layer comprising p.
A thin film source having an isotope layer comprising .sup.32P can
be made by methods similar to that described above for .sup.125I
using P-32 in the form of orthophosphoric acid
(H.sub.3.sup.32PO.sub.4). First, a substrate is provided. The
substrate may be manufactured to contain zinc or a zinc alloy, or
the substrate may be coated with zinc or a zinc alloy by vapor
deposition or other methods known in the art. The zinc is then
converted to a salt such as zinc fluoride (ZnF.sub.2,
K.sub.sp=3.04.times.10.sup.-2- ) via an oxidation-reduction process
similar to that discussed above. The source is then activated by
immersing the zinc fluoride-coated source in a solution containing
phosphate ion in the form of .sup.32PO.sub.4.sup.3- or a soluble
phosphate salt, whereby the more soluble fluoride ion is exchanged
for phosphate to form zinc phosphate (Zn.sub.3(PO.sub.4).sub.2,
K.sub.sp=5.times.10.sup.-36).
[0086] Alternatively, the substrate may be directly coated with
zinc fluoride or other similarly insoluble salt by vapor deposition
or other means known in the art, and then placed in an ion exchange
solution. Another alternative is to use a solution containing
H.sub.3.sup.32PO.sub.4 in the oxidation step so that the zinc is
directly converted to zinc phosphate containing the radioisotope,
thus eliminating the ion-exchange step. Yet another alternative is
to deposit or form calcium fluoride (CaF.sub.2,
K.sub.sp=1.61.times.10.sup.-10) and then expose this to a source of
phosphate (orthophosphate) such as H.sub.3.sup.32PO.sub.4 or
Na.sub.3.sup.32PO.sub.4.
[0087] There is an additional advantage to using zinc phosphate in
the isotope layer. Zinc phosphate is a stable molecule and is often
used in the automotive industry for paint adhesion to galvanized
steel. Zinc phosphate has anticorrosive characteristics of its own,
and has been used in the past to increase the corrosion resistance
of steel. A zinc phosphate coating on a source made of steel, such
as a wire or seed, may be an advantage to the source even in the
case that it is not used as a radiation delivery device.
[0088] Yet another preferred embodiment of thin film source of the
present invention is that which has an isotope layer comprising
tungsten-188 (W-188 or .sup.188W). Tungsten-188 undergoes beta
decay to become rhenium-188 (Re-188 or .sup.188Re). Rhenium-188
undergoes beta decay as well, but emits a much higher energy
particle than in W-188 decay. The W-188 has a much longer half-life
than does Re-188, thus the W-188 almost continuously creates more
Re-188. This process is known as "generator," and these generator
isotopes are referred to together by the shorthand W/Re-188 to
indicate the relationship between the species. Generators are
attractive for use in radiation delivery devices because they
combine the energy levels of a short half-life species with the
durability of the long half-life species. It is a general rule that
particle energy and half-life are inversely proportional, and that
long half-life species are more economical and practical to work
with than short half-life species.
[0089] W/Re-188 is a beta emitting isotope with an energy about 10%
higher than P-32. Where I-125 was discussed as a highly favorable
gamma emitting isotope, W/Re-188 fits the criteria of both Amols
and Jani for a highly favorable beta emitting species for IVRT. The
advantage of the W/Re-188 source would be that the source would
provide a dose which could be consistently administered over a long
period of time. The half-life of W-188 is 70 days as compared to 14
days for the P-32. This represents a consistent dose rate as
Re-188, itself a beta emitting isotope, is being produced by the
decay of tungsten for a longer period of time.
[0090] Tungsten, in the form of tungstate ion (WO.sub.4.sup.2-) may
be readily attached to an oxidized aluminum surface to produce a
W/Re-188-containing thin film source of the present invention. An
aluminum oxide surface may be attached to the source by sputtering
Al.sub.2O.sub.3, or Al can be attached by implantation or
deposition, followed by an oxidation step. Ambient environment will
facilitate the formation of Al.sub.2O.sub.3 from aluminum which can
be accelerated by increasing the temperature and/or using an
oxygen-rich atmosphere. The aluminum oxide surface may then be
immersed in a tungstate containing solution, such as an acidic
solution of sodium tungstate (Na.sub.2.sup.188WO.sub.4), in order
to attach the W-188 to the alumina surface.
[0091] Tungsten may also be applied together with a phosphate in a
manner similar to that disclosed by Larsen in U.S. Pat. No.
5,550,006, which is hereby incorporated into the present disclosure
by this reference thereto. The method disclosed in Larsen is
claimed for use in increasing adhesion of organic resists for
printed circuits. The method was used to perform a phosphate
conversion coating onto copper. This method may find its
application in the radiation delivery device of the present
invention in that many polymers and metals other than copper may be
coated with this solution. In this method, phosphate may be in the
form of .sup.32PO.sub.4.sup.3-, tungstate may be in the form of
.sup.188WO.sub.4.sup.2-, or any combination of the isotopes in
radioactive or stable form may be used.
[0092] Sources employing combinations of various isotopes provide
another preferred embodiment in that beta-emitting isotopes may be
combined with gamma-emitting isotopes where gamma isotopes can
deliver dosage to greater depths.
[0093] Thin film sources comprising other metals, metal salts, and
isotopes can be made by procedures similar or analogous to the
preferred embodiments disclosed above, using materials appropriate
for the chemistry of the isotope to be included, as can be
determined by one skilled in the art in view of the disclosure
herein.
[0094] In some embodiments of the thin film source of the present
invention, it may be desirable to provide a tie layer, onto which
the isotope layer will be placed. The tie layer may comprise
adhesives, chemically activated surfaces, a chemical coating layer,
or an organic or inorganic compound. Preferred tie layer materials
include metals, alloys, metal salts, metal oxides, PVP, and other
polymeric materials.
[0095] For some polymeric tie layers, the nature of the tie layer
14 will depend on the isotope to be attached. Many different
coatings and attachment technologies are available, and new ones
can be developed as applications are developed. For example,
Iodine-125 (I-125) can be bound to the substrate by passing it over
a substrate coated with a polyvinyl pyrrolidone (PVP) as discussed
previously. Other preferred polymeric-type tie layers comprise
polymeric materials such as polyesters and polyamides.
[0096] Another preferred type of tie layer is the metal-type that
which comprises a thin layer of metal, metal oxide, metal salt, or
alloy. Depending upon the composition of the other layers and
materials in the source, depositing a metal-type tie layer may
allow an "alloying" process to take place between the metal of the
tie layer and any metals present in the isotope layer. This may
serve to enhance the tenacity of attachment of the metal salt, and
hence the isotope. This may also occur if the tie layer comprises
more than one metal or if more than one tie layer is used in making
the source. Alloying of this type is common in the semiconductor
industry, wherein a chromium layer is used as an initial layer in
the deposition of gold. The chromium is alloyed with the gold in
order to increase the strength at which the gold is bound to the
substrate. If, for example, the isotope layer comprises a zinc
salt, a metal such as copper or aluminum may be used as the tie
layer. The tie layer may also be in the form of an oxide, such as
alumina (Al.sub.2O.sub.3) which may aid attachment by providing
oxygen to chemically bind the atoms of the metal salt layer thereby
increasing the tenacity of attachment. In one embodiment of source,
alumina is deposited on a substrate upon which is placed calcium
fluoride. The calcium fluoride may then undergo isotope exchange
with a source of radioactive phosphate to form a P-32 based thin
film source.
[0097] A metal-type layer to which the isotope layer is attached
may comprise any suitable metal, metal oxide, metal salt or alloy.
The layer may be deposited by vapor deposition, sputtering, ion
plating, ion implantation, electrodeposition, or other method. When
the tie layer is present, there may or may not be a clear
distinction between the tie layer and the isotope layer. In
performing its function, and depending on the chemistry of the
materials involved, the tie layer may become blended, alloyed or
intermingled with the isotope layer, thus blurring the lines
between the layers. For many of the same reasons, the distinction
between the tie layer and a metal-containing substrate layer may
also be blurred. In these cases, the term tie layer is meant to be
a functional or process-defining definition, rather than a
reference to a physically distinct layer of the thin film
source.
[0098] In another type of system that can be constructed, the tie
layer 14 can incorporate a metal exchange surface, which will
attach Pd-103 in the form of palladium metal drawn directly from
solution. For example, the substrate layer, made from polyimide as
disclosed previously, can be coated with reactive metals such as
copper, aluminum, or chromium using commonly available techniques
such as vapor deposition or sputtering. The coated substrate is
then placed in a solution containing the isotope. The difference in
oxidation-reduction (redox) potential between the coating metal and
the isotope causes the isotope to deposit on the surface of the
substrate film. This system can also be used to attach W-188 from a
solution of tungsten salts or other metal salt isotopes as
well.
[0099] Metal isotope species, such as Palladium-103 (Pd-103) or
Tungsten/Rhenium-188 (W/Re-188) or Gd-153 can be attached by
incorporating a chelating agent onto the polymer substrate, and
then soaking the sheet in a solution of Palladium salts, Tungsten
salts or Gadolinium salts. These types of chemical technologies can
be incorporated into the source design described herein.
[0100] An experiment was done to test the effectiveness of using a
copper tie layer to enhance the attachment of zinc fluoride onto a
Mylar.RTM.sheet. A layer of ZnF.sub.2 was placed on a first sheet
of Mylar by vapor deposition. On a second sheet of Mylar, a layer
of copper was placed by vapor deposition, followed by deposition of
a layer of ZnF.sub.2. The sheets were each placed into solutions of
H.sub.3.sup.32PO.sub.4 having similar activities and allowed to
react for several hours. The P-32 activity was counted via
scintillation counting. It was found that the sheet having the
copper tie layer resulted in a greater adsorption of P-32: 71.6%
for Cu/ZnF.sub.2 vs. 56% for ZnF.sub.2 after 1 hour; and 98.4% for
Cu/ZnF.sub.2 vs. 86% for ZnF.sub.2 after 24 hours. Thus, after a
significant period of time, the copper tie layer appears to promote
and maintain adherence of the zinc salt to the Mylar surface, and
can result in a source which has significantly more activity and
adhesion than that without the copper tie layer.
[0101] Although the sources of the present invention may have
isotopes which are sufficiently adherent without further treatment,
in some embodiments of the present invention, it may be desirable
to place an outer coating on the thin film source. An outer coating
can provide further advantages for the thin film source of the
present invention in that the coating can help provide additional
means to bind the layers of the source together. Perhaps more
importantly, an outer coating can increase the abrasion resistance
of the source.
[0102] Sealed radioactive sources are those which have less than 5
nCi of removable activity. By providing a coating on the source
which covers at least the isotope layer, the source can be
protected from unwanted loss of activity due to mechanical abrasion
of the surface of the source. This may be important, both for
providing safe devices for the patient which leave radioisotopes
behind only where they are desired, and for monitoring dosage to
ensure that the dose which is to be provided by a source will
actually reach the treatment site, and not be significantly
diminished due to loss of isotope from abrasion which may occur
during implantation. It also helps insure that, once the source is
positioned for treatment, the radioisotopes will remain at that
site and not be washed downstream.
[0103] Coating materials are preferably biocompatible, but not
excessively biodegradable. Preferred materials include polymeric
materials including cyanoacrylates (Loctite, Hartford, Conn.),
acrylics, ethylene methyl acrylate (Exxon Chemical Co., Houston,
Tex.), ethylene methyl acrylate/acrylic acid (EMA/AA) (Exxon
Chemical Co., Houston, Tex.), urethanes and thermal plastic
urethane (TPU) (BF Goodrich, Richfield, Ohio), PVDC, PBVC, PE, PET,
and combinations thereof. Other preferred coatings may comprise
other biocompatible materials, drugs or similar compounds, such as
heparin. Many methods are available to perform the coating process,
such as dip or immersion coating, spray coating, spin coating,
gravure or shrink wrap tubing. If curing is required, the curing
technique may be any of the various techniques available, such as
air, heat, or UV. Preferably the thickness of the coating which is
formed is 1 .mu.m to 30 .mu.m more preferably 10 .mu.m to 20
.mu.m.
[0104] One preferred embodiment of the present invention has a
coating that is formed with cyanoacrylate. Another preferred
coating layer is that formed by ethylene methyl acrylate/acrylic
acid (EMA/AA) polymer. An aqueous dispersion of this coating
material, preferably having a viscosity less than 100 centipoise,
allows for use of any of the above-mentioned coating methods. UV
curable polyurethane acrylate is also useful as a coating layer
material. Yet another preferred coating layer is that formed by
SARAN. Such a layer may be formed, for example, by immersing the
source or a portion thereof into a melt of SARAN or a solution
containing SARAN.
[0105] The coating layer may also be formed by a spin coating
process. Spin coating the thin film source finds advantage in the
flexibility to use coating materials having a wide range of
viscosities. Low viscosity liquids may be spun on slowly, while a
higher viscosity liquid may be spun at a higher velocity to
maintain a thin coating. The substrate may be held in place by
fixturing or by vacuum during the spin coating process. In an
experiment, a dispersion of cyanoacrylate in acetone was dispensed
on top of the metal salt surface while the substrate was rotated at
8000 rpm for five minutes. The resulting thickness of the coating
was about 6.5 .mu.m (0.00025 inch). When this specimen, having the
spin-coated surface curable coating of cyanoacrylate was extracted
in saline for 8 hours at 50.degree. C; the amount of radioactivity
extracted was negligible.
[0106] In another experiment, two sources were tested to
demonstrate the effectiveness of the coating layer by measuring the
amount of removable isotope on coated and uncoated sources. Both
sources comprised a Mylar thin film substrate and a
ZnF.sub.2/Zn.sub.3(.sup.32PO.sub.4).sub.2 isotope layer, with the
coated source further comprising a cyanoacrylate coating layer made
by dip coating an uncoated source. The test was performed on each
source by wiping it with a cotton swap three times on each side.
The activity of the swab was measured by scintillation counting. It
was found that the amount of removable activity on the uncoated
Mylar-based source was 6.76%, while on the coated source the
removable activity was merely 0.050%.
[0107] In making some embodiments of the thin film source of the
present invention, it may be desired that one or more portions of
the source or substrate are not covered or coated by particular
layers or portions of layers. In such embodiments, the source may
be made by the use of masking techniques. In such a technique, the
portions of the source or substrate which are to be left alone for
a particular step or steps are covered with a piece of a material
to serve as the mask. The other portions not covered by the mask
are treated (reacted, coated) and then the mask is removed. For
example, it may be preferred to have a small border of substrate
surrounding the portion of the source onto which the isotope layer
is placed. Such an arrangement may be preferred to reduce coating
of the side surfaces of the substrate by the isotope layer, reduce
edge effects or to enable several distinct and separate sources to
be prepared on a single sheet of substrate having spaces
therebetween which are not coated by isotope to that the individual
sources may be separated once they are completely prepared without
the risk of radioactive contamination of the blade or other
implement which is used to cut or separate the individual
sources.
[0108] In one embodiment, a plurality of sources comprising a Mylar
substrate, alumina tie layer and CaF.sub.2/.sup.32PO.sub.4 isotope
layer are made using a mask. In this method, the Mylar sheet is
placed between a plate and a mask. The plate may be formed of
glass, metal or other suitable material. The mask is a stainless
steel sheet from which several rectangular-shaped portions have
been removed. The three pieces (plate, Mylar, mask) are secured
together and then placed in a chamber. Alumina, which forms the tie
layer, is then deposited on the rectangular-shaped portions of the
Mylar which have been left exposed by the mask. Calcium fluoride is
then deposited on the alumina. The mask is then removed, and the
entire sheet placed in an ion-exchange bath containing
.sup.32PO.sub.4.sup.3- ions to complete formation of the isotope
layer. One or more outer coating layers may optionally be placed on
the sheet prior to separation of the individual sources. The
sources may also be coated individually following separation, such
as following incorporation onto a balloon catheter.
[0109] The masking technique is described above in terms of making
sources having a border of substrate surrounding an active area
comprising a tie layer and isotope layer coating the substrate.
Although described as such, the masking technique or variations
thereof as would be apparent to one skilled in the art, may be used
for other purposes in making the sources of the present invention,
such as placing a coating layer on selected portions of the source,
and placing different tie layers on different portions of the
source.
[0110] Referring to FIG. 2, there is disclosed a radiation delivery
catheter 18 incorporating the thin film source 10 in accordance
with one aspect of the present invention. Although the description
below is primarily directed to the radiation aspect of the
invention, catheters embodying additional features known in the
vascular dilatation art, such as carrying implantable stents, drug
delivery, perfusion and dilatation features, or any combination of
these features, can be used in combination with the balloon of the
present invention as will be readily apparent to one of skill in
the art in view of the disclosure herein.
[0111] The catheter 18 generally comprises an elongate tubular body
19 extending between a proximal control end 20 and a distal
functional end 21. The length of the tubular body 19 depends upon
the desired application. For example, lengths in the area of about
130 cm to about 150 cm are typical for use in radiation delivery by
way of a femoral access following or during percutaneous
transluminal coronary angioplasty.
[0112] The tubular body 19 may be produced in accordance with any
of a variety of known techniques for manufacturing balloon-tipped
catheter bodies, such as by extrusion of appropriate biocompatible
plastic materials. Alternatively, at least a portion or all of the
length of tubular body 19 may comprise a spring coil, solid walled
hypodermic needle tubing, or braided reinforced wall, as is
understood in the catheter and guide wire arts.
[0113] In general, tubular body 19, in accordance. with the present
invention, is provided with a generally circular exterior
cross-sectional configuration having an external diameter with the
range of from about 0.02 inches to about 0.065 inches. In
accordance with one preferred embodiment of the invention, the
tubular body 19 has an external diameter of about 0.042 inches (3.2
F) throughout most of its length for use in coronary applications.
Alternatively, generally triangular or oval cross-sectional
configurations can also be used, as well as other noncircular
configurations, depending upon the number of lumens extending
through the catheter, the method of manufacture and the intended
use.
[0114] In a catheter intended for peripheral vascular applications,
the tubular body 19 will typically have an outside diameter within
the range of from about 0.039 inches to about 0.085 inches.
Diameters outside of the preferred ranges may also be used,
provided that the functional consequences of the diameter are
acceptable for the intended purpose of the catheter. For example,
the lower limit of the diameter for tubular body 19 in a given
application will be a function of the number of fluid or other
functional lumens, support structures and the like contained in the
catheter, and the desired structural integrity.
[0115] In general, the dimensions of the catheter shaft and balloon
can be optimized by persons of skill in the art in view of the
present disclosure to suit any of a wide variety of applications.
For example, the balloon of the present invention can be used to
deliver radiation to large and small arteries and veins, as well as
other lumens, potential spaces, hollow organs and surgically
created pathways. The present inventor contemplates radiation
delivery to the esophagus, trachea, urethra, ureters, fallopian
tubes, intestines, colon, and any other location accessible by
catheter which may benefit from radiation delivery. This includes
surgically created lumens such as, for example, transjugular
intrahepatic portosystemic shunts and others which will be
recognized by those of skill in the art. Thus, although the present
invention will be described herein primarily in terms of coronary
artery applications, it is understood that this is for illustrative
purposes only, and the present invention has much broader
applicability in the field of radiation delivery.
[0116] Tubular body 19 must have sufficient structural integrity
(e.g., "pushability") to permit the catheter to be advanced to a
treatment site such as distal arterial locations without buckling
or undesirable bending of the tubular body 19. Larger diameters
generally have sufficient internal flow properties and structural
integrity, but reduce perfusion in the artery in which the catheter
is placed. Larger diameter catheter bodies also tend to exhibit
reduced flexibility, which can be disadvantageous in applications
requiring placement of the distal end of the catheter in a remote
vascular location. In addition, lesions requiring treatment are
sometimes located in particularly small diameter arteries,
necessitating the lowest possible profile.
[0117] As illustrated schematically in FIG. 2, the distal end 21 of
catheter 18 is provided with at least one inflatable balloon 22.
The proximal end 20 of catheter 18 is provided with a manifold 23
which may have one or more access ports, as is known in the art.
Generally, manifold 23 is provided with a guide wire port 24 in an
over the wire embodiment and a balloon inflation port 25.
Additional access ports are provided as needed, depending upon the
functional capabilities of the catheter 18.
[0118] The balloon 22 can also be mounted on a rapid exchange type
catheter, in which the proximal guidewire port 24 would not appear
on the manifold 23 as is understood in the art. In a rapid exchange
embodiment, the proximal guidewire access port 24 is positioned
along the length of the tubular body 19, such as between about 1
and about 20 cm from the distal end of the catheter.
[0119] Referring to the embodiment of the balloon illustrated in
FIG. 2, an enlarged zone 32 is positioned between a proximal
reference zone 28 and a distal reference zone 30. The relative
lengths of each of the three zones may vary considerably depending
upon the intended use of the balloon. In general, suitable
dimensions of the balloon, both in terms of diameters and lengths,
as well as other catheter dimensions, are disclosed in U.S. Pat.
No. 5,470,313 to Crocker, et al., entitled Variable Diameter
Balloon Dilatation Catheter, the disclosure of which is
incorporated in its entirety herein by reference.
[0120] In one particular substantially noncompliant balloon
application, the central zone 32 has an axial length of about 25
mm, and each of the proximal zone 28 and distal zone 30 have an
axial length of about 5 mm. At an inflation pressure of about 8
atmospheres, the proximal zone 28 has an outside diameter of about
3 mm, and the central zone 32 has an outside diameter of about 3.4
mm. The same balloon at 18 atmospheres inflation pressure has an
outside diameter of about 3.1 mm in the proximal zone 28 and an
outside diameter of about 3.5 mm in the central zone 32. That
particular balloon was constructed from PET, having a wall
thickness of about 0.0006 to about 0.0008 inches.
[0121] In accordance with an alternative embodiment of the balloon
of the present invention, illustrated in FIG. 3, the balloon 26 has
a generally cylindrical inflated profile throughout its axial
working length such as with conventional PTCA balloons. Either the
stepped balloon of FIG. 2 or the cylindrical balloon of FIG. 3 can
be readily provided with the radiation source 10 discussed below in
accordance with the present invention.
[0122] The overall dimensions of any particular balloon 22 or 26
will be governed by the intended use, as will be well understood to
those of ordinary skill in the art. For example, balloons can be
inflatable to a diameter of anywhere within the range of from about
1.5 mm to about 10 mm. For coronary vascular applications, the
central zone 32 or overall balloon 26 will normally be inflatable
to a diameter within the range of from about 1.5 mm to about 4 mm,
with balloons available at about every 0.25 mm increment in
between.
[0123] The proximal zone 28 and distal zone 30 are generally
inflatable to a diameter within the range of from about 1.25 mm to
about 9.5 mm. For coronary vascular applications, the proximal and
distal zones 28, 30 are preferably inflatable to a diameter within
the range of from about 1.25 mm to about 3.5 mnm.
[0124] The axial length of the central section 32 can be varied
considerably, depending upon the desired radiation delivery length
as will become apparent. For example, the axial length of the
central section 32 may be anywhere within the range of from about
0.5 cm to about 5.0 cm or longer. For coronary vascular
applications, the axial length of the central section 32 will
normally be within the range of from about 0.5 cm to about 2.0 cm,
if the balloon is designed to deliver radiation as well as
simultaneously perform conventional PTCA. In a radiation delivery
balloon which is not intended to perform PTCA, the axial length of
the central zone 32 may exceed the typical length of the lesion,
and, in coronary vascular applications, the axial length may be
within the range of from about 0.5 cm to about 5 cm or longer.
[0125] The axial length of the proximal zone 28 and distal zone 30
may also be varied considerably, depending upon the desired
performance characteristics. In general, axial lengths of the
cylindrical portion of the proximal zone 28 and distal zone 30 of
at least about 3 mm appear useful.
[0126] Referring to FIG. 4, there is disclosed a radioactive
balloon in accordance with the present invention, configured as in
FIG. 3. The balloon 26 comprises a radiation delivery zone 32. The
radiation zone 32 comprises an inner balloon wall 36 surrounded by
the radiation source 10. Preferably, the radiation source 10 is
surrounded by an outer sleeve 38 (sometimes referred to herein as
an encapsulant) several embodiments of which are described in
additional detail in connection with FIGS. 6 through 9A. In the
illustrated embodiment, the radiation source 10 is entrapped
between the outer sleeve 38 and balloon wall 36, and the outer
sleeve 38 is adhered to the balloon wall 36 or catheter shaft such
as through the use of thermal bonding or an adhesive. Suitable
adhesives include medical grade UV curable and urethane adhesives
known in the art. Any of a wide variety of alternate techniques
known to those of skill in the art can also be utilized for
securing an outer sleeve 38 to the balloon, sometimes referred to
as fusing, heat shrinking, spot welding, and the like.
[0127] The sleeve 38 may extend only slightly longer in the axial
direction than the axial length of the radiation source 10. The
outer sleeve 38 can alternatively extend the entire length of the
balloon, or longer, such that it is necked down at the proximal end
of the balloon to the catheter shaft and similarly necked down at
the distal end of the balloon to the catheter shaft. One outer
sleeve 38 comprises 0.0003 inch wall thickness PET tube. Other
materials could be polyolefins, nylons, or urethanes, or compounds
thereof, and are discussed in detail below.
[0128] The balloon 26 is mounted on a tubular body 19, which
preferably comprises at least a guidewire lumen 40 and an inflation
lumen 42. In the illustrated embodiment, the two lumens 40 and 42
are illustrated in a concentric relationship as is known in the
art. Alternatively, the two lumens 40 and 42 can be formed in a
side-by-side geometry, (FIG. 5) such as through the use of
conventional extrusion techniques.
[0129] Referring to FIG. 5, there is illustrated a perfusion
embodiment of the present invention. The radiation delivery
catheter with perfusion 50 comprises an elongate flexible tubular
body 52 having a distal balloon 54 thereon. In this embodiment the
tubular body 52 is preferably configured in a side by side
orientation, as is well understood in the catheter art. Thus, the
tubular body 52 comprises at least an inflation lumen 56 and a
guidewire lumen 58. Additional lumen may be provided, depending
upon the desired functionality of the catheter.
[0130] The guidewire lumen 58 extends from the proximal guidewire
access port (not illustrated) to the distal guidewire access port
66 as is well known in the art. The proximal guidewire access port
may either be on the side wall of the catheter as has been
discussed in a rapid exchange embodiment, or at the proximal
manifold in an over the wire embodiment. A perfusion section 60 of
the guidewire lumen 58 extends through the balloon 54, and places a
plurality of proximal ports 62 in fluid communication with a
plurality of distal ports 64. In this manner, the guidewire (not
illustrated) can be proximally retracted within the guidewire lumen
58 to a position proximal to the proximal ports 62 once the balloon
54 has been positioned at the treatment site. The balloon 54 can be
inflated by injecting inflation media through the inflation lumen
56, and the perfusion section 60 permits blood to perfuse across
the balloon by way of proximal ports 62 and distal ports 64.
[0131] As discussed elsewhere herein, the balloon 54 is provided
with a thin film source 10 which may comprise one or more layers of
radioactive thin film source. The thin film source 10 may be
adhered to or otherwise carried by the inside surface or outside
surface of the balloon wall and may be further entrapped within an
outer tubular layer 70 as illustrated. Alternatively, the thin film
source 10 is adhered to or carried by the inside surface or outside
surface of the balloon wall without an outer layer 70. Tubular
layer 70 preferably is positioned concentrically about the thin
film source 10 and heated or otherwise bonded to attach the layer
70 securely to the balloon. The axial length of the tubular layer
70 on, for example, a 3 cm long balloon, may be anywhere within the
range of from about 15 mm to about 150 mm measured along the axis
of the catheter.
[0132] In any of the foregoing embodiments, the isotope layer 16
may comprise either a homogenous isotope population, or a blend of
two or more isotopes. For example, a blend may be desirable to
achieve a desired combination of half life, activity, penetration
or other characteristics in the finished product. Two or three or
four or five or more different isotopes may be dispersed uniformly
throughout the isotope layer 16, or may be concentrated in
different zones along the isotope layer, depending upon the desired
activity profile in the finished thin film radiation source.
[0133] In accordance with another aspect of the present invention,
the thin film radiation source is applied to a delivery structure
such as a balloon in a manner that permits radially asymmetric
delivery. This may be desirable for treating only a selected site
within the circumference of the arterial wall, such as in the case
of an eccentric stenosis.
[0134] In this embodiment radioisotope is provided only along a
portion of the circumference of the delivery structure such as a
balloon. The radioisotope zone may comprise anywhere in the range
of from about 10% to about 70% of the total circumference of the
balloon, and, in one embodiment, is within the range of from about
30% to about 50% of the total circumference of the balloon. This
may be accomplished in any a variety of manners, such as masking
the thin film prior to application of the isotope, applying a
blocking layer to block release of radiation from portions of the
circumference, and the like as will be apparent to those of skill
in the art in view of the disclosure herein. In one embodiment, a
thin film sheet is prepared as has been described herein, except
that radioisotope is only adhered to the thin film substrate in a
series of discrete zones which are separated by nonradioactive
portions of substrate. The radioactive zones can be spaced apart
along the substrate sheet to correspond to the circumference of the
delivery balloon, so that when the radioactive thin film is wrapped
around the balloon, the radioactive zones align with each other to
provide a radioactive stack on only a predetermined circumferential
portion of the balloon.
[0135] Thus, at least a first and a second zone can be provided on
the thin film source in accordance with the present invention. In
one embodiment the first zone is radioactive and the second zone is
not radioactive. In another embodiment, the first zone has a first
radioactive activity and the second zone has a second, lesser
radioactive activity. Alternatively, other characteristics of the
radioactive source can be varied between the first zone and the
second zone, depending upon the desired delivery-performance.
[0136] In accordance with another aspect of the present invention,
the balloon catheter may be constructed which allows for delivery
of radiation to differing sizes of lumens. In such a device, the
balloon preferably comprises a compliant plastic material. The
substrate for the source may be either the balloon itself or
another thin film of a compliant or elastomeric plastic. As the
pressure inside the compliant balloon is increased, the outer
diameter of the balloon will increase. Thus, a single balloon
catheter may be used to treat different size lumens by simply
varying the pressure and hence the inflation diameter of the
balloon.
[0137] The increase in diameter will result in a decrease in
density of isotope atoms per surface area. By adjusting the dwell
time, the predetermined dosage can be delivered. For example, a 20
mm balloon having an outer diameter of 2.0 mm and 10.sup.17 atoms
of isotope on the surface will result in a density of
7.96.times.10.sup.14 atoms/mm.sup.2. If this balloon were
pressurized to increase to a 2.5 mm diameter, the density would
decrease to 6.34.times.10.sup.14 atoms/mm.sup.2. This is a 20%
decrease, resulting in a need for a 20% increase in dwell time to
achieve an equivalent dose. There may also be a slight decrease in
balloon length with increased diameter of inflation. This change,
however, is dependent on the level of compliance and may be
negligible in most cases, but is easily remedied by careful
selection of balloon size.
[0138] Details of an outer layer configuration for enhancing the
seal for containing the radioactive source are illustrated in FIGS.
6 and 7. The present inventors have determined that one reason for
failure of certain radiation delivery balloon designs to adequately
contain the isotope is due to the separation of the cover sheet
from the balloon or catheter shaft at the axial ends of the
balloon. The repeated inflation and deflation which is common to
dilatation procedures and/or regulatory approval protocols can
cause a separation at the bond between the cover sheet and the
balloon. The failure of the cover and the balloon to hold together
is typically due to materials disclosed in the prior art for use as
balloon and cover sheet elements, such as polyethylene, nylon and
polyethylene terephthalate. These materials, as previously
disclosed, provide a mechanical seal rather than a chemical or
fused seal to the catheter shaft and underlying balloon. Thus, heat
and adhesives are utilized to create mechanical bonds which lack
sufficient stability when they are worked in the manner often
required during balloon inflation and deflation.
[0139] In accordance with the present invention, the encapsulant
cover layer and the balloon materials are fused together at least
on either side of the source. A "fused" attachment as that term is
used herein is readily distinguishable from purely mechanical
attachment (e.g. heat shrink or adhesive bonding), wherein the
layers may become delaminated or otherwise separated as a
consequence of excessive pressure or inflation cycling. In a "fuse"
type of attachment, the two or more starting layers cannot be
peeled apart without tearing through and the line between the
original layers is oftentimes partially or completely obscured. A
fuse as contemplated in the context of the present invention thus
has a significantly reduced risk of separation or delamination
during use, and may therefore be worked by inflation and deflation
without separation. An outer sleeve such as sleeve 38 or other
encapsulant disclosed herein is at least fused to an underlying
surface on each of the proximal and distal ends of the source to
encapsulate the source in a cylindrical envelope carried by the
balloon. In a preferred embodiment, the fused seal extends
throughout the entire axial length of the source such that fluid
will not be drawn between layers enveloping the source should any
such layers be punctured and then inflated and deflated. The fused
bond may be formed between at least some of the layers, such as
between the outer cover and the balloon, to provide a sealed
encapsulated source on the balloon.
[0140] In accordance with one aspect of the invention, a
polyethylene tube is first extruded and then coextruded with an
ethyl methacrylate (EMA) layer over the PE to form a PE balloon
with an EMA bonding layer, or the two materials are coextruded
together. The extrusion process, performed at about 300-400.degree.
F., leads to a complete attachment between the EMA and PE that can
undergo the balloon forming process without forming gaps or voids
in the EMA layer. The cover tube is formed in the same way as the
balloon, only the EMA is the first (inner) layer and the PE is the
second (outer) coextruded layer.
[0141] The balloon is thereafter attached to the catheter shaft
according to methods well known to catheter manufacturers and
discussed elsewhere herein. After the source and cover layer are
assembled onto the balloon, the entire assembly can be heat fused.
At this point, the EMA layer of the PE balloon directly opposes the
EMA layer on the PE encapsulant layer proximally and distally of
the source, forming a PE-EMA-EMA-PE stack. In embodiments where the
source also comprises EMA or a material with similar melting point
characteristics, the EMA layers of the balloon and encapsulant fuse
together along the length of the source as well, forming an EMA
fuse layer 72 with the isotope suspended therein, as illustrated in
FIG. 8. Since the EMA melts at a much lower temperature than the
crosslinked PE, the cover can be heat fused in a mold under
moderate temperatures (200-300.degree. F.) and pressures (1-4 ATM)
without damaging the balloon. An annular fused seal is thus formed
at least both proximally and distally of the source to fully
encapsulate the source within the wall of the multilayer balloon.
In the case of a source having compatible fusing surfaces, the seal
continues throughout the source length increasing the strength of
the body of the balloon from about 120 psi to about 210 psi.
EXAMPLE 1
[0142] One set of ten samples constructed with a
PE-EMA-source-EMA-PE stack as described above but with an annular
source layer which is not fusable with the EMA was placed in an
experimental fixture capable of repeatedly inflating and deflating
the balloon. The PE was 0.00052" thick and the EMA was 0.000052"
thick. Each balloon/source was 2.5 nmm in diameter and 22 mm in
length. The balloon was submerged within a test tube containing a
methylene blue dye (0.5%) in order to detect separation between the
cover and balloon layers. The balloons were inflated to 3 ATM and
deflated after 5 seconds for over 250 cycles without detecting any
leaks. A second set of ten samples constructed with gaps at the
balloon necks using misformed encapsulant and little or no heat
fusion in the EMA layer were similarly tested and each sample
leaked after 10-20 cycles.
EXAMPLE 2
[0143] A set of ten samples constructed as described above
(PE-EMA-source-EMA-PE stack) with source activities in the 1 mCi
range were constructed and tested as above. The PE-EMA-EMA-PE stack
extended proximally of the source for about 5 mm and distally of
the source for about 5 mm. The devices were first wipe tested to
establish that no removable surface activity was present on the
samples. The test tubes containing one balloon each were removed
from the fixture every twenty cycles and surveyed with a Geiger
counter for removed activity. No removed activity was found after
200 cycles.
[0144] Thus, one embodiment of the sealed source configuration in
accordance with the present invention is schematically illustrated
at FIGS. 6 and 7. In these figures, the bonding surfaces are shown
for clarity as discrete layers 36b and 38b. In preferred
embodiments, however, the layers 36b and 38b would be fused
together on at least a portion of their lengths and preferably
throughout the length of the source such that the interface between
the layers would be partially or fully obscured.
[0145] In the illustrated embodiment, a radioactive source 10 is
encapsulated between a balloon 36 and an outer encapsulant 38 as
has been described. In the illustrated embodiment, however, the
balloon comprises an inner support layer 36a and an outer bonding
surface 36b. The encapsulant 38 comprises an inner bonding surface
38b and an outer support layer 38a. As illustrated, bonding surface
36b from the balloon is in contact with bonding surface 38b both
proximally and distally of the radiation source 10. The source
includes an isotope, and may comprise a single layer or a
multilayer stack as is discussed elsewhere herein. This structure
at least enables a fused annular seal beyond the axial ends of the
source. A further embodiment provides a seal completely through the
source zone. This can be accomplished by forming the source out of
appropriate materials.
[0146] In one polyethylene embodiment, the outer encapsulant
support layer 38a comprises polyethylene and the bonding layer 38b
comprises EMA. The inner balloon support layer 36a comprises
polyethylene and the balloon bonding layer 36b comprises EMA. This
construction permits a fused seal between the encapsulant and the
balloon, as has been discussed, to prevent leakage of
radioisotope.
[0147] A schematic diagram showing assembly of a sealed source is
illustrated in FIG. 8. An extruded tube 44 comprised of an outer
bonding layer 36b, preferably of EMA over an inner structural layer
36a preferably of PE, which forms the balloon, has the radiation
source layer 10 placed or formed thereon. The coextruded cover tube
46, comprised of an inner bonding layer 38b, preferably of EMA, and
an outer structural layer 38a, preferably of polyethylene, is
placed over the tube 44. Following application of heat and at least
a slight pressure to ensure contact between the bonding layers, the
sealed source 48 is formed, in which the two bonding EMA layers 36b
and 38b have fused to form a single layer 72 with the isotope
suspended therein.
[0148] In its simplest form, the source comprises an isotope
attached to or carried on a bonding layer. Due to the physical
properties of most suitable bonding materials (low softening or
melt point), the source preferably also includes at least one layer
having greater structural integrity than the bonding layer. This
construction can be accomplished in three portions or layers: two
bonding layers (B) with an isotope-containing layer (I) between
them, or (B)-(I)-(B) in shorthand. It may be desirable to add an
additional support layer (S) to one or both bonding layers to
provide greater support to the source for ease of processing or
use, if the assembly is not otherwise sufficiently supportive for a
given application. Such sources would be, in shorthand,
(SB)-(I)-(B), (B)-(I)-(BS), or (SB)-(I)-(BS). The bonding layers
all comprise fusable and preferably a common material.
[0149] The materials which form the structural layers and bonding
layers preferably have one or more characteristics which aid the
layers performing their functions within the structure. The bonding
layer and support layer materials preferably have a strong bond
between them. A strong bond may be the result of chemical or
mechanical attachment, or some combination of the two, and it may
be achieved by coextrusion or coinjection of the materials. It may
also be achieved by casting one material over the other or
injection molding one material over the other. Attachment of the
materials may also be enhanced if the bonding and support layers
have at least one material in common (e.g. a small amount of the
support layer material is incorporated into the material which
forms the bonding layer). Another preferred characteristic is for
the melting or softening points of the bonding layer and support
layer to differ, with the melting or softening point of the bonding
layer being the lower of the two. This allows for the structure or
shape of the source to be maintained by the support layer(s) when
the bonding layers are fused by the application of heat. In some
embodiments, it is preferred that the support layer material be
generally non-compliant.
[0150] In preferred embodiments, the isotope-containing layer (I)
above is a multilayer isotope-containing substructure or radiation
source which can be combined with one or more bonding layers or
bonding-support stacks (SB) and assembled into a larger structure.
For example, when the radiation delivery source is the balloon of a
balloon catheter, it may be desirable to prepare the
isotope-containing substructure portion of the source separately.
Following its preparation, the isotope-containing substructure,
preferably in a tubular form or a rolled-up sheet, is then placed
upon the balloon of a balloon catheter and then covered with a
single or multilayer encapsulant structure and heated to fuse the
bonding layers. Pressure may also be placed on the assembled stack
such as by inflation within a capture tube with heating to further
facilitate the fusing process. In another embodiment, the source
may comprise two substructures, a balloon and an encapsulant,
wherein the encapsulant substructure incorporates the
isotope-containing layer.
[0151] By using source preparation methods as described above, the
non-radioactive substructures may be prepared ahead of the time of
use and then assembled with a recently-made isotope containing
portion of the source just prior to use or shipment. Thus, one may
create separate subassemblies or substructures and assemble them
just prior to shipment or use of the catheter device. Although the
discussion which follows is in terms of a balloon catheter and a
tubular source, one skilled in the art would recognize that the
source may be used for applications other than a balloon and that
the same concepts apply to other geometries such as a sheet.
[0152] Thus, in one embodiment, the isotope-containing multilayer
substructure may simply comprise a bonding layer-isotope (BI) two
layer stack. If this substructure were assembled into a source with
a balloon and encapsulant, each of which comprise a bonding layer
and a structural layer, the source would have the following layer
structure: (SB)-(BI)-(BS). Alternatively, one can protect the
isotope-containing layer of the substructure from damage during
later processing by applying a coating layer (C) to the
isotope-containing layer and/or other exterior layer, such as is
described supra, to form sources of the type (SB)-(BIC)-(BS), and
(SB)-(CBIC)-(BS). In preferred embodiments, the coating layer is
the same material as or is heat fusable to the bonding layers.
[0153] In other embodiments, the isotope-containing substructure
further comprises a structural layer, such as to aid in formation
and processing of the source. Thus the substructure could take the
form (BSI) or (SBI), with the latter being preferred such that when
it is combined with the other portions to form the full multilayer
source, the bonding layer upon which the isotope-containing layer
sits can fuse with the bonding layer on either the balloon or the
encapsulant. In the latter structure, (SBI) it is preferred that
there be an additional bonding layer (BSBI) such that the
substructure bonding layers may fuse with bonding layers on both
the balloon and encapsulant. Substructures containing support
layers may also have an additional protective coating layer on the
isotope-containing layer, eg.. (BSIC), (CBSIC), (SBIC), (BSBIC),
and (CBSBIC).
[0154] In accordance with the present invention, one preferred
embodiment of the source is represented by the shorthand
(SB)-(CBSBIC)-(BS). A source of this type is shown in FIGS. 9. FIG.
9 is an exploded cross-section showing the source during the
assembly of the three portions: encapsulant, isotope-containing
substructure, and balloon. The upper two layer portion is the
encapsulant comprising a bonding layer 38b and a structural layer
38a. The lower two layer portion is the balloon comprising a
bonding layer 36b and a structural layer 36a. The
isotope-containing substructure or radiation source 10 initially
comprises seven layers. The core of the substructure is a three
layer stack comprising a structural layer 74a sandwiched between
two bonding layers 74b. On one bonding layer sits the isotope
containing layer, which is a two layer structure comprising a tie
layer 14 and an isotope layer 16. The isotope layer 16 preferably
comprises a metal salt or oxide with at least one isotope. The tie
layer 14 and isotope layer 16 is of the type described supra and as
such, there may not be a clear visual distinction between the
layers. The outer layers of the substructure are coating layers
17.
[0155] FIG. 9A illustrates the final configuration of the source of
the type in FIG. 9, following the application of heat, either with
or without pressure, to fuse the various bonding layers. The source
of FIG. 9A comprises two layers of fuse 72 sandwiched among the
structural layers of the balloon 36a, isotope-containing
substructure 74a, and encapsulant 38a. The upper layer of fuse 72,
between the isotope-containing substructure 74a and encapsulant 38a
support layers, is that which has the isotope embedded therein.
[0156] To aid in the formation of the complete fuse through coating
layers and isotope-containing layers, the materials which form
those layers preferably have a melting point similar to that of the
bonding materials, comprise a material common with the bonding
materials, or have some other physical or chemical property which
aids them to become part of a fuse layer 72. Alternatively, the
coating layers and/or isotope-containing layers may be porous or
comprise a plurality of apertures through which the bonding
materials may form fuses or spot welds to bind the layers
together.
[0157] Thus, using the principles described above, a wide variety
of multilayer sources encompassed within the present invention can
be prepared by combining layers, creating substructures, and fusing
bonding layers in the multilayer stacks formed.
[0158] In the above multilayer sources, the fuse between the
bonding layer adjacent to the isotope-containing layer in the
substructure and the bonding layer in either the balloon or
encapsulant may extend through the isotope-containing layer such
that the isotope-containing layer is suspended within a larger
layer of bonding material, as shown in FIG. 8. FIG. 8 depicts a
tubular structure, as would exist in a tubular source or in a
cross-section of the center portion of one embodiment of balloon
catheter incorporating a sealed source of the present invention.
Such a fully radially extending fuse may be enhanced for certain
materials if the isotope-containing layer is permeable or has gaps
therein, such that it does not create a barrier to the fusing of
the two bonding layers. This is a benefit in that even in the case
of a tear such as by calcium or a stent strut, only the edge
surface area of the tear would be exposed to the bloodstream.
[0159] In experiments, balloons having a full seal were punctured
and then inflated and deflated several times in a blue dye solution
to determine the degree of infiltration of fluid into the breach.
After several cycles of inflation and deflation, the dye solution
could be seen filling the channel formed by the needle which
created the puncture. There was, however, no separation of fused
layers adjacent to the puncture and no lateral infiltration of dye
solution between fused layers of the source, indicating that the
solution was exposed to only that small portion of the edge of the
source in the puncture channel itself. In addition, the completely
fused structure increases the surface area of fuse and decreases
the potential of a seal breach due to overhandling.
[0160] The optimal balloon bonding surface 36b and encapsulant
bonding surface 38b can be determined through routine
experimentation by those of ordinary skill in the art in view of
the disclosure herein, and depending upon the desired balloon 36a
material and encapsulant 38a material. In addition, variations can
be made on the foregoing stack depending upon the construction
materials and the desired process parameters, particularly
temperature, for a given balloon construction. In general, the
desired result is a fused or blended polymeric material along the
length of the radiation source 10, such as may be readily
accomplished through heating certain types of materials under
compression. This may be accomplished in a 4-layer stack (not
counting the source) as illustrated where the balloon material 36a
and encapsulant material 38a will not fuse as has been described
herein. Alternatively, a 2-layer stack may be used where the
balloon material 36a and the encapsulant material 38a will fuse to
form a sealed bond. A 3-layer stack such as a balloon 36a, an
encapsulant 38a, and one of 36b or 38b may be positioned
therebetween, either radially inwardly from or radially outwardly
from the radiation source 10.
[0161] The encapsulant 38 may extend any of a variety of lengths
along the balloon 26, to produce proximal and distal annular seals
of the desired length. In the illustrated embodiment, the
encapsulant 38 extends beyond the working length of the balloon by
about 5-8 mm in each of the proximal and distal directions to
maximize the total surface area of the proximal and distal seals.
The encapsulant 38 may extend proximally farther than the balloon
neck, and distally farther than the balloon neck if desired.
Encapsulant lengths of only slightly longer than the axial length
of the source 10 may also be utilized, provided the materials of
the stack provide a sufficient seal over the shortened axial
length.
[0162] The fused encapsulant layer in accordance with the present
invention can be utilized to provide a sealed source using a source
produced by any of a variety of isotope attachment techniques.
Thus, in addition to using the various binding chemistries
disclosed supra, the source layer 10 may comprise any of a variety
of alternative chemistry schemes, including chelating chemistry
reactions, ion implantation, and others as will be understood by
those of skill in the art.
[0163] In accordance with the method of the present invention, a
balloon catheter such as any described above is percutaneously
inserted and transluminally advanced through a patient's
vasculature, to the treatment site. At the treatment site, the
balloon is expanded to position the radioactive delivery layer
against the vessel wall. The balloon remains expanded for a
sufficient radiation delivery time, and is thereafter deflated and
withdrawn from the patient. The balloon may be introduced through
an introduction sheath, which can be proximally withdrawn to expose
the balloon once the balloon has been positioned at the treatment
site.
[0164] If delivery times greatly in excess of 3-4 minutes are
clinically desirable, the catheter 18 may be provided with a
perfusion conduit such as that illustrated in FIG. 5. Any of a
variety of perfusion structures can be utilized, such as any of
those disclosed in U.S. Pat. Nos. 5,344,402 to Crocker entitled Low
Profile Perfusion Catheter or U.S. Pat. No. 5,421,826 to Crocker et
al. entitled Drug Delivery and Dilatation Catheter Having a
Reinforced Perfusion Lumen, the disclosure of each of which is
incorporated in its entirety herein by reference.
[0165] In accordance with another aspect of the method of the
present invention, the radiation delivery and balloon dilatation
catheter of the present invention is utilized to simultaneously
dilate a stenosis in a vessel and deliver a treating dose of
radiation. The catheter is percutaneously introduced and
transluminally advanced through the arterial system to reach a
stenosis. The balloon is positioned within the stenosis, and
inflated to expand the stenosis as is known in the art. During the
expansion step, the balloon is delivering a treatment dose of
radiation to the vessel wall. The balloon may then be left in
position in the inflated profile optionally with perfusion for a
sufficient period of time to deliver the desired dose of radiation.
The balloon is thereafter deflated, and the catheter is withdrawn
from the treatment site.
[0166] In accordance with a further aspect of the method of the
present invention, the radiation delivery catheter of the present
invention may be utilized to simultaneously implant a stent while
delivering a dose of radiation. In accordance with this aspect of
the method, a stent is positioned on the radiation delivery balloon
prior to percutaneous insertion within the patient. The balloon
carrying a stent thereon is thereafter percutaneously inserted and
transluminally advanced through the patient's vasculature to the
treatment site. The balloon is expanded at the treatment site to
expand the stent, while simultaneously delivering a dose of
radiation. The balloon is thereafter deflated, and withdrawn from
the patient, leaving the expanded stent in position at the
site.
[0167] In accordance with another aspect of the present invention,
there is provided a method of treating a previously implanted stent
or graft with exposure to a dose of radiation. The method comprises
the steps of identifying a previously implanted stent or graft
within a body lumen. A radiation delivery catheter of the type
described elsewhere herein is positioned within the stent or graft,
and the balloon is inflated to position the radioactive source
against or near the interior wall of the stent or graft. The
balloon may either be inflated to a sufficient pressure to further
dilate the stent or graft, or inflated sufficiently to position the
radiation source against the interior wall of the stent or graft
without additional stent or graft expansion or sizing. Following
delivery of a dose of radiation, the balloon is deflated and
removed from the patient.
[0168] Any of the foregoing methods may be accomplished either with
or without the perfusion capability disclosed elsewhere herein. In
addition, any of the foregoing methods may be accomplished through
the use of an over the wire embodiment of the invention or a rapid
exchange embodiment of the invention as has been disclosed
elsewhere herein.
[0169] Thus in accordance with the present invention, there is
provided a catheter having a radiation delivery layer on the
balloon, which permits a relatively low energy thin film a source
to be positioned directly against, or within about 0.001 inches and
preferably no more than about 0.003 inches from the vascular wall,
depending upon the thickness of any outer sleeve 38 or 70 or other
coating. In addition, the present configuration expels
substantially all blood or other fluids from between the radiation
source and the vessel wall, throughout the entire interior
circumference of the vessel for the axial length of the balloon. As
a consequence, the radiation is not required to penetrate multiple
structures as well as blood within the vessel in order to reach the
vessel wall. In addition, radiation delivery is essentially uniform
throughout the entire circumference of the vessel at the delivery
site.
[0170] The configuration of the balloon of the present invention is
such that the radiation delivery layer does not need to be elastic
and can simply be folded with the balloon material into the
reduced, insertion profile. Higher radiation dosages than those
specifically described herein can be readily achieved, such as
through the use of longer dose times and/or higher activity
isotopes and/or higher density of the isotope layer and/or more
layers of the thin film source.
[0171] Although the present invention has been described in terms
of certain preferred embodiments, other embodiments of the
invention will become apparent to those of skill in the art in view
of the disclosure herein. Accordingly, the scope of the present
invention is not intended to be limited by the foregoing, but
rather by reference to the attached claims.
* * * * *