U.S. patent application number 11/635854 was filed with the patent office on 2007-04-26 for medical assembly with transducer for local delivery of a therapeutic substance and method of using same.
This patent application is currently assigned to Advanced Cardiovascular Systems, Inc.. Invention is credited to Brandon Gosiengfiao, Jeffrey A. Steward.
Application Number | 20070093745 11/635854 |
Document ID | / |
Family ID | 37663588 |
Filed Date | 2007-04-26 |
United States Patent
Application |
20070093745 |
Kind Code |
A1 |
Steward; Jeffrey A. ; et
al. |
April 26, 2007 |
Medical assembly with transducer for local delivery of a
therapeutic substance and method of using same
Abstract
A medical Assembly is used to delivery a therapeutic substance
to a treatment area. The medical assembly comprises a catheter
having a distal end and a proximal end, a transducer supported by
at least a portion of the distal end of the catheter assembly, and
a delivery lumen mounted on the catheter for delivery of a
therapeutic substance. Support for the transducer is provided at a
preselected number of anchoring points, wherein an inner surface of
the transducer is positioned at a preselected distance from an
outer surface of the catheter. The preselected distance defines a
gap that is occupied by a low density material such as a gas which
reflects acoustic pressure waves directed toward the gap by a
transducer when a voltage is applied to the transducer. The
reflected pressure wave increases the energy in the system,
enhancing transport of therapeutic substances from the delivery
lumen to the surrounding tissues and/or cells to be treated. The
medical assembly may optionally be used in conjunction with both
macroporous and microporous balloons. The medical assembly may
optionally be modified so that a plurality of transducers are used,
wherein the distal end of a transducer is positioned at a
preselected distance from the proximal end of an adjacent
transducer.
Inventors: |
Steward; Jeffrey A.; (San
Jose, CA) ; Gosiengfiao; Brandon; (Temecula,
CA) |
Correspondence
Address: |
SQUIRE, SANDERS & DEMPSEY LLP
1 MARITIME PLAZA
SUITE 300
SAN FRANCISCO
CA
94111
US
|
Assignee: |
Advanced Cardiovascular Systems,
Inc.
|
Family ID: |
37663588 |
Appl. No.: |
11/635854 |
Filed: |
December 8, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09475548 |
Dec 30, 1999 |
7166098 |
|
|
11635854 |
Dec 8, 2006 |
|
|
|
Current U.S.
Class: |
604/22 ;
604/96.01 |
Current CPC
Class: |
A61M 2025/1086 20130101;
A61M 25/104 20130101; A61M 2025/0057 20130101 |
Class at
Publication: |
604/022 ;
604/096.01 |
International
Class: |
A61B 17/20 20060101
A61B017/20 |
Claims
1. A medical assembly for local delivery of a therapeutic substance
to an internal body tissue target area comprising: (a) a catheter
having a distal end and a proximal end; (b) a delivery lumen on the
catheter, the lumen extending from the distal end of the catheter
to the proximal end of the catheter for the delivery of a
therapeutic substance therethrough; (c) a first transducer
supported at the distal end of the catheter, the first transducer
being supported by the catheter distal end at a preselected number
of anchoring points, wherein an inner surface of the transducer is
positioned at a controlled and preselected distance from an outer
surface of the catheter, wherein the distance defines a gap between
the outer surface of the catheter and the inner surface of the
transducer; and (d) a balloon incorporated at said distal end of
the catheter, disposed distally from said transducer, said balloon
being substantially impermeable to said therapeutic substance.
2. The medical assembly of claim 1, wherein the gap is occupied by
a low density material.
3. The medical assembly of claim 2, wherein the low density
material is selected from the group consisting of ambient air,
oxygen, nitrogen, helium, open-cell polymer foam, closed-cell
polymer foam and mixtures thereof.
4. The medical assembly of claim 1, wherein the transducer
comprises a hollow tubular shaped body, and wherein the catheter is
extended through the hollow body.
5. The medical assembly of claim 1, wherein said transducer is
tubular.
6. The medical assembly of claim 1, wherein the therapeutic
substance is selected from a group consisting of antineoplastic,
antiinflammatory, antiplatelet, anticoagulant, fibrinolytic,
thrombin inhibitor, antimitotic, and antiproliferative substances
and mixtures thereof.
7. The medical assembly of claim 1, wherein the balloon comprises
latex.
8. The medical assembly of claim 1, wherein the balloon is secured
to said distal end of the catheter by balloon seal members coupled
to the distal end of the catheter.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This is a divisional application of U.S. Ser. No.
09/475,548, which was filed on Dec. 30, 1999.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates generally to an apparatus for
and method of delivery of therapeutic substances. More
specifically, the invention is directed to a medical assembly
including a catheter having a transducer, which provides the
driving force for transport of therapeutic substances into a tissue
target area when an electrical signal with appropriate
characteristics is applied to the transducer. A method of using the
medical assembly is also described.
[0004] 2. Description of the Related Art
[0005] Percutaneous transluminal coronary angioplasty (PTCA) is a
procedure for treating heart disease. A catheter assembly having a
balloon portion is introduced into the cardiovascular system of a
patient via the brachial or femoral artery. The catheter assembly
is advanced through the coronary vasculature until the balloon
portion is positioned across the occlusive lesion. Once in position
across the lesion, the balloon is inflated to a predetermined size
to radically compress the atherosclerotic plaque of the lesion
against the inner wall of the artery to dilate the arterial lumen.
The balloon is then deflated to a smaller profile to allow the
catheter to be withdrawn from the patient's vasculature.
[0006] In treating the damaged vascular tissue and to deter
thrombosis and restenosis, therapeutic substances are commonly
administered systemically. For example, anticoagulants,
antiplatelets and cytostatic agents are commonly used to prevent
thrombosis of the coronary lumen, to inhibit development of
restenosis, and to reduce post-angioplasty proliferation of the
vascular tissue, respectively.
[0007] Systemic administration of such therapeutic substances in
sufficient amounts to supply an efficacious concentration to the
local treatment site often produces adverse or toxic side effects
for the patient. Accordingly, local delivery is a preferred method
of treatment since smaller total levels of medication are
administered in comparison to systemic dosages, but the medication
is concentrated at a specific treatment site. Local delivery thus
produces fewer side effects and achieves more effective
results.
[0008] However, even with most local drug delivery devices used in
conjunction with PTCA, a large majority of the drug does not go
into the artery itself, but is flushed downstream and away from the
target treatment area. Therefore, improvements in the efficiency of
delivery of therapeutic substances into coronary arteries continue
to be sought.
[0009] Phonophoresis, also referred to as sonophoresis, is a
transport mechanism that uses ultrasonic or high frequency sound
waves to drive an agent into the tissues of the passageway and, if
desired, to increase cellular uptake. These sound waves may be
produced by, for example, a transducer. Phonophoresis has several
advantages over other drug delivery techniques, such as porous
balloons and iontophoresis, including the ability to achieve
greater penetration into the internal body tissue, and the capacity
of not being limited to ionic charged forms of the agent. U.S. Pat.
No. 5,800,392 to Racchini is an example illustrating the use of
phonophoresis for the local delivery of a therapeutic substance or
substances.
[0010] Phonophoresis is also advantageous because it increases
tissue temperature, tissue permeability (i.e., permeability of the
extracellular matrix), capillary permeability, and cellular
permeability. These factors enhance intra-tissue transport of an
agent, and cause vasodilation/relaxation, which may be beneficial
in vascular applications of the present invention.
[0011] FIG. 1 illustrates a common commercial design of a
phonophoresis device 2, which includes a transducer 4 mounted on a
lumen 6 of a catheter 8. Transducer 4 may be disposed within a
balloon 10. A disadvantage associated with this design includes the
absorption of ultrasonic sound waves by lumen 6 upon which
transducer 4 is mounted, thus reducing the total energy available
for transporting therapeutic substances. To increase the
effectiveness of the performance of the transducer, the intensity
of the operating power of the transducer has to be increased.
However, higher intensity operating power generates greater heat
which can irreparably damage the tissues which are being treated.
Accordingly, there is a constant tradeoff between increasing the
performance of transducer 4 and maintaining the heat at a
temperature at which tissues cannot be damaged. Additionally,
transducer 4 is made from an inflexible ceramic material which
significantly limits the ability of catheter 8 to flexibly navigate
and maneuver through the vasculature of the subject.
[0012] What is needed is an improved transducer design which allows
an operator to increase the intensity of the ultrasonic field
generated by the transducer, thereby increasing the diffusion rate
of therapeutic substances during phonophoresis, without excessively
increasing the production of heat. Further desirable
characteristics include, but are not limited to, increased
efficiency of the phonophoresis process, and a transducer that can
be more easily navigated through the tortuous vasculature of a
subject.
SUMMARY OF THE INVENTION
[0013] In accordance with an embodiment of the present invention, a
medical assembly comprises a catheter having a distal end and a
proximal end, a transducer supported by at least a portion of the
distal end of the catheter assembly, and a delivery lumen mounted
on the catheter. The delivery lumen extends from the distal end of
the catheter to the proximal end of the catheter for the delivery
of a therapeutic substance therethrough. Support for the transducer
is provided at a preselected number of anchoring points, wherein an
inner surface of the transducer is positioned at a preselected
distance from an outer surface of the catheter assembly. This
distance defines a gap between the outer surface of the catheter
and the inner surface of the transducer.
[0014] In another embodiment, a plurality of transducers are
supported by at least a portion of the distal end of the catheter
assembly. Each transducer has a proximal end and a distal end,
wherein the distal end of a first transducer is positioned at a
preselected distance from the proximal end of a second
transducer.
[0015] In another embodiment, a plurality of transducers is
supported by at least a portion of the distal end of the catheter
assembly at a preselected number of anchoring points, wherein an
inner surface of each transducer is positioned at a preselected
distance from an outer surface of the catheter. Each transducer has
a proximal end and a distal end, wherein the distal end of the
first transducer is positioned at a preselected distance from the
proximal end of a second transducer.
[0016] In yet another embodiment, the transducers in any of the
embodiments above can be disposed within a balloon.
[0017] In yet another embodiment, a sealing balloon can be provided
distally from both the intended treatment area and the transducers
in any of the embodiments above.
[0018] In accordance with another aspect of the invention, a method
for local delivery of a therapeutic substance to an internal body
tissue target area includes providing a catheter having a distal
end and a proximal end, a delivery lumen extending from the distal
end to the proximal end of the catheter for delivery of a
therapeutic substance therethrough, and a transducer supported by
at least a portion of the distal end of the catheter at a
preselected number of anchoring points. The inner surface of the
transducer is positioned at a preselected distance from an outer
surface of the catheter. The catheter is positioned proximate to
the internal body tissue target area, a therapeutic substance is
caused to elute from the delivery lumen at the distal end of the
catheter, and an electrical signal is transmitted to the
transducer.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] Embodiments of the present invention may be better
understood, and its numerous objects, features, and advantages made
apparent to one of ordinary skill in the art by referencing the
accompanying drawings.
[0020] FIG. 1 illustrates a common commercial design of a
phonophoresis device.
[0021] FIGS. 2A and 2B illustrate a tubular piezoelectric crystal
in accordance with one embodiment of the present invention.
[0022] FIG. 3 is a graph illustrating the relationship between
expansion and compression waves which occur when sound passes
through a liquid, and the formation, growth and rapid collapse of
gas bubbles in a liquid under acoustic pressure.
[0023] FIG. 4 illustrates an electrical signal waveform and its
associated parameters that may be used when practicing a method in
accordance with various embodiments of the present invention.
[0024] FIG. 5A is a partial cross-sectional view of one embodiment
of a catheter assembly having a transducer disposed at the distal
end of the catheter assembly, wherein an inner surface of the
transducer is positioned at a preselected distance from the outer
surface of the catheter. The transducer is disposed within a
balloon.
[0025] FIG. 5B is a partial cross-sectional view of one embodiment
of a catheter assembly, wherein a sealing balloon is positioned
distal to the transducer, wherein an inner surface of the
transducer is positioned at a preselected distance from the outer
surface of the catheter.
[0026] FIG. 6 is a cross-sectional view of one embodiment of a
catheter assembly shown in FIG. 5A, taken in the direction of the
arrows and along the plane of line 5-5 of FIG. 5A.
[0027] FIG. 7 is a partial cross-sectional view of one embodiment
of a catheter assembly having a plurality of transducers disposed
at the distal end of the catheter assembly, wherein an inner
surface of each transducer is mounted directly on the shaft of the
catheter, and wherein the distal end of a first transducer is
positioned at a preselected distance from the proximal end of the
second transducer.
[0028] FIG. 8 is a partial cross-sectional view of one embodiment
of a catheter assembly having a plurality of transducers disposed
at the distal end of the catheter assembly, wherein an inner
surface of each transducer is positioned at a preselected distance
from the outer surface of the catheter, and wherein the distal end
of each transducer is positioned at a preselected distance from the
proximal end of an adjacent transducer.
[0029] The use of the same reference numbers in different drawings
indicates similar or identical items.
DETAILED DESCRIPTION
[0030] A method for generating ultrasonic or high energy sound
waves is through the application of a signal to an ultrasonic
transducer or piezoelectric crystal, which causes a mechanical
distortion and vibration of the crystal. The mechanical strain
produced in the structure of the crystal under electric stress is
called the converse piezoelectric effect. FIG. 2A illustrates a
tubular piezoelectric crystal which can be used in phonophoresis
therapy. The piezoelectric crystal has an axial length l.sub.1, a
radius r.sub.1, and a wall thickness t.sub.1. Each dimension of the
piezoelectric crystal has an associated resonant frequency value.
Under the influence of an applied signal, the piezoelectric crystal
expands and assumes a new axial length l.sub.2, a new radius
r.sub.2, and a new wall thickness t.sub.2, as illustrated in FIG.
2B. The removal of the applied voltage causes the crystalline
structure to contract and return to the original dimensions of
l.sub.1, r.sub.1 and t.sub.1.
[0031] Vibration of the crystal can be induced by driving the
piezoelectric crystal with an oscillating signal, for example, a
signal having an amplitude of 125 to 250 volts. Thus, the crystal
converts electrical signals to mechanical motion. To optimize the
vibration of the crystal, the frequency of the oscillating signal
should be approximately equal to the mechanical resonance frequency
of the crystal, usefully equal to the resonance frequency of the
radial dimension r.sub.1.
[0032] The exact mechanism by which phonophoresis enhances
penetration of the therapeutic substance into the tissues of the
walls of a blood vessel and the cytoplasms of the cells which make
up the tissues is not completely understood. In addition to the
acoustic pressure and an increase in tissue temperature caused by
the vibration of the crystal, it is proposed that acoustic
cavitation which causes microstreaming, also plays a role in
enhancing therapeutic substance penetration. Acoustic cavitation is
dependent on factors such as the geometric structure of the
crystal, the driving signal applied to the crystal, and the medium
through which the ultrasound waves travel.
[0033] Acoustic cavitation occurs when a liquid is subjected to a
sufficiently intense sound or ultrasound, e.g., sound with
frequencies of about 20 kHz to 10 MHz. As illustrated in the upper
portion of the graph in FIG. 3, sound passing through a liquid is
composed of expansion, negative pressure waves 12 and compression,
positive pressure waves 14. Gas bubbles inherently suspended in the
fluid are pulled out of suspension by applying a negative acoustic
pressure of a sufficient magnitude. The gas bubble radius, as
illustrated by curve 16, continues to increase in size as the
magnitude of the negative acoustic pressure increases. When the
magnitude of the acoustic pressure becomes greater than zero, as
illustrated by points 18, gas bubbles collapses. The development
and collapse of gas bubbles is known as acoustic cavitation. The
collapse of bubbles causes turbulent fluid zones, a phenomenon
referred to as microstreaming. Microstreaming enhances transport of
therapeutic substances into the vascular tissue matrix and the
cells.
[0034] Evidence exists to suggest that ultrasound will cause a
therapeutic substance to physically be transported into a cell
cytoplasm under conditions where pressure alone does not transport
the drug. The high energy state associated with acoustic cavitation
may temporarily create a hole in the cell wall, allowing a
therapeutic substance to actually enter the cell. It is
contemplated by one of ordinary skill in the art that physical
penetration of an agent or a therapeutic substance into the
cytoplasm of a cell could be used to perform cell-based therapies,
such as gene therapy.
[0035] The driving signal, which is comprised of frequency,
amplitude, duty cycle, and sweep time, can be controlled to adjust
crystal driving conditions. The activated crystal generates
acoustic pressure waves that oscillate at frequencies greater than
20,000 times per second, i.e., greater than 20 kHz. Driving signal
frequencies between 20 kHz and 3 MHz are useful for delivering
therapeutic substances into the cytoplasm of the cells. Slightly
higher frequencies, e.g., between 200 kHz and 8 MHz, typically with
an upper limit of 10 MHz, are useful for penetration of therapeutic
substances into the tissues of the passageway.
[0036] Generally, electrical signals with greater amplitude create
greater vibration which enhances diffusion of the drug into the
target tissues and cells. The highest value of the amplitude that
can be achieved is limited by the physical characteristics of the
crystal. Excessive amplitudes cause crystals to fracture under the
mechanical strain of vibration. In addition, the more power that is
applied to the crystal, the more heat that is developed. Excessive
heat can irreparably damage the tissue being treated.
[0037] FIG. 4 illustrates an electrical signal waveform, and its
associated parameters, that can be applied to the crystal when
using the apparatus in accordance with various embodiments of the
present invention. Delivery of a therapeutic substance appears to
be related to maximum amplitude, not time averaged amplitude
(power). By pulsing the electrical drive signal, that is,
transmitting an electrical signal for a period of time, the time
defining the pulse width 20, followed by a quiescent period 22,
wherein there is no electrical signal, before again transmitting an
electrical signal, a high amplitude can be maintained while
providing a relatively low total power input level. The time
defining the pulse width 20, added to the quiescent period 22 is
herein called the sweep time 24. The ratio of pulse width to sweep
time is herein called the duty cycle.
[0038] FIG. 5A illustrates a medical assembly in accordance with an
embodiment of the invention. The type of catheter assembly 30 is
not of critical importance. The illustrative catheter assembly 30
includes an elongated catheter tube 36 having a guidewire/perfusion
lumen 34 and a delivery/electrical lumen 32. Guidewire/perfusion
lumen 34 is configured to receive guidewire 38 which is used to
maneuver catheter assembly 30 through a passageway 40.
[0039] In one embodiment, a transducer 42 is supported by at least
a portion of a distal portion 44 of the catheter assembly 30 at a
preselected number of anchoring points 46. Transducer 42 may be a
piezoelectric crystal or any other suitable material. For use in
diagnostic ultrasound and delivery of therapeutic substances, the
piezoelectric crystal may be formed from, for example, a lead
zirconate titanate compound. Model Nos. PZT4 and PZT8, manufactured
by Morgan Matroc, are considered to be "hard" materials, i.e., can
withstand high levels of electrical excitation and mechanical
stress, and are formed from a lead zirconate titanate compound.
Transducer 42 can be defined by a hollow tubular body having an
outer surface 48 and an opposing inner surface 50. Outer surface 48
and inner surface 50 can be coated conformally with perylene or a
similar compound. The addition of the coating to outer surface 48
both electrically insulates the positive and negative poles of the
crystal, and also isolates fluids, such as a therapeutic substance
solution, from transducer 42. Anchoring points 46 are formed from
medical grade adhesives. The selected choice of medical grade
adhesive should be mutually compatible both with the coating and
the material forming distal portion 44 of catheter assembly 30.
Anchoring points 46 should act as standoffs to separate inner
surface 50 of transducer 42 from an outer surface 52 of
guidewire/perfusion lumen 34, thereby creating a gap 54.
[0040] Gap 54 may contain any suitable low density material,
including gaseous substances such as ambient air, oxygen, nitrogen,
helium, an open-cell polymeric foam, a closed-cell polymeric foam,
and other similar polymeric materials and mixtures thereof. When an
electrical signal is applied to the crystal, the crystal radiates
in the thickness, radial, and length dimensions. Usefully, the
frequency of the ultrasound signal applied matches the resonance
frequency which optimizes radial vibration. As is best illustrated
in FIG. 6, vibration results in acoustic pressure radiating
outwardly toward a balloon 58 and a target tissue 60, and inwardly
toward gap 54. Ultrasonic acoustic pressure waves do not travel
through low density materials; they are reflected by low density
materials. Since gap 54, according to one embodiment of the present
invention, contains a low density material, the acoustic pressure
waves which radiate inwardly are reflected, rather than being
absorbed by the catheter. The reflected pressure waves then radiate
outwardly toward balloon 58 and target tissue 60, resulting in
increased energy available for the transport of therapeutic
substances. The increase in energy available for transport of
therapeutic substances is achieved without a concomitant increase
in transducer size, or increase in power supplied to the
transducer. Incorporating gap 54 into the design also permits the
use of a smaller transducer for a given desired energy level, which
results in a smaller catheter profile, enhancing maneuverability
through body passageways. In addition, more energy can be applied
to the crystal without causing the temperature of the crystal to
increase.
[0041] Referring again to FIG. 5A, an electrical lead 56 is a
coaxial cable and electrically connects transducer 42 to an
electrical power supply (not shown) via delivery/electrical lumen
32. The coaxial cable contains an inner wire for carrying the
electrical signal, and a ground wire surrounding the inner wire to
shield the inner wire from electrical noise. The coaxial cable must
be used in lieu of a twisted pair or bare wire in order to minimize
impedance loss over the length of the wire.
[0042] In one embodiment, balloon 58 is incorporated at the distal
end of the catheter, in fluid communication with
delivery/electrical lumen 32, through which a therapeutic substance
is delivered, as illustrated in FIG. 5A. Balloon 58 can be made
from a membrane having pores, and is inflated by introduction of
the therapeutic substance through delivery/electrical lumen 32. The
pressure of the therapeutic substance within balloon 58 causes
balloon 58 to dilate from a collapsed configuration to an expanded
configuration, wherein the outer surface of the balloon wall is
compressed against the inner surface of passageway 40. The pressure
inside balloon 58 is usefully not great enough to cause more than a
minimal amount of therapeutic substance to escape from balloon 58.
Vibrating transducer 42 supplies acoustic pressure to assist in
transport of the therapeutic substance through balloon 58 and into
the surrounding target tissue 60. The therapeutic substance can
then be delivered from balloon 58 to the treatment area, via
ultrasonic energy provided by the transducer 42.
[0043] Balloon 58 can be microporous, i.e., having many pores of
smaller diameter. By way of example, and not limitation, a
microporous membrane could contain 10.sup.6 pores having a diameter
ranging from about 0.3 .mu.m to about 2.5 .mu.m. Alternatively
balloon 58, can be macroporous, i.e., having fewer pores of larger
diameter. By way of example, and not limitation, a macroporous
balloon could have 100 pores with a 25 .mu.m diameter. Suitable
membrane materials include polyester, polyolefin, fluoropolymer,
and polyamide. The membrane thickness should be less than 0.005
inches, and in any event, due to the physics of ultrasound, should
be less than or equal to 1/4 of the driving ultrasound
wavelength.
[0044] Perfusion holes 62 can be incorporated on
guidewire/perfusion lumen 34, which allow blood to continue to flow
past balloon 58 which would otherwise occlude flow when balloon 58
is expanded, and simultaneously cool transducer 42. Providing
continued blood flow during treatment allows longer treatment
times.
[0045] In lieu of having a porous balloon, in an alternative
embodiment illustrated in FIG. 5B, a sealing balloon 64 can be
mounted on distal portion 44 of the catheter tube 36 and is
inflated by an inflation lumen 66, which can be exterior to
guidewire/perfusion lumen 34, to engage the walls of passageway 40.
Sealing balloon 64 can be located distal to transducer 42. Sealing
balloon 64 may be made of an impermeable expandable material, for
example latex, and prevents the therapeutic substance eluted from
the distal end of delivery/electrical lumen 32 from being carried
off by the downstream flow of the blood. Sealing balloon 64 is kept
in position by balloon seal members 68, which, for example, may be
laser welded to the catheter distal portion 44, or secured to the
catheter distal portion 44 by medical grade adhesive. This
embodiment may optionally include perfusion holes 62 on
guidewire/perfusion lumen 34 to maintain blood flow across sealing
balloon 64, and cool transducer 42, increasing possible treatment
time as described earlier. It is contemplated by one of ordinary
skill in the art that any suitable combination of the above
described embodiments can be used in combination with one another.
For example, the combination of both a porous balloon in addition
to the sealing balloon 64 can be used with any of catheter
assemblies 30 of the present invention.
[0046] Catheter assembly 30 shown in FIG. 5A may be used for
delivery of a therapeutic substance in the following manner.
Guidewire 38 is inserted into guidewire/perfusion lumen 34, and the
user advances the catheter assembly 30 through the subject's
vasculature until transducer 42 is positioned across the intended
treatment area. For penetration of the therapeutic substance into
the tissue matrix, delivery/electrical lumen 32 is loaded with
therapeutic substance, and a voltage is applied to transducer 42
simultaneously via electrical lead 56 contained within
delivery/electrical lumen 32. The electrical signal supplied to
transducer 42 typically can have a frequency between 200 kHz and 8
MHz, an amplitude between 125V and 250V, a duty cycle between 5%
and 10%, and a sweep time between 50 .mu.s and 300 .mu.s. The
electrical signal is provided by a frequency generator, for
example, Hewlett Packard Model No. HP 3314A, electrically connected
to an amplifier, for example, ENI Model 240L.
[0047] For penetration of therapeutic substance into cells which
form the tissue matrix, the therapeutic substance can be first
delivered to the intended treatment area through
delivery/electrical lumen 32. An electrical signal is supplied to
transducer 42 after the requisite volume of therapeutic substance
has passed through the distal end of delivery/electrical lumen 32
and into the intended treatment area. The electrical signal
supplied to transducer 42 can have a frequency between 20 kHz and 3
MHz, an amplitude greater than 94.8V, a duty cycle between 5% and
20%, and a sweep time between 5,000 .mu.s and 20,000 .mu.s.
Vibrating transducer 42 supplies acoustic pressure which is
believed to disrupt individual cell walls, permitting the
therapeutic substance to enter target tissue 60.
[0048] For diagnostic ultrasound, the electrical signal supplied to
transducer 42 can have a frequency between 20 MHz and 40 MHz.
[0049] Examples of therapeutic substances or agents that are
typically used to treat a subject and are appropriate for use in
conjunction with the catheter assembly 30 via delivery/electrical
lumen 32 include, for example, antineoplastic, antiinflammatory,
antiplatelet, anticoagulants, fibrinolytic, thrombin inhibitor,
antimitotic, and antiproliferative substances. Examples of
antineoplastics include paclitaxel and docetaxel. Examples of
antiplatelets, anticoagulant, fibrinolytics, and thrombin
inhibitors include sodium heparin, low molecular weight heparin,
hirudin, argatroban, forskolin, vapiprost, prostacyclin and
prostacyclin analogues, dextran, D-phe-pro-argchloromethylketone
(synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa
platelet membrane receptor antibody, recombinant hirudin, thrombin
inhibitor (available from Biogen`), and 7E-3B.RTM. (an antiplatelet
drug from Centocore). Examples of suitable antimitotic agents
include methotrexate, azathioprine, vincristine, vinblastine,
fluorouracil, adriamycin, and mutamycine. Examples of cytostatic or
antiproliferative agents include rapamycin, angiopeptin (a
somatostatin analogue from Ibsen), angiotensin converting enzyme
inhibitors such as Captopril.RTM. (available from Squibb),
Cilazapril.RTM. (available from Hoffman-LaRoche), or
Lisinopril.RTM. (available from Merck); calcium channel blockers
(such as Nifedipine), colchicine, fibroblast growth factor (FGF)
antagonists, fish oil (omega 3-fatty acid), histamine antagonist,
Lovastatin.RTM. (an inhibitor of HMG-CoA reductase, a cholesterol
lowering drug from Merck), methotrexate, monoclonal antibodies
(such as PDGF receptors), nitroprusside, phosphodiesterase
inhibitors, prostaglandin inhibitor (available from Glazo), Seramin
(a PDGF antagonist), serotonin blockers, steroids, thioprotease
inhibitors, triazolopyrimidine (a PDGF antagonist), pemirolast
potassium and nitric oxide. Other therapeutic substances or agents
which may be appropriate include alpha-interferon, genetically
engineered epithelial cells, prostaglandins such as PGE-1, and
dexamethasone. While the foregoing therapeutic substances or agents
are well known for preventative and treatment purposes, the
substances or agents are provided by way of example and are not
meant to be limiting. Other therapeutic substances which are
currently available or that may be developed in the future are
equally applicable for use with the present invention. The
treatment of patients using the above mentioned medicines is well
known to those having ordinary skill in the art.
[0050] FIG. 7 illustrates another embodiment of catheter assembly
30 having three transducers 42a, 42b and 42c disposed at distal
portion 57 of guidewire/perfusion lumen 34. Each transducer 42a-42c
has a proximal end 72 and a distal end 74, which defines the
length, l.sub.3, of each transducer 42a-42c. Each distal end 74 of
transducers 42a and 42b is positioned at a preselected distance
d.sub.1 from the proximal end 72 of the adjacent transducer.
[0051] The length, l.sub.3, of each transducer 42a-42c can be of
equal or different measurement. To treat an active area in the
vasculature of a subject that is about 1 centimeter long (0.395
inches, or 395 "mils"), exemplary length, l.sub.3, and distance
d.sub.1 can be 100 mils and 50 mils, respectively. The number of
transducers is not limited to the illustration of FIG. 7, and any
suitable number of transducers can be used with this embodiment of
the invention.
[0052] Transducers 42a-42c are mounted to the distal portion 44 of
the catheter with medical grade adhesive. The selected medical
grade adhesive is compatible both with the perylene or other
compound coating transducers 42a-42c and the material forming the
distal portion 57 of guidewire/perfusion lumen 34.
[0053] Transducers 42a-42c can be electrically connected in
parallel, or in series. Electrically connecting transducers 42a-42c
in parallel provides a more consistent electrical signal from
crystal to crystal, in part because the resulting voltage drops
across inner and outer surfaces 50 and 48 are equal. However, this
parallel configuration is more difficult to fabricate than the
configuration where transducers 42a-42c are electrically connected
in series. Electrical lead 56, a coaxial cable, is electrically
connected to a conductive outer surface 76 of proximal transducer
42a, which in turn is electrically connected to the conductive
outer surface 76 of adjacent transducer 42b. The electrical
connection can be made by insulated magnet wire 78. Electrical
connections are repeated along the outer surface 76 of each
transducer 42a-42c until distal. transducer 42c is reached.
Electrical connections are similarly made to connect conductive
inner surfaces 80 of each transducer 42a-42c to electrical lead 56.
The electrical connections can be made by soldering, welding, or
conductive epoxy.
[0054] Since transducers 42a-42c are fabricated from, for example,
a hard ceramic, transducers 42a-42c are very stiff. Segmenting
transducer 42 into transducers 42a-42c permits the user to more
easily direct the catheter assembly 30 around curves and corners in
the subject's vasculature.
[0055] In accordance with another embodiment, illustrated in FIG.
8, inner surface 50 of each transducer 42a-42c is positioned at a
preselected distance from outer surface 52 of the distal portion 57
of guidewire/perfusion lumen 34. The preselected distance defines
gap 54 between inner surface 50 of transducers 42a-42c and outer
surface 52. Gap 54 may contain any suitable low density material,
including gaseous substances such as ambient air, oxygen, nitrogen,
helium, an open-cell polymeric foam, a closed-cell polymeric foam,
or other low density materials. Gap 54 functions to increase
available ultrasound energy as described above. Delivery of a
therapeutic substance is accomplished as described above under the
detailed description for FIG. 5A.
[0056] Each transducer 42a-42c has a proximal end 72 and a distal
end 74, which defines the length, l.sub.3, of each transducer
42a-42c. Each distal end 74 of transducers 42a-42c is positioned at
a preselected distance d.sub.1 from proximal end 72 of adjacent
transducer 42a-42c.
[0057] Transducers 42a-42c can be defined by a hollow tubular body
having an outer surface 48 and an inner surface 50. Outer surface
48 and inner surface 50 can be coated conformally with perylene or
a similar compound. Anchoring points 46 are formed from medical
grade adhesives. The selected choice of medical grade adhesive
should be mutually compatible both with the coating and the
material forming distal end 57 of catheter assembly 30. Anchoring
points 46 should act as standoffs to separate inner surface 50 of
transducers 42a-42c from outer surface 52 of guidewire/perfusion
lumen 34, thereby creating gap 54.
[0058] The length, l.sub.3, of each transducer 42a-42c can be of
equal or different measurement. To treat an active area in the
vasculature of a subject that is about 1 centimeter long (0.395
inches, or 395 "mils"), exemplary length, l.sub.3, and distance
d.sub.1 can be 100 mils and 50 mils, respectively. The number of
transducers is not limited to the illustration of FIG. 8, and any
suitable number of transducers can be used with this embodiment of
the invention.
[0059] While particular embodiments of the invention have been
shown and described, it will be obvious to those skilled in the art
that modifications, combinations, and substitutions can be made
without departing from the invention in its broader aspects. For
example, the embodiment described in FIG. 5A could be modified so
that a sealing balloon is positioned distal or proximal to a
plurality of transducers, rather than a single transducer.
Similarly, a sealing balloon could be positioned distal or proximal
to a plurality of transducers that are disposed within a balloon
themselves. Therefore, the appended claims are to encompass within
their scope all such changes and modifications as fall within the
true spirit and scope of this invention.
* * * * *