U.S. patent application number 13/880066 was filed with the patent office on 2013-08-15 for tissue treatment.
This patent application is currently assigned to CardioSonic Ltd.. The applicant listed for this patent is Or Shabtay, Ariel Sverdlik, Iris Szwarcfiter. Invention is credited to Or Shabtay, Ariel Sverdlik, Iris Szwarcfiter.
Application Number | 20130211396 13/880066 |
Document ID | / |
Family ID | 44993632 |
Filed Date | 2013-08-15 |
United States Patent
Application |
20130211396 |
Kind Code |
A1 |
Sverdlik; Ariel ; et
al. |
August 15, 2013 |
TISSUE TREATMENT
Abstract
There is provided in accordance with an exemplary embodiment of
the a method of selectively treating tissue using non-focused
ultrasound energy delivered intrabody comprising: selectively
determining a target tissue in a wall of a lumen or cavity;
selecting parameters sufficient to provide a desired effect in the
target tissue; and applying the parameters to treat the target
tissue using non-focused ultrasound to achieve the desired
effect.
Inventors: |
Sverdlik; Ariel; (Tel-Aviv,
IL) ; Szwarcfiter; Iris; (Tel-Aviv, IL) ;
Shabtay; Or; (Kibbutz Farod, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sverdlik; Ariel
Szwarcfiter; Iris
Shabtay; Or |
Tel-Aviv
Tel-Aviv
Kibbutz Farod |
|
IL
IL
IL |
|
|
Assignee: |
CardioSonic Ltd.
Tel-Aviv
IL
|
Family ID: |
44993632 |
Appl. No.: |
13/880066 |
Filed: |
October 18, 2011 |
PCT Filed: |
October 18, 2011 |
PCT NO: |
PCT/IB11/54640 |
371 Date: |
April 18, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61393947 |
Oct 18, 2010 |
|
|
|
61453239 |
Mar 16, 2011 |
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Current U.S.
Class: |
606/28 |
Current CPC
Class: |
A61N 2007/0026 20130101;
A61B 6/504 20130101; A61M 2025/1052 20130101; A61F 2007/0063
20130101; A61B 2017/320069 20170801; A61B 2017/22027 20130101; A61M
25/10 20130101; A61B 6/12 20130101; A61B 17/22012 20130101; A61M
25/007 20130101; A61B 8/12 20130101; A61M 2025/091 20130101; A61B
8/481 20130101; A61B 2017/00106 20130101; A61N 2007/0039 20130101;
A61M 31/00 20130101; A61N 2007/0082 20130101 |
Class at
Publication: |
606/28 |
International
Class: |
A61B 17/32 20060101
A61B017/32 |
Claims
1. A method of setting up a treatment system for non-focused
ultrasound energy delivered intrabody comprising: selectively
determining a target tissue in a wall of a lumen or cavity;
selecting parameters sufficient to provide a desired therapeutic
effect in said target tissue and which start a thermal damage
effect only at a distance of at least 0.2 mm from an inner side of
said wall; and setting up a treatment system using said
parameters.
2. A method according to claim 1, further comprising deciding an
amount of desired thermal damage.
3. A method according to claim 2, wherein said amount of thermal
damage comprises a volume where thermal damage is desired.
4. A method according to claim 2, wherein said amount of thermal
damage comprises the degree of thermal damage.
5. A method according to claim 1, further comprising selecting an
anatomical location from which to treat said target tissue.
6. A method according to claim 5, wherein said anatomical location
comprises a renal artery and said target tissue comprises renal
artery nerves.
7. A method according to claim 5, wherein said anatomical location
comprises an aorta and said target tissue comprises renal
nerves.
8. A method according to claim 5, wherein said anatomical location
comprises a carotid artery and said target tissue comprises
nerves.
9. A method according to claim 1, wherein selecting comprises
taking blood cooling into account.
10. A method according to claim 1, wherein selecting comprises
selecting in a manner which avoids significant stenosis.
11. A method according to claim 1, wherein selecting comprises
selecting in a manner which avoids significant damage to non-target
tissue.
12. A method according to claim 1, wherein selecting comprises
selecting in a manner which avoids significant shrinkage in target
tissue.
13. A method according to claim 1, wherein said desired effect
comprises denaturing at least some of said target tissue.
14. A method according to claim 13, further comprising applying
said ultrasound energy so as to not denature at least some part of
said target tissue.
15. A method according to claim 1, wherein said target tissue and
said parameters are preselected so that said parameters have said
desired effect on said target.
16. A method according to claim 1, wherein said selecting comprises
determining according to an attenuation coefficient of tissues.
17. A method according to claim 1, further comprising selecting a
margin of safety.
18. A method according to claim 17, wherein said selecting a margin
of safety comprises selecting an allowed amount of thermal damage
to tissues surrounding said target tissue.
19. A method according to claim 17, wherein said selecting a margin
of safety comprises reducing or preventing contraction of said
lumen or said cavity.
20. A method according to claim 1, wherein said selectively
determining said target tissue comprises selecting a type of
tissue.
21. A method according to claim 20, wherein said type of tissue
comprises nerve tissue.
22. A method according to claim 20, wherein said target tissue is
selected from tissue located at a tissue layer selected from the
group comprising peri-adventitia, adventitia, media, intima.
23. A method according to claim 1, wherein said target tissue is
located less than 10 mm from a renal ostium.
24. A method according to claim 1, wherein said determining initial
parameters comprises determining according to a distance of said
target tissue from an intima.
25. A method according to claim 24, wherein said target tissue is
outside said wall of said lumen or said cavity.
26. A method according to claim 1, further comprising selecting a
frequency of treatment in the range of 8-25 Mhz.
27. A method according to claim 1, further comprising selecting an
ultrasound intensity in the range of 1-100 Watt/square
centimeter.
28. A method according to claim 1, wherein said target tissue is a
renal nerve, and said parameters are an applied frequency of
10[MHz]-22[MHz], and an intensity of 10-40[W/cm 2].
29. A method according to claim 1, wherein a duration of said
treatment is 5-30 seconds.
30. A method according to claim 1, wherein a length of said lumen
or cavity is less than 20 mm.
31. A method according to claim 1, comprising applying said
parameters to selectively treat said target tissue using
non-focused ultrasound to achieve said desired effect.
32. A method according to claim 31, further comprising obtaining
feedback associated with said treatment.
33. A method according to claim 32, further comprising adjusting
said parameters according to said feedback and retreating said
target tissue.
34. A method according to claim 31, further comprising a controlled
adjustable treatment according to online measurements including at
least one of the following group of measurements: flow
measurements, current measurement, voltage measurement, power
measurement, acoustic backscatter measurements, temperature
measurements, pressure measurements.
35. A method according to claim 31, wherein treating comprises
applying said ultrasound away from said wall but inside a body.
36. A method according to claim 31, applying so that a desired
effect comprises temporary change in tissue functionality is
achieved.
37. A method according to claim 31, wherein said applying said
parameters comprises applying said parameters in an open loop
manner.
38. A method according to claim 31, wherein applying comprises
applying said ultrasound energy so as to not denature most of the
tissue between said target tissue and an edge of said wall.
39. A method according to claim 31, wherein applying comprises
maintaining blood in said lumen at a temperature below 50 degrees
Celsius.
40. A method according to claim 31, wherein applying comprises
maintaining blood in said lumen at a temperature below 43 degrees
Celsius.
41. A method according to claim 31, wherein said applying comprises
heating a nerve while not heating tissue outside of a fat sheath
surrounding said nerve.
42. A method according to claim 31, wherein said applying comprises
localizing heating by having a gradient of cooling from blood and a
gradient of heating from a distance.
43. A method according to claim 31, wherein applying comprises
heating nerves sufficiently to reduce renal norepinephrine levels
by at least 50%.
44. A method according to claim 31, wherein applying comprises
heating a part of a nerve to necrosis while not heating another
part of said nerve in a same axial location along said nerve to
necrosis.
45. A method according to claim 31, further comprising adjusting a
property of at least one of said target tissue, said wall and blood
in said lumen to provide said desired effect.
46. A method according to claim 45, wherein said property comprises
a rate of heat removal.
47. A method according to claim 45, wherein said property comprises
a flow rate of said blood.
48. A method according to claim 45, wherein said property comprises
a temperature.
49. A method according to claim 31, wherein said applying comprises
applying said ultrasound energy so as to treat a patient suffering
from hypertension.
50. A method according to claim 31, wherein said applying comprises
applying said ultrasound energy so as to prevent signals from
propagating through at least one renal nerve.
51. A method according to claim 31, wherein said applying comprises
applying said ultrasound energy so as to position said treatment
area with an accuracy of better than 0.2 mm along an axis
perpendicular to said wall.
52. A system for treating a blood vessel wall comprising: a
catheter; at least one ultrasound emitter mounted on the catheter
and adapted for emitting unfocused ultrasound at a frequency of
10-40 Mhz at a target tissue located a distance from an intima of
the blood vessel wall with a power setting sufficient to heat said
target tissue; and a controller, wherein the controller is
configured to deliver enough power to heat said target tissue to a
selected size and to a desired thermal effect, said thermal effect
starting only after at least a distance of 0.2 mm from said
wall.
53. A system according to claim 52 wherein said target tissue
comprises nerves, and said desired thermal effect comprises
reducing signals through said nerves by at least 50%.
54. A system according to claim 52, wherein said catheter is
configured so that said emitter does not contact said wall.
55. A system according to claim 52, wherein said controller is
configured to selectively treat a volume of tissue distanced from
an intima of a blood vessel wall.
56. A system according to claim 52, wherein said controller is
configured for thermal treatment of renal nerves.
57. A system according to claim 52, wherein said controller is
configured for treatment accuracy of better than 0.5 mm positioning
of the treatment area, along a dimension perpendicular to said
blood vessel.
58. A system according to claim 52, wherein said controller is
configured for treatment specificity which avoids significant
vessel stenosis as an aftermath of said treatment.
59. A system according to claim 52, wherein said controller is
configured to selectively heat nerves within a fat sheath
thereof.
60. A system according to claim 52, wherein said controller is
configured with a protocol including a plurality of treatment
regions and sufficient to reduce hypertension if applied to renal
nerves.
61. A system according to claim 52, wherein said controller is
pre-configured with sets of parameters matching different target
tissues and target tissue locations.
62. A system according to claim 52, wherein said controller
includes a feedback circuit for real-time control of settings of
said system.
63. A method of setting up a device to selectively treating tissue
using non-focused ultrasound energy delivered intrabody comprising:
setting up said device to be suitable for heating a selected area
of tissue at a selected location from an arterial wall.
64-67. (canceled)
68. A method of setting up a device to selectively treating tissue
using non-focused ultrasound energy delivered intrabody comprising:
setting up said device to be suitable for heating nerve tissue
while not heating, to a tissue damaging level, tissue outside a fat
sheath surrounding said nerve.
69. A method of reducing blood pressure comprising: applying
unfocused ultrasonic energy to the renal ostium from within a blood
vessel, said energy sufficient to disrupt signals propagating
through renal nerves.
70-71. (canceled)
72. A method for treating a patient experiencing a clinical
disorder, the method comprising: positioning at least one unfocused
ultrasound emitter at an anatomical location proximate to a target
tissue; selectively delivering unfocused ultrasound energy to the
target tissue; and selectively causing thermal damage to at least a
portion of the target tissue, to provide a desired treatment, no
significant thermal damage being caused closer than 0.2 mm to said
wall.
73. The method of claim 72 wherein the target tissue comprises body
lumen, fat, nerves, vasa vasora, lymph, tumor, connective tissue,
or plaque.
74. The method of claim 72 wherein the anatomical location
comprises a blood vessel or artery.
75. The method of claim 74 wherein the anatomical location is the
renal artery and the target tissue comprises one or more renal
artery nerves.
76. The method of claim 74 wherein the at least one unfocused
ultrasound emitter is configured not to touch the wall of the blood
vessel or artery.
77. The method of claim 74 wherein the at least one unfocused
ultrasound emitter is positioned as to not substantially block
blood flow in the blood vessel or artery.
78. The method of claim 77 wherein the at least one unfocused
ultrasound emitter, in operation, is cooled by the blood flow.
79. The method of claim 72 wherein the clinical disorder comprises
at least one of sleep apnea, obesity, diabetes, end stage renal
disease, lesion on a body lumen, contrast nephropathy, heart
arrhythmia, congestive heart failure, and hypertension.
80. The method of claim 74 further comprising determining the
distance from the blood vessel or artery wall to the target tissue
and selecting the frequency of the unfocused ultrasound energy
based upon on said distance of the target tissue.
81. The method of claim 72 wherein the frequency of the unfocused
ultrasound energy is 10-22 Mhz.
82. The method of claim 72 wherein the target tissue comprises a
treatment region.
83. The method of claim 82 further comprising determining the
treatment region and selecting the intensity of the unfocused
ultrasound energy according to the size of the treatment
region.
84. The method of claim 77 further comprising delivering the at
least one unfocused ultrasound emitter intrabody within the blood
vessel or artery by a delivery catheter and configuring the
delivery catheter to prevent the at least one unfocused ultrasound
emitter from touching the wall of the blood vessel or artery.
85. The method of claim 72 further comprising selecting the target
tissue using parameters obtained from an equation based upon
empirical data.
86. The method of claim 85 wherein the equation is: x(f,I)
[mm]=(C6+a*Exp(flow*b)-C2*log(C3*I [W/cm 2]))/(C4*f [MHz]+C5)
Wherein, "I" is excitation intensity [W/cm 2]; "f" is working
excitation frequency [MHz]; "x" is minimal radial distance from the
artery wall [mm]; and "flow" is blood flow rate in the artery
[ml/mm].
87. The method of claim 72 further comprising receiving feedback
indicating the thermal damage to the target tissue.
88. The method of claim 87 further comprising modifying the
parameters in response to said feedback.
89. The method of claim 72 further comprising selectively
delivering the unfocused ultrasound energy in a manner such that
there is no significant damage to non-target tissue.
90. The method of claim 72 further comprising selectively
delivering the unfocused ultrasound energy in a manner such that
there is no significant stenosis.
91. The method of claim 72 further comprising delivering unfocused
ultrasound energy to at least one treatment region, each treatment
region being at a separate circumferential location.
92. The method of claim 91 wherein the duration that unfocused
ultrasound energy is delivered to the target tissue is 5-30 seconds
per treatment region.
93. The method of claim 91 wherein the treatment comprises between
1 and 8 treatment regions.
Description
RELATED APPLICATIONS
[0001] This is a PCT application which claims the benefit of
priority of U.S. Provisional Patent Applications No. 61/393,947
filed Oct. 18, 2010, and No. 61/453,239 filed Mar. 16, 2011, the
contents of which are incorporated herein by reference in their
entirety.
[0002] The present application is related to co-filed, co-pending
and co-assigned patent applications entitled:
[0003] "THERAPEUTICS RESERVOIR" (attorney docket no. 52341), which
teaches an apparatus and a method for forming a drug reservoir as a
possible application of the ultrasound energy application described
herein;
[0004] "AN ULTRASOUND TRANSCEIVER AND CONTROL OF A THERMAL DAMAGE
PROCESS" (attorney docket no. 52342), which teaches an apparatus
and method for performing ultrasonic imaging, such as to provide
feedback about the effect of treatment on tissues as described
herein;
[0005] "ULTRASOUND EMISSION ELEMENT" (attorney docket no. 52344),
which teaches an apparatus for generating relatively high intensity
ultrasound, such as to apply energy to cause the desired effects in
tissue as described herein;
[0006] "AN ULTRASOUND TRANSCEIVER AND USES THEREOF" (attorney
docket no. 52345), which teaches a method for feedback and control
of the ultrasonic emission element, such as to use the same
ultrasonic element for treatment and imaging, potentially useful
when treating and imaging as described herein;
[0007] "AN ULTRASOUND TRANSCEIVER AND COOLING THEREOF" (attorney
docket no. 52346), which teaches a method for cooling of the
ultrasonic emission element, potentially useful when applying
energy as described herein;
[0008] "SEPARATION DEVICE FOR ULTRASOUND ELEMENT" (attorney docket
no. 52348), which teaches a device to prevent the ultrasonic
emission element from touching the blood vessel wall, potentially
useful for preventing damage to the intima layer when applying
energy as described herein;
[0009] the disclosures of which are incorporated herein by
reference.
FIELD AND BACKGROUND OF THE INVENTION
[0010] The present invention, in some embodiments thereof, relates
to a method of treatment of tissue and, more particularly, but not
exclusively, to a method of selectively targeting and treating
tissue using unfocused ultrasound energy.
[0011] Sverdlik et al, in PCT/IL2008/000234, filed FEB 21, 2008
disclose:
"Described is a method of stabilizing blood vessel wall
abnormality. The method includes ultrasonically heating at least a
portion of the blood vessel wall having the abnormality; monitoring
a parameter related to a property of at least a portion of the
heated portion of the blood vessel wall; and stopping the heating
when the monitored parameter changes by a predetermined factor or
after the monitored parameter changes in a slow enough rate."
[0012] Additional background art includes: [0013] EP 1769759 [0014]
U.S. Pat. No. 5,699,804 [0015] U.S. Pat. No. 7,410,486 [0016] U.S.
Pat. No. 7,621,929 [0017] U.S. Pat. No. 7,717,948 [0018] U.S. Pat.
No. 7,771,372 [0019] US patent application 2008228111 [0020] US
patent application 2009216246 [0021] US patent application
2010091112 [0022] Xu, D. S., & Pollock, M. (1994). Experimental
nerve thermal-injury. Brain, 117, 375-384. [0023] Katholi et al.
"Renal nerves in the maintenance of hypertension: a potential
therapeutic target" Curr Hypertens Rep. 2010 June; 12(3):196-204.
[0024] Lele, P. P. (1963). Effects of Focused Ultrasonic Radiation
on Peripheral Nerve, With Observations On Local Heating.
Experimental Neurology, 8(1), 47-83. [0025] Fung L C et al. Effects
of temperature on tissue thermal injury and wound strength after
photothermal wound closure. Lasers Surg Med. 1999; 25(4):285-90.
[0026] Worthington, A. E., et al, Ultrasound in Med. & Biol.,
Vol. 28, No. 10, pp. 1311-1318, 2002. [0027] Damianou et al, J
Acoust Soc Am. 1997 July; 102(1):628-34.
SUMMARY OF THE INVENTION
[0028] An aspect of some embodiments of the invention relates to a
method of selectively treating a volume of tissue using unfocused
ultrasound energy having an acoustic intensity profile of over 1
Watt per square centimeter.
[0029] There is provided in accordance with an exemplary embodiment
of the invention a method of setting up a treatment system for
non-focused ultrasound energy delivered intrabody comprising:
[0030] selectively determining a target tissue in a wall of a lumen
or cavity;
[0031] selecting parameters sufficient to provide a desired
therapeutic effect in said target tissue; and
[0032] setting up a treatment system using said parameters
[0033] In an exemplary embodiment of the invention, the method
comprises deciding an amount of desired thermal damage. Optionally,
said amount of thermal damage comprises a volume where thermal
damage is desired. Optionally or alternatively, said amount of
thermal damage comprises the degree of thermal damage.
[0034] In an exemplary embodiment of the invention, the method
comprises selecting an anatomical location from which to treat said
target tissue. Optionally, said anatomical location comprises a
renal artery and said target tissue comprises renal artery nerves.
Optionally or alternatively, said anatomical location comprises an
aorta and said target tissue comprises renal nerves. Optionally or
alternatively, said anatomical location comprises a carotid artery
and said target tissue comprises nerves.
[0035] In an exemplary embodiment of the invention, selecting
comprises taking blood cooling into account.
[0036] In an exemplary embodiment of the invention, selecting
comprises selecting in a manner which avoids significant
stenosis.
[0037] In an exemplary embodiment of the invention, selecting
comprises selecting in a manner which avoids significant damage to
non-target tissue.
[0038] In an exemplary embodiment of the invention, selecting
comprises selecting in a manner which avoids significant shrinkage
in target tissue.
[0039] In an exemplary embodiment of the invention, said desired
effect comprises denaturing at least some of said target tissue.
Optionally, the method comprises applying said ultrasound energy so
as to not denature at least some part of said target tissue.
[0040] In an exemplary embodiment of the invention, said target
tissue and said parameters are preselected so that said parameters
have said desired effect on said target.
[0041] In an exemplary embodiment of the invention, selecting
comprises determining according to an attenuation coefficient of
tissues.
[0042] In an exemplary embodiment of the invention, the method
comprises selecting a margin of safety. Optionally, said selecting
a margin of safety comprises selecting an allowed amount of thermal
damage to tissues surrounding said target tissue. Optionally or
alternatively, selecting a margin of safety comprises reducing or
preventing contraction of said lumen or said cavity.
[0043] In an exemplary embodiment of the invention, selectively
determining said target tissue comprises selecting a type of
tissue. Optionally, said type of tissue comprises nerve tissue.
Optionally or alternatively, said target tissue is selected from
tissue located at a tissue layer selected from the group comprising
peri-adventitia, adventitia, media, intima.
[0044] In an exemplary embodiment of the invention, said target
tissue is located less than 10 mm from a renal ostium.
[0045] In an exemplary embodiment of the invention, said
determining initial parameters comprises determining according to a
distance of said target tissue from an intima. Optionally, said
target tissue is outside said wall of said lumen or said
cavity.
[0046] In an exemplary embodiment of the invention, the method
comprises selecting a frequency of treatment in the range of 8-25
Mhz.
[0047] In an exemplary embodiment of the invention, the method
comprises selecting an ultrasound intensity in the range of 1-100
Watt/square centimeter.
[0048] In an exemplary embodiment of the invention, said target
tissue is a renal nerve, and said parameters are an applied
frequency of 10[MHz]-22[MHz], and an intensity of 10-40 [W/cm
2].
[0049] In an exemplary embodiment of the invention, a duration of
said treatment is 5-30 seconds.
[0050] In an exemplary embodiment of the invention, a length of
said lumen or cavity is less than 20 mm.
[0051] In an exemplary embodiment of the invention, the method
comprises applying said parameters to selectively treat said target
tissue using non-focused ultrasound to achieve said desired effect.
Optionally, the method comprises obtaining feedback associated with
said treatment. Optionally, the method comprises adjusting said
parameters according to said feedback and retreating said target
tissue.
[0052] In an exemplary embodiment of the invention, the method
comprises a controlled adjustable treatment according to online
measurements including at least one of the following group of
measurements: flow measurements, current measurement, voltage
measurement, power measurement, acoustic backscatter measurements,
temperature measurements, pressure measurements.
[0053] In an exemplary embodiment of the invention, treating
comprises applying said ultrasound away from said wall but inside a
body.
[0054] In an exemplary embodiment of the invention, applying so
that a desired effect comprises temporary change in tissue
functionality is achieved.
[0055] In an exemplary embodiment of the invention, said applying
said parameters comprises applying said parameters in an open loop
manner.
[0056] In an exemplary embodiment of the invention, applying
comprises applying said ultrasound energy so as to not denature
most of the tissue between said target tissue and an edge of said
wall.
[0057] In an exemplary embodiment of the invention, applying
comprises maintaining blood in said lumen at a temperature below 50
degrees Celsius.
[0058] In an exemplary embodiment of the invention, applying
comprises maintaining blood in said lumen at a temperature below 43
degrees Celsius.
[0059] In an exemplary embodiment of the invention, applying
comprises heating a nerve while not heating tissue outside of a fat
sheath surrounding said nerve.
[0060] In an exemplary embodiment of the invention, applying
comprises localizing heating by having a gradient of cooling from
blood and a gradient of heating from a distance.
[0061] In an exemplary embodiment of the invention, applying
comprises heating nerves sufficiently to reduce renal
norepinephrine levels by at least 50%.
[0062] In an exemplary embodiment of the invention, applying
comprises heating a part of a nerve to necrosis while not heating
another part of said nerve in a same axial location along said
nerve to necrosis.
[0063] In an exemplary embodiment of the invention, the method
comprises adjusting a property of at least one of said target
tissue, said wall and blood in said lumen to provide said desired
effect. Optionally, said property comprises a rate of heat removal.
Optionally or alternatively, said property comprises a flow rate of
said blood. Optionally or alternatively, said property comprises a
temperature.
[0064] In an exemplary embodiment of the invention, applying
comprises applying said ultrasound energy so as to treat a patient
suffering from hypertension.
[0065] In an exemplary embodiment of the invention, applying
comprises applying said ultrasound energy so as to prevent signals
from propagating through at least one renal nerve.
[0066] In an exemplary embodiment of the invention, applying
comprises applying said ultrasound energy so as to position said
treatment area with an accuracy of better than 0.2 mm along an axis
perpendicular to said wall.
[0067] There is provided in accordance with an exemplary embodiment
of the invention a system configured for carrying out the method as
described herein.
[0068] There is provided in accordance with an exemplary embodiment
of the invention a system for treating a blood vessel wall
comprising:
[0069] a catheter;
[0070] at least one ultrasound emitter mounted on the catheter and
adapted for emitting unfocused ultrasound at a frequency of 10-40
Mhz at a target tissue located a distance from an intima of the
blood vessel wall with a power setting sufficient to heat said
target tissue; and
[0071] a controller,
[0072] wherein the controller is configured to deliver enough power
to heat said target tissue to a selected size and to a desired
thermal effect. Optionally, said target tissue comprises nerves,
and said desired thermal effect comprises reducing signals through
said nerves by at least 50%. Optionally or alternatively, said
catheter is configured so that said emitter does not contact said
wall. Optionally or alternatively, said controller is configured to
selectively treat a volume of tissue distanced from an intima of a
blood vessel wall. Optionally or alternatively, said controller is
configured for thermal treatment of renal nerves. Optionally or
alternatively, said controller is configured for treatment accuracy
of better than 0.5 mm positioning of the treatment area, along a
dimension perpendicular to said blood vessel. Optionally or
alternatively, said controller is configured for treatment
specificity which avoids significant vessel stenosis as an
aftermath of said treatment. Optionally or alternatively, said
controller is configured to selectively heat nerves within a fat
sheath thereof. Optionally or alternatively, said controller is
configured with a protocol including a plurality of treatment
regions and sufficient to reduce hypertension if applied to renal
nerves. Optionally or alternatively, said controller is
pre-configured with sets of parameters matching different target
tissues and target tissue locations. Optionally or alternatively,
said controller includes a feedback circuit for real-time control
of settings of said system.
[0073] There is provided in accordance with an exemplary embodiment
of the invention a method of setting up a device to selectively
treating tissue using non-focused ultrasound energy delivered
intrabody comprising:
[0074] setting up said device to be suitable for heating a selected
area of tissue at a selected location from an arterial wall.
[0075] There is provided in accordance with an exemplary embodiment
of the invention a method of treating a blood vessel wall
comprising:
adjusting a said blood vessel during intravascular ultrasound
treatment, other than by said treatment. Optionally, said adjusting
comprises adjusting blood flow through said blood vessel.
Optionally or alternatively, said adjusting comprises adjusting a
thickness of said blood vessel wall. Optionally or alternatively,
said adjusting comprises adjusting a temperature of at least one of
said blood and said blood vessel wall.
[0076] There is provided in accordance with an exemplary embodiment
of the invention a method of setting up a device to selectively
treating tissue using non-focused ultrasound energy delivered
intrabody comprising:
[0077] setting up said device to be suitable for heating nerve
tissue while not heating, to a tissue damaging level, tissue
outside a fat sheath surrounding said nerve.
[0078] There is provided in accordance with an exemplary embodiment
of the invention a method of reducing blood pressure
comprising:
[0079] applying unfocused ultrasonic energy to the renal ostium
from within a blood vessel, said energy sufficient to disrupt
signals propagating through renal nerves.
[0080] There is provided in accordance with an exemplary embodiment
of the invention a device for treating blood pressure
comprising:
[0081] a catheter configured to position an ultrasonic emission
element close to a renal ostium, said element configured to emit
unfocused ultrasonic energy to nerves. Optionally, close comprises
less than 10 mm.
[0082] There is provided in accordance with an exemplary embodiment
of the invention a method for treating a patient experiencing a
clinical disorder, the method comprising:
[0083] positioning at least one unfocused ultrasound emitter at an
anatomical location proximate to a target tissue;
[0084] selectively delivering unfocused ultrasound energy to the
target tissue; and
[0085] selectively causing thermal damage to at least a portion of
the target tissue, to provide a desired treatment. Optionally, the
target tissue comprises body lumen, fat, nerves, vasa vasora,
lymph, tumor, connective tissue, or plaque. Optionally or
alternatively, the anatomical location comprises a blood vessel or
artery. Optionally, the anatomical location is the renal artery and
the target tissue comprises one or more renal artery nerves.
Optionally or alternatively, the at least one unfocused ultrasound
emitter is configured not to touch the wall of the blood vessel or
artery. Optionally or alternatively, the at least one unfocused
ultrasound emitter is positioned as to not substantially block
blood flow in the blood vessel or artery. Optionally, the at least
one unfocused ultrasound emitter, in operation, is cooled by the
blood flow.
[0086] In an exemplary embodiment of the invention, the clinical
disorder comprises at least one of sleep apnea, obesity, diabetes,
end stage renal disease, lesion on a body lumen, contrast
nephropathy, heart arrhythmia, congestive heart failure, and
hypertension.
[0087] In an exemplary embodiment of the invention, the method
comprises determining the distance from the blood vessel or artery
wall to the target tissue and selecting the frequency of the
unfocused ultrasound energy based upon on said distance of the
target tissue.
[0088] In an exemplary embodiment of the invention, the frequency
of the unfocused ultrasound energy is 10-22 Mhz.
[0089] In an exemplary embodiment of the invention, the target
tissue comprises a treatment region. Optionally, the method
comprises determining the treatment region and selecting the
intensity of the unfocused ultrasound energy according to the size
of the treatment region.
[0090] In an exemplary embodiment of the invention, the method
comprises delivering the at least one unfocused ultrasound emitter
intrabody within the blood vessel or artery by a delivery catheter
and configuring the delivery catheter to prevent the at least one
unfocused ultrasound emitter from touching the wall of the blood
vessel or artery.
[0091] In an exemplary embodiment of the invention, the method
comprises selecting the target tissue using parameters obtained
from an equation based upon empirical data. Optionally, the
equation is:
x(f,I) [mm]=(C6+a*Exp(flow*b)-C2*log(C3*I [W/cm 2]))/(C4*f
[MHz]+C5)
Wherein, "I" is excitation intensity [W/cm 2]; "f" is working
excitation frequency [MHz]; "x" is minimal radial distance from the
artery wall [mm]; and "flow" is blood flow rate in the artery
[ml/mm].
[0092] In an exemplary embodiment of the invention, the method
comprises receiving feedback indicating the thermal damage to the
target tissue. Optionally, the method comprises modifying the
parameters in response to said feedback.
[0093] In an exemplary embodiment of the invention, the method
comprises selectively delivering the unfocused ultrasound energy in
a manner such that there is no significant damage to non-target
tissue.
[0094] In an exemplary embodiment of the invention, the method
comprises selectively delivering the unfocused ultrasound energy in
a manner such that there is no significant stenosis.
[0095] In an exemplary embodiment of the invention, the method
comprises delivering unfocused ultrasound energy to at least one
treatment region, each treatment region being at a separate
circumferential location. Optionally, the duration that unfocused
ultrasound energy is delivered to the target tissue is 5-30 seconds
per treatment region. Optionally or alternatively, the treatment
comprises between 1 and 8 treatment regions.
[0096] Unless otherwise defined, all technical and/or scientific
terms used herein have the same meaning as commonly understood by
one of ordinary skill in the art to which the invention pertains.
Although methods and materials similar or equivalent to those
described herein can be used in the practice or testing of
embodiments of the invention, exemplary methods and/or materials
are described below. In case of conflict, the patent specification,
including definitions, will control. In addition, the materials,
methods, and examples are illustrative only and are not intended to
be necessarily limiting.
[0097] Implementation of the method and/or system of embodiments of
the invention can involve performing or completing selected tasks
manually, automatically, or a combination thereof. Moreover,
according to actual instrumentation and equipment of embodiments of
the method and/or system of the invention, several selected tasks
could be implemented by hardware, by software or by firmware or by
a combination thereof using an operating system.
[0098] For example, hardware for performing selected tasks
according to embodiments of the invention could be implemented as a
chip or a circuit. As software, selected tasks according to
embodiments of the invention could be implemented as a plurality of
software instructions being executed by a computer using any
suitable operating system. In an exemplary embodiment of the
invention, one or more tasks according to exemplary embodiments of
method and/or system as described herein are performed by a data
processor, such as a computing platform for executing a plurality
of instructions. Optionally, the data processor includes a volatile
memory for storing instructions and/or data and/or a non-volatile
storage, for example, a magnetic hard-disk and/or removable media,
for storing instructions and/or data. Optionally, a network
connection is provided as well. A display and/or a user input
device such as a keyboard or mouse are optionally provided as
well.
BRIEF DESCRIPTION OF THE DRAWINGS
[0099] Some embodiments of the invention are herein described, by
way of example only, with reference to the accompanying drawings.
With specific reference now to the drawings in detail, it is
stressed that the particulars shown are by way of example and for
purposes of illustrative discussion of embodiments of the
invention. In this regard, the description taken with the drawings
makes apparent to those skilled in the art how embodiments of the
invention may be practiced.
[0100] In the drawings:
[0101] FIG. 1A is a flowchart of a treatment method, in accordance
with an exemplary embodiment of the invention;
[0102] FIG. 1B is a flowchart of a more detailed treatment method
of FIG. 1A, in accordance with an exemplary embodiment of the
invention;
[0103] FIG. 2 is an illustration of an embodiment of the treatment
system for selectively treating tissues, in accordance with an
exemplary embodiment of the invention;
[0104] FIG. 3 is an illustration of the human body showing
exemplary treatment locations, useful in practicing some
embodiments of the invention;
[0105] FIG. 4 is an illustration of the renal artery, showing
exemplary treatment locations, in accordance with an exemplary
embodiment of the invention;
[0106] FIG. 5 is an illustration of ultrasound energy treating
tissues, in accordance with an exemplary embodiment of the
invention;
[0107] FIG. 6A is a cross section of an arterial wall, illustrating
selective tissue treatment, in accordance with an exemplary
embodiment of the invention;
[0108] FIG. 6B is a cross sectional view, FIG. 6C is a side view
and FIG. 6D is a top view illustrating a controllable volume of
thermal effect to tissue, in accordance with an exemplary
embodiment of the invention;
[0109] FIG. 7A is an exemplary graph illustrating a temperature
profile, useful in practicing some embodiments of the
invention;
[0110] FIG. 7B is an exemplary graph illustrating relative tissue
attenuation, useful in practicing some embodiments of the
invention;
[0111] FIG. 7C is an exemplary graph illustrating some associations
between heat removal rates and treatment, useful in practicing some
embodiments of the invention;
[0112] FIGS. 7D-7E illustrate the adjustment of one or more tissue
properties, in accordance with some embodiments of the
invention;
[0113] FIG. 8 is an exemplary graph illustrating some associations
between frequency and treatment, useful in practicing some
embodiments of the invention;
[0114] FIG. 9 is an exemplary graph illustrating some associations
between ultrasound intensity profile and treatment, useful in
practicing some embodiments of the invention;
[0115] FIG. 10 is a flow chart of monitoring during treatment, in
accordance with an exemplary embodiment of the invention;
[0116] FIG. 11 is a flow chart of feedback during treatment, in
accordance with an exemplary embodiment of the invention;
[0117] FIG. 12A is a table summarizing experimental results
obtained using some embodiments of the invention;
[0118] FIG. 12B is a table summarizing experimental results at 10
Mhz, obtained using some embodiments of the invention;
[0119] FIG. 12C is a table summarizing experimental results at 20
Mhz, obtained using some embodiments of the invention;
[0120] FIG. 12D illustrates graphs summarizing the values in FIGS.
12B-12C, useful in practicing some embodiments of the
invention;
[0121] FIG. 12E is an image illustrating the variables described in
FIGS. 12B-12D, useful in practicing some embodiments of the
invention;
[0122] FIGS. 13A-B are graphs of associations between thermal
damage results and ultrasound parameters according to the results
of FIG. 12A, useful in practicing using some embodiments of the
invention;
[0123] FIGS. 13C-H are exemplary graphs of thermal damage results
and ultrasound parameters according to the results as shown in
FIGS. 12B-12D, useful in practicing some embodiments of the
invention;
[0124] FIGS. 14A-C are images of experimental results in the aorta
obtained using some embodiments of the invention;
[0125] FIGS. 15A-D are images of experimental results in the aorta
obtained using some embodiments of the invention;
[0126] FIGS. 16A-C are images of experimental results in the
carotid artery obtained using some embodiments of the
invention;
[0127] FIGS. 17A-B are images of experimental results in the
carotid artery obtained using some embodiments of the
invention;
[0128] FIGS. 18A-G are images of experimental results in the renal
artery obtained using some embodiments of the invention;
[0129] FIGS. 19A-C are images of experimental results in the renal
artery obtained using some embodiments of the invention; and
[0130] FIGS. 20A-J are images of experimental results in the renal
artery obtained using some embodiments of the invention.
DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION
[0131] The present invention, in some embodiments thereof, relates
to a method of treatment of tissue and, more particularly, but not
exclusively, to a method of selectively targeting and treating
tissue using unfocused ultrasound energy. In an exemplary
embodiment of the invention, the tissue is in a mammal, for
example, a pig or a human.
[0132] An aspect of some embodiments of the invention relates to a
method of selectively treating tissue using ultrasound energy
delivered intrabody. Optionally, the ultrasound energy is
non-focused.
[0133] In an exemplary embodiment of the invention, tissues can be
targeted spatially, for example, a volume of tissue located in a
wall of a blood vessel. Optionally, the tissue to be targeted is
defined spatially, for example, using x, y, z coordinates.
[0134] In an exemplary embodiment of the invention, target tissues
are treated with ultrasound energy, for example, heated using
ultrasound energy. Optionally, tissues are thermally damaged,
non-limiting examples of damage include; burning, coagulation,
denaturation, ablation, necrosis, disruption (e.g., of signal
propagation in nerves), degeneration, destruction. Optionally or
additionally, tissues are heated sufficiently without causing
immediate damage and/or shrinkage.
[0135] In an exemplary embodiment of the invention, target tissues
are heated to a selected temperature. For example, about 43, 45,
50, 55, 60, 65, 70, 80, 85, 90, 95 degrees Celsius, or other
smaller, intermediate or larger temperatures are used, or subranges
thereof.
[0136] In an exemplary embodiment of the invention, the time to
reach the peak temperature is selected. For example, about 0.1
seconds, about 1 second, about 3 seconds, about 5 seconds, about 10
seconds, about 15 seconds, about 30 seconds, or other smaller,
intermediate or larger values are used.
[0137] In an exemplary embodiment of the invention, the acoustic
intensity profile is high intensity, for example, about 11-20, or
21-30 or 31-40, or 41-50 or 51-60 or 61-70 or >=71 Watt/square
centimeter, or other smaller, intermediate or larger values are
used.
[0138] In an exemplary embodiment of the invention, the initial
thermal effect is selected to start away from the intima of the
artery, for example, about 0.2 mm away from the intima, or 0.3 mm,
0.5 mm, 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 7 mm, away, or other smaller,
intermediate or larger distances are selected.
[0139] In an exemplary embodiment of the invention, the location,
the volume and/or the extent of the thermal effect is selected.
[0140] In an exemplary embodiment of the invention, the treatment
is selected to treat only a portion of the target tissue, for
example, half of the target tissue. Alternatively, the treatment is
selected to treat the entire target tissue.
[0141] In an exemplary embodiment of the invention, the treatment
is selected according to safety considerations. Optionally, a
safety consideration is treating with a margin of safety around the
target tissue, for example, the treatment is selected to treat the
target tissue without treating surrounding tissue. Alternatively,
the treatment is selected to treat at least some tissue surrounding
the target tissue. Alternatively or additionally, a safety
consideration is side effects of treatment, for example, treatment
is selected to reduce and/or prevent contraction (e.g., stenosis)
of the artery, for example, due to scarring of tissue in the
arterial wall.
[0142] In an exemplary embodiment of the invention, the treated is
selected for a type of tissue. Optionally, the treatment is
selected towards nerves in the adventia or peri-adventitia.
Optionally or additionally, the treated is selected towards nerves
are in the renal artery wall. Alternatively, the treatment is
selected towards renal nerves in the aorta. Alternatively, the
treatment is selected towards nerves in the carotid artery
wall.
[0143] In an exemplary embodiment of the invention, the treatment
is selected by taking into account the cooling capacity of the
vessel wall, such as a blood flow in the artery.
[0144] In an exemplary embodiment of the invention, the frequency
of vibration of the acoustic element of the transducer is selected
according to the depth of the target tissue.
[0145] In an exemplary embodiment of the invention, the ultrasonic
intensity profile is selected according to the size of the
treatment region. Optionally, a relatively low ultrasonic intensity
profile treats a relatively small area in the peri-adventitia.
Optionally, a relatively higher ultrasonic intensity profile is
selected to increase the treatment region from the peri-adventitia
towards the intima, for example until the adventia, until the
media, or to increase the size of the treatment region in the
peri-adventia.
[0146] In an exemplary embodiment of the invention, one or more
tissue properties are adjusted, for example, increased and/or
decreased. Non-limiting examples of tissues include; target tissue,
surrounding tissue, blood flowing in vessel. Optionally, tissue
properties are adjusted in accordance with the selected thermal
effect, for example, to relatively increase the size of the
thermally affected area. Optionally or additionally, tissue
properties are adjusted in accordance with the selected safety
parameters, for example, to relatively increase the margin of
safety. Non-limiting examples of tissues properties that are
adjusted include; the temperature of the tissue, the heat removal
rate from the tissue, the acoustic energy absorption of the
tissue.
[0147] In an exemplary embodiment of the invention, feedback
associated with the treatment is obtained. Optionally, the desired
result is used as a target, such as in an open-loop manner. For
example, initial parameters are set and the tissue is treated to
achieve the result. Alternatively or additionally, the desired
result is used as feedback of the treatment, such as in a
close-loop manner. For example, treatment is applied, imaging of
the treatment region is performed to check if the desired result
has been met and treatment is reapplied, optionally with
adjustments to the treatment.
[0148] In an exemplary embodiment of the invention, the treatment
region is defined by a circumferential extent and by a distance
extent and also by a starting distance (e.g., from an intima). In
an exemplary embodiment of the invention, the distance extent
and/or starting distance are controlled with an accuracy of, for
example, better than 2 mm, 1 mm, 0.5 mm, or 0.2 mm. Optionally or
alternatively, the circumferential extent of treatment is
controlled with an accuracy of better than 30 degrees, 10 degrees,
or 5 degrees, which can be, for example, 3 mm, 2 mm, 1 mm, 0.5 mm
or better or intermediate accuracy.
[0149] In an exemplary embodiment of the invention, the amount,
pattern and/or extent of the treated region is selected according
to a desired effect and/or a probability of affecting sufficient
tissue to be treated (e.g., nerves). Optionally, the amount of
treatment is curtailed, for example, to reduce side effects, such
as constriction of the lumen caused by too much damage in the lumen
wall.
[0150] In an exemplary embodiment of the invention, for a section
of treated lumen of, for example, 1-5 cm in length (e.g., axial
distance between outermost treatment locations), the percentage of
axial locations treated is, for example, 10%, 30%, 50%, 80% or
smaller or intermediate or greater percentages.
[0151] In an exemplary embodiment of the invention, when
considering the surface area of the intima of such a treated
section, and mapping treated regions by "collapsing" them towards
the intima, the percentage of area treated can be, for example, 5%,
15%, 30%, 60%, 80% or smaller or intermediate or larger
percentages.
[0152] In an exemplary embodiment of the invention, when
considering the circumference of the intima of such a treated
section at an axial location where treatment is applied, and
mapping treated regions by "collapsing" them towards the intima,
the percentage of circumference treated can be, for example, 5%,
15%, 30%, 60%, 80% or smaller or intermediate or larger
percentages, for example, for between 1 and 8 axial treatment
locations.
[0153] A particular feature of some embodiments of the invention is
that an extent of treatment in a dimension perpendicular to the
lumen wall is affected both by cooling of the lumen wall, e.g., by
natural blood flow and by dissipation of energy as the energy
penetrates into the tissue. In an exemplary embodiment of the
invention, the frequency and/or other properties of the energy
affect the absorption per unit distance, which results in reduced
energy deposition as distance increases. Optionally or
alternatively, cooling effects of nearby tissue reduce energy
deposition. Optionally or alternatively, divergence of the beam
reduces energy deposition. Optionally or alternatively, tissue
properties, for example, insulation of a sheath surrounding nerves,
serves to increase the effect of energy deposition at some tissues.
Optionally or alternatively, tissue characteristics affect energy
deposition thereat.
[0154] A particular feature of some embodiments of the invention is
the use of an unfocused energy field, which, in some embodiments,
can preserve a uniform definition of its edges for a considerable
distance, thereby providing definition of circumferential edges of
a treated area.
[0155] A particular feature of some embodiments of the invention
relates to the ability to reduce mechanical positioning
requirements while maintaining and/or increasing accuracy of
spatial selectivity of treatment.
[0156] With respect to a direction perpendicular to the vessel
wall, in a focused system, position control is provided by accurate
focusing and control of catheter position (e.g., to be in contact
with a wall). In an exemplary embodiment of the invention, however,
position control in that direction is provided by a tradeoff
between cooling by blood flow and energy application. This is not
dependent on the catheter position in a blood flow, as there is
relatively little loss in the blood, in some embodiments. This
means that variations of several millimeters in catheter distance
form the wall need not have a significant effect on spatial
treatment location. Moreover, not having contact with the vessel
wall can ensure, in some embodiments, sufficient cooling to prevent
damage at any part of the intima.
[0157] Use of non-focused beams can also help in the
circumferential accuracy requirements. In one example, it allows
the treated "spot" to be quite large, which means there need not be
any scanning of a focal point of a focused beam, which scanning may
be complex and/or inaccurate. Optionally, the circumferential
profile of the beam is selected so that it provides a gradual
cut-off in degree of damage, for example, along a border of, for
example, 1-2 mm in width. Alternatively, a sharp cut-off is
provided, for example, by suitable selection of emitter design to
have a sharp cut-off in intensity profile.
[0158] In an exemplary embodiment of the invention, provision of
high power allows the treatment time to be short enough so that,
for example, treatment can be applied while blood velocity is
constant (e.g., during cardiac disatole) and/or while the vessel
wall is not moving (e.g., relative to catheter, which is optionally
determined using a distance sensor and/or estimated using a pulse
sensor and/or ECG sensor).
[0159] In an exemplary embodiment of the invention, cooling of an
ultrasonic emitter by blood flow allows higher power to be
used.
Overview of Treatment
[0160] FIG. 1A is a flow chart of a method of selectively treating
tissues using ultrasound energy, in accordance with an exemplary
embodiment of the invention. Optionally, the ultrasound energy is
applied at a selected frequency. Optionally or additionally, the
ultrasound energy is applied at a selected intensity profile (e.g.,
watts per square centimeters, time of treatment). The method
described in the flowchart is non-limiting. For example, some steps
are optional. Furthermore, there can be other methods and/or other
apparatus used to obtain the results.
[0161] At 102, a target tissue is optionally determined, for
example, to treat a clinical disorder by thermally damaging (e.g.,
ablating) the target tissue, in accordance with an exemplary
embodiment of the invention.
[0162] In an exemplary embodiment of the invention, one or more
factors related to the thermal effect are optionally determined
(e.g. manually by a physician, automatically by software), for
example, the anatomical location (e.g., the blood vessel where the
catheter will be inserted) of the lesion, the type of tissue to
ablate (e.g. nerve), an extent of the thermal effect (e.g., the
entire tissue, part of the tissue), and/or safety
considerations.
[0163] At 104, one or more parameters to result in the desired
thermal effect of the target tissue are optionally determined, in
accordance with an exemplary embodiment of the invention.
[0164] Optionally, feedback is obtained about the treatment effect,
for example, imaging of the target tissues. Alternatively, feedback
is not required, as the initial settings are sufficient to achieve
the desired treatment effect.
[0165] In an exemplary embodiment of the invention, localization of
the treatment effect is optionally provided by one or more factors
including, the blood cooling the vessel wall, the ultrasonic beam
amplitude attenuation, the ultrasonic beam dispersion, and/or
tissue types.
[0166] At 106, the target tissue as determined in 110 is treated
using parameter settings as in 104, in accordance with an exemplary
embodiment of the invention. Optionally, ultrasound energy is
delivered by a transducer on a catheter inserted into the body.
Optionally, the treatment is monitored.
[0167] Optionally, at 108, treatment is repeated, for example,
immediately and/or at a later point in time. Optionally, treatment
is adjusted in response to feedback.
[0168] In an exemplary embodiment of the invention, feedback
optionally is related to the parameters used for transmission of
ultrasonic energy, for example, associated with the treatment
intensity profile. Optionally, feedback is related to the
environment, for example, the rate of blood flow. Alternatively or
additionally, feedback is related to the impedance of the acoustic
element, such as to estimate changes in efficiency that can affect
the transmitted acoustic intensity profile.
[0169] In an exemplary embodiment of the invention, feedback is
optionally functionally related to the effects of the ultrasonic
energy on tissues. Optionally, feedback in the form of imaging is
used to detect the effect of treatment on tissues. Alternatively or
additionally, feedback in the form of clinical measurements (e.g.,
blood pressure changes) are used to detect the effect.
[0170] In some embodiments, imaging is optionally used to evaluate
the treatment (e.g., thermal damage to target tissue).
Alternatively or additionally, the treatment is evaluated using
other methods, such as clinical measurements, sometimes over the
long term.
Control System
[0171] FIG. 2 illustrates an exemplary ultrasound treatment system
1600 for selectively treating tissues, in accordance with an
exemplary embodiment of the invention. System 1600 provides for the
control of the ultrasound treatment and/or monitoring of the
treatment using catheter 1222. A transducer 300 comprising an
acoustic element 102 to produce ultrasound energy is optionally
located on a distal end of catheter 1222.
[0172] In an exemplary embodiment of the invention, an operator
(e.g., physician performing the procedure) programs a controller
1602 (e.g., computer) for treatment using a user interface 1604
(e.g., keyboard, mouse, monitor). Optionally, treatment is
monitored, for example, by viewing feedback parameters on interface
1604.
[0173] In an exemplary embodiment of the invention, a power port
1606 provides electrical power to electrodes across element 102,
causing element 102 to vibrate at the set frequency, outputting a
set ultrasound intensity profile.
[0174] In an exemplary embodiment of the invention, one or more
functions and/or parameters and/or settings are programmed and/or
set into controller 1602 (e.g., automatically determined by
software such as according to a treatment plan). Optionally or
additionally, one or more functions and/or parameters are
selectable (e.g., manually set by a user, automatically selected by
software).
[0175] One or more non-limiting examples of settable parameters
include: [0176] Impedance of element 102. [0177] Acoustic feedback
is feedback obtained by analyzing echoes of a diagnostic ultrasound
signal returning from tissues, for example, as will be described in
more detail with reference to FIG. 11. [0178] Estimated or measured
flow rate of blood across the surface of the acoustic element is
important for controlling the temperature of the element to prevent
overheating. In some embodiments, the flow rate of the blood is
adjusted relatively higher or relatively lower, such as to control
the temperature. [0179] Estimated or measured flow rate of blood
across the wall of the treatment target (e.g., blood vessel) is
important for estimating the cooling capacity of the blood on the
tissues of the wall being heated by ultrasound. [0180] Efficiency
is the estimated efficiency of converting electrical energy into
ultrasound energy by the acoustic element. [0181] Temperature
control system cools and/or heats the element and/or tissues (e.g.,
blood vessel wall) to the desired temperature. Optionally, the
temperature control system is used in combination with the blood
flow. In some embodiments, the blood and/or tissue is pre-heated,
for example, to obtain a relatively larger thermal effect. [0182]
Impulse excitation is the application of an impulse function (e.g.,
delta function) to the element, causing the element to vibrate with
a decreasing amplitude. Impulse excitation is used to estimate a
reduction in efficiency, useful as feedback, for example, to
determine one or more of, thrombus formation on the element, the
element coming in contact with the vessel wall, mechanical damage
to the element. [0183] Navigation system controls the movement
and/or positioning and/or orientation of catheter 1222 and/or the
transducer. [0184] Pressure is the pressure caused by sound (e.g.,
acoustic intensity) during treatment and/or imaging. [0185]
Electric power is the applied power to the transducer. [0186]
Reflected electric power from the transducer back to the
controller. [0187] Voltage is the measured and/or applied voltage
on the transducer. [0188] Current is the measured and/or applied
current in the transducer.
[0189] One or more non-limiting examples of selectable parameters
include: [0190] Frequency of the ultrasound energy produced by
vibration of the acoustic element. [0191] Waveform applied to the
acoustic element, for example, a sinusoidal wave form. [0192]
Intensity is the produced ultrasound power divided by the surface
area of the acoustic element. [0193] Pulse duration is the length
of a pulse of acoustic energy measured in time. [0194] Duty cycle
is the percentage of time in a single pulse that ultrasound energy
is transmitted. [0195] Temperature threshold is the approximate
temperature of the element and/or the liquid (e.g., blood, saline)
that should not be exceeded. [0196] Treatment pattern is the
spatial and/or temporal combination of one or more of the above
variables, for example, a single pulse, a sequence of pulses, a
train of pulses. [0197] Focusing is the setting of non-focused vs.
focused ultrasound energy.
[0198] The table below sets out some examples of the selectable
parameters, and provides their theoretical limits, an exemplary
treatment range, and an exemplary treatment sub range (e.g., most
commonly used settings). It is important to note that some
selectable parameters can only be selected from a pre-determined
set, for example, in some embodiments, catheters are designed to
operate at a specific frequency, in which case the user selects the
frequency according to the catheter available.
TABLE-US-00001 Exemplary Exemplary Theoretical Treatment Treatment
Parameter range range sub range Frequency (MHz): Treatment 1-60
8-30 10-22 Imaging 1-60 10-60 10-25 Intensity (Watts/sq cm) 1-200
10-100 10-60 Duty cycle (%) 0.1-100 10-100 50-100 Pulse duration
(seconds) 0.01-1000 0.1-4 0.1-2.sup. Duration of treatment 0.1-1000
2-120 3-60 (Seconds) per location Efficiency (%) .sup. 1-70% 20-70%
.sup. 35-70% Temperature (Celsius) 10-100 15-80 25-80
Some Examples of Expected Effects Associated with Variables
[0199] The following are some non-limiting examples illustrating
some parameters under control, and their association with some
expected treatment effects, in accordance with an exemplary
embodiment of the invention: [0200] Impedance: a decrease of more
than 10% suggests a decrease in efficiency of the acoustic element.
The element will heat up more (e.g., requiring more cooling),
and/or the acoustic intensity will decrease (e.g., requiring a
higher intensity). In some embodiments, the impulse excitation is
used to estimate the change in efficiency. [0201] Acoustic
feedback: imaging of the treatment region for the desired thermal
effects can be used to decide if to continue treatment, stop
treatment or change treatment (e.g., increase or decrease acoustic
intensity profile, change positions of catheter). [0202] Estimated
flow rate of blood across acoustic element: a change in blood flow
can cause the element to overheat, potentially damaging the
element. [0203] Estimated flow rate of blood across wall of blood
vessel: a decrease in flow rate reduces the cooling of tissues,
potentially resulting in a larger thermal effect for the given
acoustic intensity. An increase in flow increases the cooling of
the tissues, potentially resulting in a smaller thermal effect.
Alternatively, the location of the thermal effect will be shifted.
In some embodiments, the flow rate is controlled to within a
predetermined range (e.g., as will be described below).
Alternatively or additionally, the acoustic intensity profile is
adjusted. Alternatively or additionally, the cooling system is used
to maintain the temperature of the element and/or wall within the
range. [0204] Navigation system: imaging feedback can be used to
detect if the thermal effect is at the desired location (e.g., to
the target tissue). Adjustments in position can be made
accordingly. [0205] Frequency: a relatively lower frequency of
ultrasonic energy is able to penetrate relatively deeper into
tissue. In some embodiments, relatively lower frequencies are used
to achieve thermal effects relatively further away from the blood
vessel wall. [0206] Intensity: a relatively higher intensity of
ultrasonic energy is able to penetrate relatively deeper into
tissue and/or achieves a relatively higher heating of tissues
quicker. In some embodiments, relatively higher intensities are
used to achieve relatively larger thermal effects. Alternatively or
additionally, thermal effects are further away from the vessel
wall. [0207] Pulse duration: a relatively longer pulse will deliver
a relatively larger amount of ultrasonic energy to tissues,
achieving a relatively larger thermal effect. [0208] Duty cycle: a
relatively higher duty cycle will deliver a relatively higher
amount of ultrasonic energy to tissues, achieving a relatively
larger thermal effect. In some embodiments, a relatively short duty
cycle acts as a train of short pulses separated by delays, the
effect of which is described below with reference to `treatment
pattern`. [0209] Treatment Pattern: can be applied to achieve
various treatment objectives, for example, a pulse of acoustic
energy can be applied, followed by a delay period to allow cooling
(e.g., by spreading of heat) before applying another pulse of
energy. In another example, tissue can be targeted for treatment at
one location, followed by a rotation (e.g., 10 degrees), followed
by treatment at the second location, followed by a rotation to the
first location. [0210] Focusing: non-focused application of energy
does not require precise anatomical positioning of the distance
from the transducer to the target tissue throughout treatment, and
achieves a relatively larger treatment volume using a relatively
lower acoustic intensity. Focused application of energy requires
precise positioning of the focal point to the target tissue
throughout treatment, and achieves a relatively smaller treatment
volume using a relatively higher intensity (e.g., total intensity
at focal point).
Exemplary Method of Treatment
[0211] FIG. 1B is a detailed method of treatment of FIG. 1A, in
accordance with an exemplary embodiment of the invention. It should
be noted that the method described in the flowchart is
non-limiting. For example, some steps are optional. Furthermore,
there can be other methods and/or other apparatus used to obtain
the results.
[0212] Optionally, at 152, a decision to treat is made, for
example, as will be described in the section "DECIDING TO
TREAT".
[0213] Optionally, at 154, the anatomical location to treat is
selected, for example, as will be described in the section
"SELECTING ANATOMICAL LOCATION OF TREATMENT".
[0214] Optionally, at 156, a decision is made with regards to the
amount of thermal damage to cause, for example, as will be
described in the section, "DECIDE AMOUNT OF THEMAL EFFECT".
[0215] Optionally, at 158, a decision is made with regards to
tradeoffs related to safety considerations, for example, increasing
the margin of safety will result in less damage to surrounding
tissue, but may not result in full treatment of the target tissue,
for example, as will be described in the section "DECIDE SAFETY
CONSIDERATIONS".
[0216] Optionally, at 160, the rate of blood flow in the artery is
estimated, for example, as will be described in the section
"ESTIMATE BLOOD FLOW".
[0217] Optionally, at 174, one or more tissue properties of the
target tissue and/or surrounding tissue are adjusted, such as
temperature and/or heat removal rate, for example, as will be
described in the section "ADJUSTING TISSUE PROPERTIES". In some
embodiments, the tissue properties are adjusted according to one or
more parameters, such as the amount of thermal effect and/or safety
considerations.
[0218] Optionally, at 162, the frequency of the ultrasound energy
to apply is selected, such as by choosing a catheter designed to
operate at that frequency, for example, as will be described in the
section "CHOOSE CATHETER (FREQUENCY) ACCORDING TO TREATMENT". In
some embodiments, the user is limited in the selection of the
frequency according to the available frequency. At 164, the
ultrasonic intensity profile is selected according to the treatment
(e.g. watts per square centimeter, time of treatment, profile over
time) for example, as will be described in the section "CHOOSE
ULTRASONIC INTENSITY PROFILE ACCORDING TO TREATMENT".
[0219] Optionally, at 166, the catheter (e.g., as selected in 162)
is inserted into the body of the patient and threaded to the
treatment site (e.g., as selected in 154), for example, as will be
described in the section "INSERT CATHETER".
[0220] At 168, the patient is treated, for example, as will be
described in the section "TREAT".
[0221] Optionally, at 170, feedback is obtained, for example, as
will be described in the section "FEEDBACK".
[0222] Optionally, at 172, adjustments are made, for example, to
one or more parameters, and treatment continues as in 168, for
example, as will be described in the section "ADJUST".
Deciding to Treat
[0223] In an exemplary embodiment of the invention, a decision to
treat by thermally damaging target tissue is made, for example, by
a physician according to clinical indications.
[0224] Non-limiting examples of clinical applications are listed in
the table below. The applications listed in the table are
referenced (e.g., according to numbers) to FIG. 3, which is an
illustration of the human body showing the major arteries as
reference points, useful in practicing some embodiments of the
invention.
Exemplary Clinical Applications
TABLE-US-00002 [0225] # Application Name Anatomy Target 402 Renal
sympathetic Renal artery Renal sympathetic nerve modulation nerves
404 Carotid sympathetic Carotid artery Carotid sympathetic nerve
modulation nerves 406 Vagus sympathetic Aorta Vagus sympathetic
nerve modulation nerve 408 Peripheral sympathetic Peripheral
Peripheral sympathetic nerve modulation blood vessels nerves 410
Pain nerve modulation Spinal cord Pain nerves cannel 412 Restenosis
decrease All relevant Artery media and arteries adventitia 414
Vulnerable plaque All relevant Artery media and stabilization
arteries adventitia 416 Atherosclerosis All relevant Artery media
and passivation arteries adventitia 418 Plaque volume decrease All
relevant Artery media and arteries adventitia 420 Plaque thrombosis
All relevant Artery media and decrease arteries adventitia 422
Tetanic limb muscle Limb arteries Peripheral motor tonus decrease
or veins nerves 424 Atrial fibrillation Right atria Pulmonary vain
prevention insertion 426 Cardiac arrhythmia Coronary Cardiac tissue
prevention arteries pathology 428 Liver tumor necrosis Inferior
vena Tumor cava 430 None-malignant Urethra Sick prostate tissue
prostate treatment 432 Malignant prostate Urethra Sick prostate
tissue treatment 434 Artery aneurysms All relevant Aneurysm wall
stabilization arteries 436 Aortic aneurysms Aorta Aneurysm wall
stabilization 438 Berry aneurysms Brain arteries Aneurysm wall
sealing 440 Erectile dysfunction Internal Iliac Artery media and
treatment adventitia
[0226] A non-limiting method of stabilizing a plaque and/or
aneurysm using ultrasound energy is described for example, in
Sverdlik et al, in PCT/IL2008/000234, incorporated herein by
reference in its entirety.
[0227] In an exemplary embodiment of the invention, nerve tissue is
selectable for treatment by ultrasonic energy, for example, as will
be described below with reference to FIG. 7B.
[0228] Some exemplary medical conditions and their proposed
treatment by treating nerves (examples not limited to the nerves
described, treating other nerves may achieve a similar clinical
outcome) in accordance with an exemplary embodiment of the
invention include: [0229] Frozen shoulder--suprascapular nerve.
[0230] Zygapophysial joint pain--cervical medial branch nerves.
[0231] Chronic Pelvic Pain (in women)--uterosacral nerve. [0232]
Glabellar Frowning--facial nerve. [0233] Phantom Pain--lumbar
dorsal root ganglia. [0234] Trigeminal Neuralgia--branches of the
trigeminal nerve. [0235] Cluster Headache--trigeminal and/or
sphenopalatine ganglions. [0236] Complex Regional Pain
Syndrome--stellate ganglion.
[0237] In some embodiments, electrical signals through nerves are
reduced by treatment, for example, by damaging some neurons in the
nerve bundle. Alternatively or additionally, electrical signals
through nerves are prevented from passing through, for example, by
damaging the entire nerve bundle.
[0238] In some embodiments, malignant tissues (e.g., in the liver)
and/or hypertrophic tissues (e.g., in the prostate) are
damaged.
[0239] In some embodiments, the parameters to treat the tissues are
obtained from a mathematical model, for example, as described in
the section "EXEMPLARY DEVELOPMENT OF AN EQUATION" parts A and/or
B.
[0240] Some non-limiting examples of how to achieve various desired
effects using some embodiments of the invention are described. The
description refers to obtaining the described effect. However, it
should be noted that some effects overlap, and so some embodiments
achieve one or more effects. In some embodiments, only the desired
effect is achieved without other effects. [0241] Coagulation--In
some embodiments, heating tissue including blood to the range of
42-55 or 42-50 or other smaller, intermediate or larger values,
results in blood coagulation without damage to surrounding tissues.
[0242] Denaturation--In some embodiments, heating tissue above 50,
above 55, above 60 or other smaller, intermediate or larger values
results in denaturation of collagen. [0243] Apoptosis--In some
embodiments, tissues are heated to over 85, over 95 degrees
Celsius, or other smaller, intermediate or larger values to cause
apoptosis, for example, as taught by Fung et al. Tissues affected
are located about 0-0.5 mm away from the area of the applied
energy. [0244] Temporary/permanent disruption of nerve signals--In
some embodiments, the length of nerve that is disrupted (e.g.,
burned) is selected to result in temporary or permanent disruption
of nerve signals. For example, a relatively short disruption length
can allow nerves to regenerate and reconnect, for example, about
0.1 mm, about 0.5 mm, about 1 mm, about 2 mm, about 5 mm, or other
smaller, intermediate or larger values are used. Optionally,
relatively long disruption lengths prevent nerves from regenerating
and reconnecting, for example, about 10 mm, about 15 mm, about 20
mm, about 30 mm, or other smaller, intermediate or larger values
are used. [0245] Destruction--In some embodiments of the invention,
tissues are heated to over 100 degrees Celsius to result in tissue
destruction. A temperature of over 100 degrees Celsius results in
vaporization of water, which can cause cells to burst. [0246]
Burning--In some embodiments, tissues are heated for relatively
long periods of time to result in burning of the tissue, for
example, over 10, 20, 30, 50, 100 seconds, or other smaller,
intermediate or larger time periods. Alternatively or additionally,
relatively high intensities are applied to result in the burn.
[0247] Degeneration--In some embodiments, tissues are heated to
cause degeneration of the tissue, such as to about 47 degrees
Celsius, for example, as taught by Xu & Pollock (see
below).
Selecting Anatomical Location of Treatment
[0248] In an exemplary embodiment of the invention, the anatomical
location for treatment (e.g., thermal effect) is selected.
Optionally, a factor in the selection is the ability to apply
ultrasound energy to the target tissue. One or more non-limiting
examples of target tissues include, fat, nerves, vasa vasora,
lymph, tumor, connective tissue, plaque (e.g.,
atherosclerotic).
[0249] In an exemplary embodiment of the invention, ultrasonic
energy is applied invasively, for example, using a catheter and/or
an endoscope. Alternatively, ultrasonic energy is applied
non-invasively. Non-limiting examples from which thermal effects
can be applied include one or more of, a fluid filled lumen (e.g.,
blood vessel), a non-fluid filled lumen (e.g., ureter), a fluid
filled cavity (e.g., spinal canal), a non-fluid filled cavity
(e.g., stomach), from outside the body (e.g., ultrasonic transducer
is placed in a liquid such as water, and energy is delivered across
the skin).
[0250] In an exemplary embodiment of the invention, a decision on
the location of treatment is made from one or more different
possible anatomical locations. Optionally, a factor in the
selection is the location inside the lumen from which ultrasonic
energy is applied, for example some locations are more easily
accessed by using a catheter than others. Alternatively or
additionally, a factor in the selection is the rate of blood flow
in the blood vessel where the catheter will be positioned (e.g.,
some areas have more uniform flow), potentially important for
cooling, for example, as will be described in the section "Estimate
blood flow". In some cases, similar clinical effects will be
achieved by thermal effects (e.g., damage) of at least one of the
different locations.
[0251] For example, a treatment of resistant essential hypertension
is renal denervation. Reference is made to FIG. 4, which is an
illustration of the anatomy of renal nerves 350 in relation to a
right renal artery 352. Right renal artery 352 supplies blood to a
right kidney 354 from an aorta 356. Commonly, renal nerves 350
arise from T10-L2 spinal roots, travel along aorta 356 and along
renal artery 352 to innervate kidney 354. In some anatomies, renal
nerves 350 primarily lie within the adventia of the renal artery
352 and/or aorta 356.
[0252] Non-limiting examples of conditions likely to respond to
renal denervation: [0253] Resistant essential hypertension. [0254]
Essential hypertension intolerant to medications. [0255] Nondipping
essential hypertension. [0256] Resistant renovascular hypertension.
[0257] Hypertension with chronic renal disease (unilateral or
bilateral). [0258] Hypertension with obstructive sleep apnea
intolerant to continuous positive airway pressure. [0259]
Congestive heart failure (with reduced or preserved left
ventricular systolic function) with cardiorenal syndrome. [0260]
Hypertension in end-stage kidney disease on dialysis with native
kidneys. [0261] Hypertension in renal transplant patients with
remaining native kidneys. Non-limiting examples of potential
long-term benefits of renal denervation: [0262] Attenuation of
arterial pressure. [0263] Stabilization of renal function with
attenuation of the rate of decline of estimated glomerular
filtration rate and reduction of proteinuria in hypertensive
patients. [0264] Restoration of nocturnal dipping. [0265]
Regression of left ventricular hypertrophy. [0266] Decreased
insulin resistance. [0267] Slower progression of vascular disease.
[0268] Decreased incidence of congestive heart failure with reduced
ventricular hypertrophy, reduced salt and water retention, and
improved exercise tolerance. [0269] Decreased risk of stroke.
[0270] Decreased risk of atrial and ventricular arrhythmias. [0271]
Decreased risk of sudden cardiac death.
[0272] Further details about renal denervation can be found in an
article by Katholi et al. "Renal nerves in the maintenance of
hypertension: a potential therapeutic target" Curr Hypertens Rep.
2010 June; 12(3):196-204, incorporated herein by reference in its
entirety.
[0273] There are one or more exemplary locations for performing the
renal denervation procedure, useful in practicing some embodiments
of the invention. For example, the procedure can be performed at a
renal artery location 358 (e.g., from inside renal artery 352), at
an ostium location 360 (e.g., the branch of renal artery 352 off
aorta 356) and/or at an aorta location 362 (e.g., from inside aorta
356).
[0274] Non-limiting examples of factors affecting the location
(e.g., 358, 360, 362) of treatment include simplicity of access,
simplicity of the treatment procedure. For example, at location 358
multiple treatment areas may be required to ablate enough renal
nerves 350 to achieve a desired clinical result of lowering blood
pressure. For example, at location 360 and/or 362 two treatments
can achieve the same effect, as the renal nerves 350 are
concentrated together (e.g., afferent and efferent renal nerves
travel together).
[0275] In some embodiments, catheters with ultrasound transducers
for treatment at specific locations can be custom designed. For
example, a straight catheter 364 with a transducer 368 can be
designed for treatment at location 362. For example, a curved
catheter 366 can be designed for treatment at location 360 (e.g.,
by placing a transducer 370 at the curve) and/or at location 358
(e.g., by placing a transducer 372 at the distal end of catheter
366).
[0276] In an exemplary embodiment of the invention, the ultrasound
energy used to treat the target tissues does not need to be applied
directly to the vessel wall. Optionally, the ultrasound energy is
applied away from the vessel wall, for example, the transducer is
not in contact with the wall.
[0277] In an exemplary embodiment of the invention, damage to the
intima layer (e.g., endothelium) and/or internal elastic lamina of
the vessel wall is prevented and/or reduced. A potential advantage
is preventing and/or reducing the risk of adverse clinical
outcomes, for example, one or more of, triggering a coagulation
cascade, causing a vessel spasm, causing stenosis, blood loss due
to injury to the vessel wall.
Exemplary Treatment Device
[0278] FIG. 5 illustrates a target tissue being irradiated with
ultrasonic energy, in accordance with an exemplary embodiment of
the invention. Shown is catheter 1222 inside a lumen 1240 of a
blood vessel 1242 (e.g., artery). Optionally, an acoustic element
102 (e.g., part of transducer 300) emits a beam 1228 of ultrasound
energy towards a target tissue 1216.
[0279] In an exemplary embodiment of the invention, the ultrasonic
emission element and/or transducer 300 is capable of relatively
high intensity ultrasound output. Optionally, transducer 300 is
gas-backed, such as with a bubble of gas. Non-limiting examples of
high intensity ultrasound include at least 20 watts/cm.sup.2, at
least 30 watts/cm.sup.2, at least 50 watts/cm.sup.2, at least 100
watts/cm.sup.2 or other smaller, intermediate or larger
intensities.
[0280] In an exemplary embodiment of the invention, beam 1228 is
unfocused, for example, beam does not converged at a point, for
example, beam diverges relatively little.
[0281] In an exemplary embodiment of the invention, the shape of
element 102 is rectangular. Optionally, element 102 is planar.
Optionally, a length of element 102 is, for example, about 1 mm,
about 2 mm, about 4 mm, about 6 mm, about 8 mm, about 10 mm, or
other smaller, intermediate or larger lengths are used. Optionally,
a width of element 102 is, for example, about 0.2 mm, about 0.6 mm,
about 1.0 mm, about 1.4 mm, about 2.0 mm, or other smaller,
intermediate or larger widths are used.
[0282] In an exemplary embodiment of the invention, beam 1228
produced by a rectangular acoustic element is relatively straight,
spreading an angle of about fifteen degrees relative to the exposed
surface of element 102, when measured along the length.
[0283] In an exemplary embodiment of the invention, target tissue
1216 is located a distance 1232 away from wall 1226. Non-limiting
examples of the maximum distance 1232 of target tissue 1216 that
can be treated include 0.5 mm, 1 mm, 2 mm, 5 mm, 10 mm, or other
smaller, intermediate or larger distances.
[0284] In an exemplary embodiment of the invention, target tissue
1216 is treated by an ultrasound beam 1228 from transducer 300. In
an exemplary embodiment of the invention, treating comprises a
thermal effect (e.g., heating to above 55 degrees Celsius) and/or a
cavitation effect.
[0285] The table below illustrates some non-limiting examples of
the effect of temperature on nerves over time. The rise in
temperature is due to heat sources in general and is not limited to
ultrasonic heating.
TABLE-US-00003 Temp Histological findings - Article (.degree. C.)
Follow up summary Xu & 47 Immediately Schwann cells - disrupted
Pollock, after cytoplasmic organelles 1994 treatment Blood vessels
- collapsed; endothelia separated from overlying pericytes; swollen
endothelia and perivascular oedema in endoneurial capillaries;
Axoplasm - `watery` Xu & 47 2 hours after Myelinated axons -
degenerating Pollock, thermal 1994 injury Xu & 47 6 hours after
Myelin - decrease in diameter Pollock, thermal Myelinated axons -
degenerated 1994 injury Myelinated fibers - distended Xu & 47 1
day after Axons - degenerated Pollock, thermal Schwann cells -
hypertrophied 1994 injury Xu & 58 immediately Myelin - widened
Schmidt-Lanterman Pollock, after incisures; disruption of myelin
1994 treatment lamellae Blood vessels - endothelia separated from
overlying pericytes; thrombosed; perivascular oedema Unmyelinated
fiber - degenerated Unmyelinated axons - swollen and devoid of
organelles Xu & 58 3 days after Nerve fibers - destructed
Pollock, thermal 1994 injury Lele, 24-48 Axons -fragmented; nodular
appearance; 1963 continuity interrupted; decreased in length Myelin
- vacuolated
[0286] In an exemplary embodiment of the invention, damage and/or
treatment to tissues (e.g., normal, healthy) surrounding target
tissue 1216 is reduced and/or prevented. Optionally, treatment
and/or damage to a volume of tissue between target tissue 1216 and
wall 1226 is reduced and/or prevented.
[0287] In some embodiments, contact between an acoustic element 102
of transducer 300 and wall 1226 of vessel 1240, is reduced and/or
prevented, for example, by a separation device 1204. Optionally,
device 1204 maintains a distance 1218 between element 102 and wall
1226 of at least 1 mm. Optionally, a relatively cool liquid (e.g.,
blood, injected saline) flows in distance 1218. In an exemplary
embodiment of the invention, the liquid cools element 102 and/or
wall 1226.
[0288] In some embodiments, catheter 1222 comprises at least one
transducer 300, positioned for example, on the side, such as inside
a window cut into the catheter shaft 1230.
[0289] In an exemplary embodiment of the invention, element 102 is
cooled. Optionally, cooling occurs by transfer of heat from element
102 to a surrounding fluid such as blood 1220, saline, urine,
water, angiography contrast fluids, cerebrospinal fluid, lymph,
mucous, stomach acid. Alternatively or additionally, cooling occurs
by injection of a volume of a liquid (e.g., saline, radio-opaque
dye) through tube 1206, and/or circulation of a liquid through tube
1208. Alternatively or additionally, cooling is increased using an
active heat flux, such as a thermoelectric cooler. It should be
noted, that herein cooling by blood flow also refers to cooling
using other fluids (e.g., saline) in addition to blood, or cooling
using other fluids as a substitution for blood cooling.
[0290] In an exemplary embodiment of the invention, a temperature
sensing element, such as sensor 308, measures and/or estimates the
temperature of element 102. In an exemplary embodiment of the
invention, sensor 308 measures the temperature of blood that has
flowed 1220 over a surface 1224 of element 102. In an exemplary
embodiment of the invention, the temperature of the blood that has
flowed 1220 over surface 1224 is used as an estimate of the
temperature of element 102.
[0291] In an exemplary embodiment of the invention, a 6 mm long X 1
mm wide transducer emitting ultrasound energy at an intensity of
100 Watts/square centimeter, is calculated to generate about 11-24
Watts of excess heat (variation according to efficiency of
operation) for removal. The amount of heat generated varies
linearly with the size of the element and/or the intensity of
emitted ultrasound energy.
Decide Amount of Thermal Effect
[0292] FIG. 6A is a schematic diagram of a cross section of an
artery 600, useful in practicing some embodiments of the invention.
The layers of the wall of artery 600, from a lumen 602 outwards
are: endothelium 604, internal elastic media 606, media 608,
adventia 610 having vasa vosorum 612 embedded therein,
peri-adventitia 614, peri-vess (peri-adventitia blood vessels
(capillaries)) 616, peri-nerv (peri-adventitia nerve fibers)
618.
[0293] In an exemplary embodiment of the invention, one type of
target tissue is nerve tissue 620. In some anatomies, nerves 620
surrounded by fat are especially well suited for targeted
treatment, for example, as will be discussed with reference to FIG.
7B. Nerve tissue 620 is commonly located in peri-adventitia
614.
[0294] In an exemplary embodiment of the invention, the extent of
thermal damage is selectable and/or controllable. Optionally,
thermal damage is selected to include only the target tissue, for
example, thermal damaged nerves 622. Alternatively or additionally,
thermal damage is selected to include tissue surrounding the target
tissue.
[0295] In an exemplary embodiment of the invention, the portion of
the target tissue to treat by thermal effect is selected.
Optionally, a portion of the target tissue experiences thermal
damage and a portion of the same target tissue does not experience
damage, for example, as shown with reference to nerve 624. The left
side of nerve 624 experienced thermal damage and the right side of
nerve 624 did not experience thermal damage. In an exemplary
embodiment of the invention, the effect of thermal damage to
portion of the target tissue is associated with an unfocused
ultrasound beam that is relatively high in acoustic intensity, and
diverges a relatively small amount. In some embodiments, a portion
of the nerve is treated by directing the ultrasound beam to the
desired targeted portion of the nerve. Alternatively or
additionally, parameters are selected to treat the portion of the
nerve, for example, a thermal effect that starts a first distance
away from the intima and ends a relatively closer second distance
away from the intima, where the target portion of the nerve falls
between the first and second distances, and the portion not to be
treated falls between the second distance and the intima.
[0296] In an exemplary embodiment of the invention, the extent of
the thermal effect to the target tissue is selected, for example,
tissues can be partially thermally damaged to the extent that the
damage is reversible (e.g., tissue can self regenerate and/or
heal).
[0297] In an exemplary embodiment of the invention, the functional
result of the thermal effect is selected, for example, to achieve a
temporary effect (e.g., reversible effect).
[0298] In an exemplary embodiment of the invention, the spatial
profile of the thermal effect is selectable, for example, the
volume of the thermal effect.
[0299] FIG. 6B is a cross sectional view, FIG. 6C is a side view
and FIG. 6D is a top view illustrating a controllable volume of
thermal damage 648 to tissue, for example to a blood vessel wall
640, in accordance with an exemplary embodiment of the invention.
Optionally, thermal damage is caused by an ultrasound beam 642 from
a transducer 644.
[0300] In an exemplary embodiment of the invention, thermal damage
is selectable a distance into wall 640 as measured from a lumen
646, for example, zero is set at the boundary of wall 640 and lumen
646. Optionally, thermal damage starts at about a distance "r1" and
ends at about a distance "r2", wherein r1 is greater than or equal
to zero and r2>r1. In some embodiments, r2 is greater than the
thickness of wall 640, for example, tissues outside of the blood
vessel can be thermally damaged.
[0301] In an exemplary embodiment of the invention, the volume of
thermal damage 648 is selectable, for example, the volume of
thermal damage is an area of about "x2-x1" (e.g., measured along
the cross section of the blood vessel) multiplied by about "y2-y1"
(e.g., measured along the long axis of the blood vessel) multiplied
by about "z2-z1" (e.g., measured parallel to the diameter of the
blood vessel). Optionally, the volume of the thermal damage is
associated with one or more factors, such as the size and/or area
of an acoustic element of transducer 644, the tissues in the wall
(e.g., the tissues from the intima to the target tissue, as well as
the target tissue), and/or the interaction between the tissues and
the ultrasonic energy (e.g., attenuation).
[0302] In an exemplary embodiment of the invention, the location of
thermal damage 648 is selectable. Optionally, an angular location
660 of thermal damage is selectable, for example, in the range of
0-360 degrees, as determined by an arbitrary reference such as on a
fluoroscopic image. Alternatively or additionally, a longitudinal
location 652 in the artery is selectable, for example, measured in
centimeters, as determined by an arbitrary reference such as
distance from an arterial branch. Optionally, angle 660 and/or
longitudinal location 652 are selected according to the position of
transducer 644, for example, rotating transducer and/or
longitudinal positioning of transducer 644. Optionally or
additionally, the extent of the thermal effect and/or thermal
damage is selectable.
[0303] In an exemplary embodiment of the invention, a damage axis
(e.g., the volume of thermal damage) is aligned with the tissue
axis. For example, to cause a clinical effect in elongated nerves
such as by thermally damaging them, it is sufficient to treat a
section of the nerve as opposed to the entire nerve.
Partial Denervation
[0304] In some embodiments of the invention, only partial
denervation is desired, for example, it may be desired to reduce
the function of the nerves by, for example, 20%, 30%, 50%, 80%, 90%
or intermediate or larger amounts. In an exemplary embodiment of
the invention, the function of the nerves is measured by the effect
on the target tissue controlled by the nerves and/or providing
signals to the nerves, rather than by the nerves ability to
transmit signals.
[0305] In an exemplary embodiment of the invention, it is desirable
to maintain some of the natural feedback controls over blood
pressure and/or other biological functions, provided by the nerve
(e.g., as part of a biological system), albeit, at an attenuated
level, for example, to compensate in part or in full and/or
overcompensate for a diseased state caused by such feedback. It
has, in fact, been found that even partial denervation which only
causes a drop of Renal Norepinephrine spillover to about 50% from
baseline (e.g., in a diseased patient), still provides a
significant drop in blood pressure.
[0306] In greater detail. In the kidney, Norepinephrine (NE) is
stored only in the renal sympathetic nerve terminals from where it
is released in relation to increases in renal sympathetic nerve
activity (renal Norepinephrine spillover (NESO)). Thus, it is
reasonable to assume that if renal tissue NE content is decreased,
then there is less NE in the renal sympathetic nerve terminals
available for release and that renal NESO will be decreased
somewhat in proportion to the decrease in renal tissue NE content.
Thus, in this way, a rough correlation is to be expected between
the renal tissue NE content and renal NESO. It is noted that this
relationship is not a precise and/or necessarily a linear
relationship.
[0307] In organ physiology, the assumption is made that if a
control mechanism exists, then it is meant to fulfill a vital
function, even if it is redundant to other control systems. Thus,
the efferent renal nerves are involved in controlling certain renal
functions (GFR, RBF, sodium handling, renin release, etc.).
Activation of these mechanisms in times of volume depletion
(hemorrhage, etc.) can be of value in preserving integrity of body
fluid volumes and cardiovascular integrity. The afferent renal
nerves sense pain (e.g., due to kidney stone) as well as provide
other reflex inputs to the central nervous system that influence
systemic sympathetic outflow to the periphery. While it believed
that efferent renal nerves grow back and that afferent renal nerves
do not grow back, the consequences of total (afferent and efferent)
renal denervation over a long time future is not clear and it may
be desirable to avoid.
[0308] In an exemplary embodiment of the invention, selecting the
treatment parameters includes deciding on a desired degree of
denervation and/or desired change in NE, for example, a change over
time, for example, a change at one day (from denervation), 10 days,
30 days, 90 days and/or intermediate and/or longer times and/or at
a plurality of times. Optionally, after a period of time, for
example, 1 month or several months, a partial denervation may be
repeated (e.g., at one or both kidneys), for example, to achieve a
desired results shown by the NE levels (or a marker thereof) not to
have been achieved.
Decide Safety Considerations
[0309] In an exemplary embodiment of the invention, a margin of
safety is selectable.
[0310] In an exemplary embodiment of the invention, the extent of
thermal damage to tissues (e.g., normal and/or healthy) surrounding
a target tissue 650 (e.g., nerve) is selectable. Optionally, volume
of thermal damage 648 is approximately a volume of target tissue
650. Alternatively, volume of thermal damage 648 is relatively
larger than the volume of target tissue 650.
[0311] In an exemplary embodiment of the invention, the volume of
normal tissue thermally treated (e.g., in volume of thermal damage
648) surrounding target tissue 650 is selectable, for example, as a
margin of safety. A potential advantage is a trade-off between
certainty of thermally damaging target tissue 650 and damaging
nearby tissue (e.g., healthy and/or normal).
[0312] In an exemplary embodiment of the invention, side effects as
a result of treatment are selectively reduced and/or prevented by
proper selection of treatment parameters. For example, one or more
scarring, shrinking and/or spasm of the blood vessel may be reduced
such as by a treatment profile that maintains a temperature
sufficiently low to achieve a thermal effect while avoiding side
effects (e.g., 55 degrees Celsius) and/or for a time period
sufficiently long to achieve the thermal effect while avoiding side
effects.
Estimate Blood Flow
[0313] In an exemplary embodiment of the invention, the rate of
blood flow is measured and/or estimated, for example, using one or
more methods including, a look-up table of estimated blood flow
rates in blood vessels, Doppler, flow sensor, temperature
measurement downstream of the transducer (e.g., measuring
temperature to estimate if blood flow is sufficient). Optionally,
the rate of blood flow as a function of time is controlled, for
example, by inflating and/or deflating a balloon upstream from the
transducer. Alternatively or additionally, a liquid (e.g., saline,
radio-opaque dye) is injected to create flow.
[0314] In some embodiments of the invention, the diameter of the
catheter is selected according to the desired rate of blood flow.
For example, a relatively smaller catheter is selected to provide
for relatively greater blood flow, such as a relatively faster rate
of blood flow. For example, a relatively larger catheter is
selected to provide for relatively slower blood flow. Non-limiting
examples of diameters include; 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, or
other smaller, intermediate or larger values are used. Optionally,
the diameter of the catheter is selected relative to the diameter
of the blood vessel, for example, about 20%, 30%, 40%, 50%, 75% of
the vessel diameter, or other smaller, intermediate or larger
values are used.
[0315] FIG. 7A illustrates an exemplary of a simplified estimate of
the association between a flow of blood and the location of an area
of thermal damage.
[0316] The upper part of FIG. 7A shows an ultrasound transducer 706
emitting ultrasound energy 708 at a target tissue 712. Energy 708
travels across a lumen 730 (e.g., of a blood vessel) into a blood
vessel wall 710. Energy 708 causes an area of thermal damage 704.
Blood flows 702 inside lumen 730.
[0317] Without being bound to theory, the lower part of FIG. 7A
illustrates an exemplary association between blood flow 702 and the
resulting area of thermal damage 704. Thermal damage 704 is
hypothesized to occur when the temperature of a tissue reaches 55
degrees Celsius or higher. The temperature in tissues of blood
vessel wall 710 is a tradeoff between the tissues being heated by
ultrasonic energy 708 (e.g., mechanical friction) and the tissues
being cooled by flow of blood 702 (e.g., convection).
[0318] Curve 714 is an exemplary illustration of a simplified
estimate of the effect of heating of wall 710 due to ultrasonic
energy 708 absorption (e.g., attenuation) as a function of distance
away from lumen 730. As energy 708 travels through wall 710, it is
absorbed, resulting in tissue of wall 710 heating up. Without blood
flow 702, the tissues closest to lumen 730 heat up the most and the
tissues furthest away heat up the least.
[0319] Curve 716 is an exemplary illustration of the cooling effect
on wall 710 due to blood flow 702 as a function of distance away
from lumen 730. Tissues closest to lumen 730 are cooled relatively
more by blood flow 702, and tissues furthest away are cooled
relatively less.
[0320] Without being bound to theory, if heat generated by
ultrasonic energy 708 is removed sufficiently quickly by blood flow
702, the tissues in wall 710 will not heat up enough to achieve a
thermal effect. At the point where the heat due to energy 708 is
not removed fast enough, the tissue can heat up to 55 degrees,
potentially resulting in area of thermal damage 704.
[0321] In an exemplary embodiment of the invention, blood flow 702
is taken into account to adjust parameters to treat target tissue
712 and/or to set area of thermal damage 704, for example, by using
a look-up table of correlated values and/or using a mathematical
formula modeling (e.g., manually by a user, automatically by a
software module). Optionally, the intensity profile of energy 708
(e.g., time of treatment, intensity of energy emitted) is selected
according to target tissue 712 and/or area of thermal damage 704.
Alternatively or additionally, the frequency of ultrasonic energy
708 is selected.
[0322] FIG. 7B is an exemplary graph illustrating a simplified
estimate of the effects of various tissues absorbing ultrasound
energy in obtaining a desired thermal effect, useful in practicing
some embodiments of the invention. In an exemplary embodiment of
the invention, selecting target tissue for treatment is associated
with the ability of the target tissue and/or tissues between the
transducer and the target tissues in attenuating ultrasonic
energy.
[0323] The table below illustrates the ability of different types
of tissues to absorb (e.g., attenuate) ultrasound energy. Tissues
having relatively higher coefficients of attenuation, heat
relatively more.
[0324] In an exemplary embodiment of the invention, the relatively
values as shown in the table are used to prepare a treatment plan
to selectively target tissues. For example, to selectively target
connective tissue (.alpha.=1.57) surrounding muscle (.alpha.=1.09),
the treatment plan can consist of bursts of ultrasonic energy
separated by gaps without energy transmission. During the bursts,
the ultrasonic energy will be attenuated relatively more by the
connective tissue resulting in a relatively higher temperature.
During the gaps, the ultrasonic energy will be dispersed relatively
more quickly by the muscle. The net result of the treatment pattern
is that connective tissues will be heated to a thermal effect,
while the muscle will not achieve a temperature high enough to be
thermally affected.
TABLE-US-00004 Material .alpha.(dB/(MHz cm)) Blood 0.2 Fat 0.48
Liver 0.5 Cardiac 0.52 Brain 0.6 Breast 0.75 Muscle 1.09 Connective
tissue 1.57 Tendon 4.7 Bone, cortical 6.9
[0325] The top part of FIG. 7B illustrates transducer 706 emitting
ultrasonic energy 708 into arterial wall 710. The bottom part of
FIG. 7B illustrates relative energy 708 absorption by different
tissues.
[0326] Starting from lumen 730, the layers of wall 710 can be
categorized as intima 718, media 720 and adventitia 722. As intima
718 is a single layer of endothelial cells, energy 708 absorption
can be assumed to be negligible. Media 720 is primarily muscle,
having a relatively low level of absorption. Adventitia is
primarily connective tissue, having a relatively higher level of
absorption. The attenuation of acoustic energy is inversely related
to frequency, for example, a relatively higher frequency results in
relatively higher attenuation. In an exemplary embodiment of the
invention, an area of thermal damage is associated with relatively
higher levels of energy 708 absorption by adventitia 722.
[0327] In an exemplary embodiment of the invention, the relative
attenuation of energy 708 by tissues is taken into account when
deciding on treatment parameters for the target tissue. In some
embodiments, the target tissue is nerve 724. Nerve 724 is primarily
connective tissue, having a relatively higher US attenuation
coefficient. In some embodiments, nerve 724 is selectively targeted
for thermal damage.
[0328] In some cases, nerve 724 is surrounded by a layer of fat
726. Fat 726 has a relatively lower level of absorption (e.g.,
attenuation of the acoustic energy) and relatively low level of
thermal conductivity (e.g., doesn't transfer the thermal energy).
Inventors hypothesize that fat 726 acts as a thermal insulator for
nerve 724, trapping the US energy absorbed by nerve 724 (e.g.,
heat), as the heat dissipation outside fat ring 726 is relatively
higher (e.g., relatively lower attenuation coefficient), the
outside tissues do not heat up as much. In an exemplary embodiment
of the invention, nerve 724 surrounded by fat 726 is selectively
targeted for thermal damage. In an exemplary embodiment of the
invention, energy 708 causes temperature in nerve 724 surrounded by
fat 726 to exceed a threshold, resulting in thermal damage 728 to
nerve 724, while tissues surrounding fat 726 are not thermally
affected (e.g., damaged).
[0329] FIG. 7C is an exemplary graph illustrating a simplified
estimate of the effect of the ability of heat removal in obtaining
a desired thermal effect, useful in practicing some embodiments of
the invention. In an exemplary embodiment of the invention,
selecting target tissue for thermal damage is associated with the
capacity of heat removal from the target tissues and/or surrounding
tissues.
[0330] In an exemplary embodiment of the invention, heat removal
from tissues in wall 710 occurs from lumen 730. Optionally, the
rate of heat removal is variable. Alternatively or additionally,
the rate of heat removal is controllable.
[0331] In an exemplary embodiment of the invention, heat removal is
accomplished by a flow of blood in the lumen. Without being bound
to theory, a higher flow of blood results in a higher rate of heat
removal. Optionally, the flow of blood in the lumen is selectable
and/or controllable, for example, by one or more methods such as,
cardiac pacing (e.g., artificially controlling the heart rate),
inflating a balloon inside the artery, and/or operating an
obstructing structure on the catheter, to at least partially block
the flow of blood and/or to direct the flow to the target artery
wall.
[0332] In an exemplary embodiment of the invention, heat removal is
associated with the temperature of the blood in the lumen. Without
being bound to theory, a lower blood temperature results in a
higher rate of heat removal. Optionally, the temperature of blood
is selectable and/or controllable, for example, by injection of a
relatively cold liquid upstream from the treatment area (e.g.
saline, radio-opaque dye, patient's own blood that has been
cooled).
[0333] For illustrative purposes, FIG. 7C shows a relatively slow
heat removal 740 and a relatively fast heat removal 742 in lumen
730. In some embodiments, slow heat removal 740 results in a
thermal damage area 744 that is relatively closer to lumen 730. In
some embodiments, fast heat removal 742 results in a thermal damage
area 746 that is relatively further away from lumen 730.
[0334] Without being bound to theory, the bottom part of FIG. 7C
shows that for the same ultrasound attenuation curve 714 (e.g.
ultrasound energy 708 produced by transducer 706), a slow removal
curve 748 causes thermal damage area 744 relatively closer to lumen
730 as compared with a fast removal curve 750 that causes thermal
damage area 746 relatively further from lumen 730.
Adjusting Tissue Properties
[0335] In some embodiments of the invention, one or more tissue
parameters are adjusted. Optionally, the tissue is adjusted (which
affects the tissue parameters) in accordance with one or more
treatment parameters, for example, the selected safety profile
and/or selected amount of thermal effect. Optionally, parameters
are adjusted relatively higher or relatively lower.
[0336] In an exemplary embodiment of the invention, adjustment is
provided by the controller, optionally using the catheter, for
example, to deliver an electrical current or a drug to the artery
and/or to the heart and/or other tissue, such as tissue near the
artery. Alternatively a separate application device is provided. In
an exemplary embodiment of the invention, the adjustment is
automatic. Alternatively, the adjustment is in response to a manual
control. Optionally, the adjustment is semi automatic, with the
controller, for example, modifying the adjustment means to maintain
a user-indicated result, such as vessel diameter. In an exemplary
embodiment of the invention, the treatment is modified (e.g.,
automatically, by the controller) in realtime to match the
modification and/or so it is applied when the blood vessel
properties are within a given window (e.g., timed to thickness
changes associated with the pulse wave), even if no intentional
adjustments is applied.
[0337] FIGS. 7D and 7E illustrate non-limiting examples of
adjustments of tissue parameters, in accordance with some
embodiments of the invention. FIG. 7D illustrates a relative
decrease in tissue parameters; temperature, thickness of vessel
wall, diameter of blood vessel, rate of blood flow. FIG. 7E
illustrates a relative increase in tissue parameters; temperature,
thickness of vessel wall, diameter of blood vessel, rate of blood
flow. Catheter 1222 having ultrasonic emission element 300 is
located inside blood vessel 1242. Ultrasound is used to treat
target tissue 1216 surrounded by tissue 1304. Blood 1302 is flowing
through vessel 1342.
[0338] In some embodiments of the invention, the temperatures of
one or more of blood 1302, surrounding tissue 1304 and/or target
tissue 1216 are adjusted, for example, to one or more different
temperatures. Optionally, the temperature of one or more tissues is
relatively increased (shown as T1), for example, by 0.2 degrees
Celsius, or 0.5 or 1 or 2 or 5 or 10 degrees Celsius above body
temperature, or other smaller, intermediate or larger values are
used. Alternatively or additionally the temperature of one or more
tissues is relatively reduced (shown as T2), for example, by 0.2
degrees, Celsius, or 0.5 or 1 or 2 or 5 or 10 or 20 or 30 or 35
degrees Celsius below body temperature or other smaller,
intermediate or larger values are used. Non-limiting options of
adjusting the temperature include: inserting the patient and/or
region of the body into a solution of relatively cooler or
relatively hotter liquid, blowing cold or hot gas (e.g., room air)
on the patient, infusing relatively cold or relatively hot liquid
(e.g., saline) into the patient. Exemplary reasons for changing the
temperature of tissues will be described below.
[0339] In some embodiments of the invention, the thickness of the
arterial wall is adjusted. Optionally, the arterial wall is
maintained and/or expanded (if in a contracted state). Optionally
or alternatively, the arterial wall is contracted, for example, by
about 10%, about 20%, about 30%, or other smaller, intermediate or
larger values. The rate of evacuation of heat from surrounding
tissues 1304 and/or target tissue 1216 can be related to
contraction and/or expansion of the arterial wall. For example,
expanding and/or relaxing the arterial wall can cause a dilation of
the vasa vasorum, thereby increasing blood flow and the evacuation
of heat. For example, contraction of the arterial wall can cause
contraction of the vasa vasorum, thereby decreasing blood flow and
the evacuation of heat.
[0340] In some embodiments, the entire circumference of the vessel
is adjusted. Alternatively, an arc of the circumference of the
vessel is adjusted, for example, about 10, 15, 30, 45, 60, 90
degrees, or other smaller, intermediate or larger values are
adjusted. One part (e.g., arc) of the vessel around the
circumference is adjusted, for example, 2, 3, 4 or other smaller,
intermediate or larger numbers of areas around the circumference.
Optionally, the adjusted areas correspond to the treatment
areas.
[0341] In some embodiments, a portion of the blood vessel length is
adjusted. For example, about 5 mm, about 10 mm, about 20 mm, about
30 mm, about 50 mm, about 100 mm, or other smaller, intermediate or
larger values are used. Alternatively, areas substantially larger
than the blood vessel itself are affected, for example, an organ, a
limb, the entire body, the entire vasculature.
[0342] In some embodiments, the volume of the adjusted tissue
corresponds to the selected volume of the desired thermal effect.
Optionally, the target tissue is within the adjusted tissue. For
example, the volume of adjusted tissue is about 100%, 150%, 200%,
500%, 1000%, 10000% of the volume of the desired thermal effect, or
other smaller, intermediate or larger values are used.
[0343] In some embodiments of the invention, the rate of evacuation
of heat from one or more of blood 1302, surrounding tissues 1304
and/or target tissue 1216 are adjusted, for example, by varying
amounts. Optionally, the rate of evacuation of heat is relatively
increased. Alternatively or additionally, the rate of evacuation of
heat is relatively decreased.
[0344] In some embodiments of the invention, flow of blood 1302
through vessel 1242 is adjusted. Optionally, a relatively higher
rate of blood flow 1302 (shown as long arrows) relatively increases
the rate of heat removal. Optionally or additionally, a relatively
lower rate of blood flow 1302 (shown as short arrows) relatively
reduces the rate of heat removal. The effect of heat removal, such
as on the area of thermal damage, has been described with reference
to FIGS. 7A-7C.
[0345] Non-limiting examples of methods to adjust the rate of blood
flow 1302 include: [0346] Increasing or decreasing the cardiac
output, for example, by artificially pacing the heart (e.g.,
external pacemaker) to a relatively higher or relatively lower
rate, for example, to 120, 150, 180, 200 beats per minute or other
smaller, intermediate or larger values. [0347] Dilating blood
vessel 1242 (shown as d1), such as by administration (e.g., into
the vasculature) of vasodilatory agents such as nitrates (e.g.,
nitroglycerin) and/or agents to relax the muscles of arterial wall
1242, such as muscle paralyzing agents such as botulinum (blocks
release of acetylcholine). Agents can be delivered locally and/or
systemically. Electricity can also be applied in a pattern and/or
settings (e.g., long DC signal) that relaxes the arterial wall.
[0348] Constricting blood vessel 1242 (shown as d2), such as by
administration of vasoconstricting agents such as alpha-1 agonists
(e.g., phenylephrine), by applying an electrical current to cause
muscle contraction in arterial wall 1242, and/or by mechanically
agitating tissues (e.g., traumatizing) to cause constriction.
[0349] In some embodiments of the invention, the absorption to
applied ultrasound energy of one or more of blood 1302, surrounding
tissues 1304 and/or target tissue 1216 are adjusted, for example,
by varying amounts. Optionally, the absorption is relatively
increased (shown as TR). A non-limiting example of relatively
increasing the absorption to ultrasound is by injecting a material
that absorbs ultrasound energy to a relatively higher degree, such
as microbubbles.
[0350] In some embodiments of the invention, tissue properties are
adjusted in accordance with the selected safety parameters, for
example, to relatively increase the margin of safety. Optionally,
the rate of heat removal from surrounding tissues 1304 is
relatively increased, for example, as described herein.
Alternatively or additionally, the temperature of tissues 1304 is
relatively reduced, for example, as described herein. A potential
advantage of increasing the rate of heat removal and/or reducing
the temperature is reducing thermal damage to surrounding tissues
1304, for example, as described with reference to FIGS. 7A-7C.
[0351] In some embodiments of the invention, tissue properties are
adjusted in accordance with the selected thermal damage profile,
for example, to relatively increase the area of thermal damage.
Optionally, the ability of surrounding tissues 1304 to absorb
ultrasound energy is relatively increased, for example, as
described herein. Alternatively or additionally, the temperature of
tissues 1304 is relatively increased. A potential advantage of
increasing the temperature and/or acoustic absorption is increasing
the thermal effect of the applied ultrasonic energy, for example,
as described with reference to FIGS. 7A-7C and/or FIG. 9. For
example, if the tissue temperature is increased and/or the rate of
heat removal is decreased, the thermal effects resulting from an
amount of acoustic energy can be relatively increased.
Selecting parameters--example of choosing catheter (Frequency)
According to Treatment
[0352] FIG. 8 is an exemplary illustration of a simplified estimate
of the effect of frequency of ultrasound energy on an area of
thermal damage, in accordance with an exemplary embodiment of the
invention.
[0353] The top part of FIG. 8 illustrates an ultrasound transducer
806 emitting ultrasound energy towards an arterial wall 812.
Non-limiting examples of the ultrasound energy include 20 Mhz
ultrasound energy 808 and/or 10 Mhz ultrasound energy 810.
[0354] The bottom part of FIG. 8 illustrates the attenuation of
energy 808 and/or 810 by the tissues of wall 812. As illustrated by
the table in the section "ESTIMATE BLOOD FLOW", attenuation of
ultrasound energy by tissue is inversely proportional to frequency.
An exemplary attenuation graph for 20 Mhz 816 shows relatively
higher attenuation relatively closer to a lumen 818. In some
embodiments, an area of thermal damage 802 is relatively closer to
lumen 818. An exemplary attenuation graph for 10 Mhz 814 shows
relatively lower attenuation as a function of distance from lumen
818. In some embodiments, an area of thermal damage 810 is
relatively further from lumen 810.
[0355] In an exemplary embodiment of the invention, the frequency
of ultrasound energy used for selectively targeting tissue is
selected according to the treatment plan. For example, target
tissue relatively further from the lumen and/or from the intima
layer is selectively treated by using a relatively lower frequency
of ultrasound energy.
[0356] In an exemplary embodiment of the invention, the frequency
of the ultrasound energy used for treatment is selected, for
example to be about 5 Mhz, about 8 Mhz, about 10 Mhz, about 15 Mhz,
about 8 Mhz-15 Mhz, about 20 Mhz, about 10 Mhz-20 Mhz, about 30
Mhz, or other smaller, intermediate or larger frequencies. IN some
cases, et frequncy will be substantially narrow band, for example,
les sthan 30%, 20%, 10%, 5% of the application frequency.
Optionally or alternatively, a wide band or multi frequency signal
is used, for example, with 2, 3, 4, 5 or more discrete frequencies
and/or with a range of, for example, 1 Mhz, 3 Mhz, 5 Mhz or smaller
or intermediate widths.
[0357] In an exemplary embodiment of the invention, for example for
renal denervation, a lower frequency may be used to achieve a
higher reduction in norepinephrine levels.
[0358] In an exemplary embodiment of the invention, the signal
parameters are selected according to a desired functional effect,
in addition to or instead of according to a desired structural
effect (e.g., tissue ablation).
[0359] In an exemplary embodiment of the invention, a catheter is
selected according to the frequency of the selected ultrasound
energy. Optionally, the acoustic element on the transducer is
designed to vibrate at the treatment frequency. For example, the
thickness of the acoustic element is related to the expected
frequency of vibration of element, optionally linearly related, for
example, a thickness of 100 micrometers for a frequency of 20 Mhz,
a thickness of 200 micrometers for a frequency of 10 Mhz.
Selecting Parameters--Choosing an Ultrasonic Intensity Profile
According to Treatment
[0360] FIG. 9 is an exemplary illustration of a simplified estimate
of the association between an ultrasonic intensity profile and
thermally damaged areas, useful in practicing some embodiments of
the invention.
[0361] In an exemplary embodiment of the invention, the ultrasonic
intensity profile for treatment is selected. Optionally, the
ultrasonic intensity profile is related to the ultrasonic intensity
emitted by the acoustic element (e.g., in watts per square
centimeter) over time (e.g., in seconds), for example, relatively
longer times relatively increase the ultrasonic intensity profile,
for example, relatively higher acoustic intensities relatively
increase the ultrasound intensity profile. Optionally or
additionally, the ultrasonic profile is selected to vary over time.
In some embodiments, the ultrasonic profile is associated with the
total amount of ultrasonic energy delivered to the tissues. In some
embodiments, the profile is substantially a temporal square wave.
Optionally or alternatively, the profile is substantially a spatial
square wave (e.g., sharp cut-offs at the edges of the beam), in one
or two dimensions.
[0362] FIG. 9 shows an ultrasound transducer 902, emitting
ultrasonic energy at various intensity profiles, for example, a
relatively low intensity profile 904, a relatively medium intensity
profile 906 and/or a relatively high intensity profile 908.
[0363] In some embodiments, the area of thermal damage begins
relatively far from an intima 916, for example, at a
peri-adventitia 918. In some embodiments, the area of thermal
damage increases towards the intima with relatively increased
ultrasonic intensity profiles.
[0364] In an exemplary embodiment of the invention, tissues
relatively closer to the blood cool relatively faster. In an
exemplary embodiment of the invention, a treatment plan comprising
of a series of pulses with a delay between the pulses will have a
greater cumulative effect away from the wall. In an exemplary
embodiment of the intervention, a treatment plan of pulses with
delays causes a thermal effect to tissues relatively further away
from the wall, without causing a thermal effect to tissues
relatively closer to the wall.
[0365] In an exemplary embodiment of the invention, the extent of
thermal damage is settable according to the ultrasound intensity
profile, such as 904, 906 and/or 908. For example, thermal damage
is localized to target tissue 910 (e.g., no damage to surrounding
tissue). For example, an area of thermal damage 912 extends
somewhat beyond target tissue 910. For example, a relatively large
area of thermal damage 914 extends a relatively larger area beyond
target tissue 910.
[0366] In an exemplary embodiment of the invention, the extent of
thermal damage is selected to not reach intima 916.
Insert Catheter
[0367] In an exemplary embodiment of the invention, catheter 1222
(e.g., as shown in FIG. 5) in inserted into the body of a patient.
Standard vascular access methods can be used, for example, from the
femoral artery. Optionally, catheter 1222 is threaded using a
guidewire 1202 (e.g., over the wire, rapid exchange, "buddy" wire)
to the target treatment site (e.g., an artery such as the iliac,
renal, carotid, aorta) under image guidance, such as fluoroscopy.
Alternatively or additionally, catheter 1222 is directed inside a
guiding sheath, for example to protect the ultrasound transducer
from mechanical damage during delivery to the target site.
Alternatively or additionally, catheter 1222 is directed inside a
guiding catheter.
[0368] In an exemplary embodiment of the invention, catheter 1222
is guided during delivery using imaging, for example fluoroscopic
image.
[0369] Referring back to FIG. 5, in an exemplary embodiment of the
invention, element 102 on catheter 1222 is prevented from
contacting vessel wall 1226, for example, by using separation
device 1204. Details about separation device are provided with
reference to attorney docket number 50824, incorporated herein by
reference in its entirety. Optionally, element 102 contacts wall
1226 if treatment parameters are set and/or adjusted accordingly,
for example, if element 102 is sufficiently cooled and/or if the
intensity profile is reduced.
[0370] In an exemplary embodiment of the invention, distance 1218
(between element 102 and wall 1226) does not have to be taken into
account for setting treatment parameters. Optionally distance 1218
varies during treatment. In some embodiments, the attenuation of
ultrasonic beam 1228 by blood flow 1220 is relatively
insignificant.
[0371] A potential advantage of preventing contact between element
102 and wall 1226 is reducing or preventing thermal damage to the
endothelium, basal membrane and/or internal elastic lamina.
[0372] In some embodiments of the invention, catheter 1222 includes
one or more elements to move transducer 300. Optionally, the
element is a piezoelectric element that can be vibrated by applying
electrical power. Alternatively or additionally, the element moves
transducer 300 for relatively fine positioning, for example, an
electrically controlled motor. In some embodiments, the element
vibrates and/or moves transducer 300 to position the strongest part
of the ultrasound beam at the target tissue.
[0373] In some embodiments the controller can be calibrated
according to the expected intensity profile of the produced
ultrasound beam, for example, the controller vibrates and/or moves
transducer 300 in order to obtain a desired position for thermally
affecting the tissues.
Treat
[0374] FIG. 10 is a flow chart of monitoring during treatment, in
accordance with an exemplary embodiment of the invention. In some
embodiments, monitoring is a type of feedback associated with the
parameters affecting treatment.
[0375] At 1002, the target tissue is treated. The ultrasound
transducer emits ultrasound energy towards the target tissue at the
selected acoustic intensity profile and/or at the selected
frequency.
[0376] In an exemplary embodiment of the invention, the target
tissue can be treated according to the selected treatment plan
(e.g., acoustic intensity profile, frequency) without requiring
monitoring and/or feedback.
[0377] Optionally, at 1004, monitoring of the treatment is
performed.
[0378] In some embodiments of the invention, monitoring occurs at
the same time as treatment is occurring (e.g., in parallel with the
treatment). Alternatively or additionally, treatment (e.g.,
transmission of ultrasonic energy) occurs in pulses separated by a
delay, with the monitoring occurring during the delay. Optionally,
monitoring is carried out continuously during the entire
treatment.
[0379] Optionally, at 1006, the environment surrounding the
treatment procedure is monitored. In some embodiments, changes in
environmental conditions affect the treatment if the treatment
parameters remain unchanged. For example, if blood flow is
increased without changing the treatment parameters, the treatment
may not be effective due to the increased rate of cooling. In some
embodiments, changes in environmental conditions are taken into
account when adjusting treatment parameters, for example, if an
increase in blood flow is detected, the intensity profile is
increased accordingly to achieve the desired effect in the selected
tissues.
[0380] In some embodiments, the temperature of the blood flow is
monitored, for example, by a sensor placed downstream from the
transducer.
[0381] Optionally, at 1008, the integrity of the transducer is
monitored. In some embodiments, changes in the integrity suggest
one or more causes such as blood clots on the transducer,
overheating of the transducer, mechanical damage. In some
embodiments, changes in the integrity of the transducer are
monitored to prevent adverse events. Optionally, the treatment
parameters are adjusted according to the integrity. For example, if
the transducer comes closer to the wall or contacts the wall,
potentially the intima can overheat, resulting in thermal damage to
the intima if the treatment parameters are not adjusted accordingly
(e.g., increased cooling, reducing the intensity profile).
[0382] In some embodiments, the integrity of the transducer is
monitored by measuring changes in the impedance, for example, a
change greater than 3%, 5%, 10%, 20%, or other smaller,
intermediate or larger percent changes.
[0383] In some embodiments, the integrity of the transducer is
monitored by measuring the distance from the transducer to the
arterial wall (e.g. to the intima). Optionally, the distance is
measured by a returning echo. Alternatively or additionally, the
distance is measured on x-ray images.
Feedback
[0384] In some embodiments of the invention, acoustic energy is
applied to the target tissue in an open loop manner. For example,
the target is set and the target is met, without using feedback.
Alternatively, acoustic energy is applied to the target tissue in a
closed loop manner, such as with feedback.
[0385] In some embodiments, feedback is a measure of the physical
effect of the treatment on the tissue. Optionally or alternatively,
feedback is a functional measurement. In some embodiments, feedback
is provided on the transmission of the energy and/or parameters of
the emitter and/or catheter (e.g., distance), in addition to or
instead of on the target tissue. While, in an exemplary embodiment
of the invention, feedback is during the procedure, possibly during
a single application of energy (e.g., within less than 30 seconds),
in some embodiments, feedback is on longer time scales, such as 1-3
minutes (e.g., between applications and/or after a set of
applications is provided) or days or more.
[0386] FIG. 11 is a flow chart showing optional functional feedback
associated with treatment, in accordance with an exemplary
embodiment of the invention.
[0387] Optionally, at 1102 feedback is obtained about the results
of the treatment.
[0388] Optionally, at 1104, functional feedback is obtained about
the effect of treatment on tissues. Optionally, imaging is
performed of the target tissue to detect and/or estimate the extent
of therapy. Alternatively or additionally, imaging is performed of
the surrounding tissue to detect and/or estimate the extent of
damage (e.g., margin of safety). In some embodiments, some changes
(e.g., due to denaturation of collagen) are detected as they
happen. In some embodiments, some changes are detected after a
period of time (e.g., several days), for example, anatomical
changes secondary to the inflammatory response, such as
fibrosis.
[0389] In some embodiments, imaging is performed by the using the
same ultrasound transducer used for treatment, for example, by
treating at a first treatment frequency for a period of time, then
imaging at a second diagnostic frequency for another period of time
(e.g., analyzing the ultrasonic echoes returning from the tissues).
Alternatively or additionally, the same ultrasound transducer is
used, but with different electrodes which separate the transducer
into an imaging region and a treatment region. Alternatively or
additionally, one or more acoustic elements are used, for example,
one element for imaging and one element for treatment.
[0390] In some embodiments, one or more other imaging modalities
are used instead or in addition to the element, such as CT, MRI,
x-ray.
[0391] One or more non-limiting examples of ultrasound imaging
methods for feedback include,
[0392] Measuring the ultrasonic attenuation of the target tissues,
for example, as described by Damianou et al, J Acoust Soc Am. 1997
July; 102(1):628-34, incorporated herein by reference in its
entirety. Damianou found that the rate at which the thermal dose
was applied was associated with the total attenuation absorption,
for example, relatively lower thermal dose rates resulted in
relatively larger attenuation coefficients. In some embodiments,
the intensity profile that is applied to the target tissues is
estimated by measuring the attenuation coefficient and/or the
absorption. Optionally, the measurements are compared to expected
values according to the set intensity profile. Optionally or
additionally, the intensity profile is adjusted relatively higher
or relatively lower according to the comparison, for example, to
achieve the resulting thermal damage to the target tissue.
[0393] Measuring the ultrasound attenuation coefficient and/or
backscatter power for example, as described by Worthington, A. E.,
et al, Ultrasound in Med. & Biol., Vol. 28, No. 10, pp.
1311-1318, 2002, incorporated herein by reference in its entirety.
Worthington found that the attenuation coefficient and/or
backscatter power increased with relatively higher temperatures. In
some embodiments, the temperature of the target tissues is
estimated according to the attenuation coefficient and/or
backscatter power. Optionally, the temperature of the tissue is
compared to the temperature range and/or threshold required to
achieve a desirable effect in the tissues (e.g., collagen
denaturation above 55 degrees Celsius). Optionally or additionally,
the intensity profile is adjusted relatively higher or relatively
lower according to the comparison, for example, to achieve the
target temperature in the target tissue.
[0394] Optionally, at 1106, feedback consists of clinical effects,
for example, desired clinical effects, adverse clinical effects,
lack of clinical effects.
[0395] In some embodiments, clinical measurements are used as
feedback. For example, the results of renal denervation to treat
persistent hypertension can be measured by one or more of, blood
pressure, norepinephrine spillover, norepinephrine levels, renal
artery blood flow.
[0396] In some embodiments of the invention, the distance from the
acoustic element to the arterial wall is measured, optionally
continuously measured. Optionally, the distance is measured using
the acoustic element itself, for example, as described in co-filed
PCT applications attorney docket numbers 52345 and/or 52342,
incorporated herein entirely by reference. In some embodiments, the
distance is used as feedback to prevent high power operation of the
acoustic element while touching the arterial wall, for example, if
the distance is measured to be zero (e.g., contact) or relatively
close to contact (e.g., 0.1 mm, 0.3 mm or other smaller,
intermediate or larger distances), the power to the transducer can
be reduced and/or shut off. A potential advantage of measuring the
distance using the element is a relatively more accurate
measurement of the distance as compared with measuring the distance
from angiographic images.
Adjust
[0397] In some embodiments of the invention, monitoring of the
treatment and/or feedback of the treatment can increase the level
of control of the treatment (e.g., in real time, overall effect
over several treatment sessions). Optionally, desired clinical
results are achieved by the treatment.
[0398] In some embodiments, data from feedback and/or monitoring is
used to adjust treatment parameters (e.g., frequency, ultrasonic
intensity profile), for example, by a look-up table (e.g., stored
in a memory), calculations, trial and error (e.g., slowly changing
a parameter and/or monitoring changes). Optionally, parameters are
adjusted manually (e.g., by a user) using an interface coupled to a
controller. Alternatively or additionally, parameters are
automatically adjusted, such as by a software module of
controller.
[0399] One or more non-limiting examples of adjustments include,
increasing the treatment, reducing the treatment, stopping the
treatment.
[0400] A non-limiting example to illustrate the concept of
adjusting variables according to measurements is provided:
[0401] A patient with resistant essential hypertension was proposed
treatment by a renal denervation procedure. A renal nerve
surrounded by fat located about 4 mm away from the renal vessel
wall in the peri-adventitia was targeted for thermal effect. A
catheter designed for a frequency of 10 Mhz was selected (e.g., due
to the relative distance away from the wall) and an initial
intensity of 30 watt/cm 2 was selected based on standard blood flow
rates expected (e.g., according to a look-up table of patient
profiles). The catheter was inserted into the renal artery. A pulse
of duration 1 second was used to initially treat the vessel wall
for calibration purposes. Imaging results indicated that the area
of thermal effect was located 15 degrees clockwise, and 5 mm away
from the wall. Based on the results, the catheter was manually
rotated 15 degrees towards the target. Treatment started again,
using a pulse of 30 seconds duration. About 5 seconds into
treatment, the cardiac output of the patient suddenly increased,
causing a 50% increase in the rate of blood flow through the renal
artery. The controller automatically increased the intensity
profile to 40 watt/cm 2 to offset the increased cooling rate of the
tissue wall by the blood. Another calibration pulse of 1 second was
applied. Imaging indicated that the nerve was being thermally
damaged. Treatment was stopped after 22 seconds, once imaging
results indicated that the nerve was fully damaged, along with a
tissue margin around the nerve of at least 0.5 mm. The patient was
followed in clinic for several weeks to verify the expected
treatment effect of a reduction in blood pressure.
[0402] In some embodiments of the invention, treatment is
synchronized (e.g., at a same time or otherwise timed thereto, such
as at a delay after or before) to the adjustments, for example, as
will be described at the end of the section "EXEMPLARY DEVELOPMENT
OF AN EQUATION--Part B"
Examplary Treatment Protocols
[0403] The table below describes some possible treatment protocols,
in accordance with some embodiments of the invention. Optionally,
the `Thermal Effect Location` and/or related `Information" is
determined by imaging, for example, as described in the section
"FEEDBACK". Optionally, action is taken, such as based on the
"Information", for example, by the `Cardiologist` and/or by the
`System` (for example, the controller, such as using software
stored thereon containing the `algorithm`). Details related to
`Action` can be found for example in the section "ADJUST".
Table of Some Possible Treatment Protocols
TABLE-US-00005 [0404] Thermal effect Action: Action: location
Criteria Subject Information Cardiologist System/algorithm Minimal
Minimal Thermal Thermal Reduce If distance <1- system distance
of 1 mm effect effect energy- stops excitation thermal effect
location area/volume change If distance >10- system from artery
during treatment alerts- thermal effect is lumen treatment
parameters or too far duration Maximal Maximal Thermal Thermal If
distance >15- system distance of 15 mm effect effect stops
excitation thermal effect location area/volume from artery during
lumen treatment Rate of Thermal Rate of Reduce If (maximal -
minimal thermal effect effect thermal effect energy- distance)
difference is formation location formation change higher than 2
mm/sec- during treatment system stops excitation treatment
parameters or duration Enable If (maximal - minimal treatment
distance) difference is lower than 2 mm/sec- system enables
excitation Location Thermal Thermal Decision- Up to 50% of artery
along the effect effect width Continue length-system alert for
artery location in artery Adjust cardiologist decision post length
Sufficient treatment Location in Thermal Thermal Decision- Up to
50% of artery the artery effect effect width Continue circumference
-system circumference location in artery Adjust alert for
cardiologist post circumference Sufficient decision treatment
Minimal Minimal Thermal Thermal Decision- If thermal effect is too
distance of 1 mm effect effect Repeat close to lumen (<1 mm)-
thermal effect location area/volume Adjust system suggests from
artery post Sufficient cardiologist to add extra lumen treatment
anti-coagulation treatment Maximal Maximal Thermal Thermal distance
of 15 mm effect effect thermal effect location area/volume from
artery post lumen treatment
[0405] The following table shows exemplary activities by the
controller and/or operator in various conditions, in accordance
with some embodiments of the invention, base on the distance
between the ultrasound emitter and the wall. Such distance can be
measured, for example, using an external system (e.g., angiography
or ultrasound), by processing signals received by the emitter or by
a separate ultrasonic element.
TABLE-US-00006 Distance (calculated/ Value System/ measured) (mm)
Subject Criterion Cardiologist algorithm Distance <1.4 Catheter
>1 * Change GC (guide * System alert- measurement position
catheter) position short distance before before * Change US *
System disables treatment treatment transducer angle excitation
until * Change US distance is changed transducer position according
to along the artery criterion >1 Catheter >1 Enable
excitation Enable excitation position before treatment >5
Catheter 1 < x < 5 Too large distance: System alert- position
Confirm possible bifurcation, change before bifurcation or US
transducer treatment dislocation with position contrast injection
and angiography and move US transducer 1 > x > 1.3 Catheter
>1 Unreliable distance- Angle position Confirm US between before
transducer angle with US treatment contrast injection and
transducer angiography: and artery Change GC position wall is
larger than 10.degree. >1.3 Catheter >1 Enable excitation
Enable excitation Angle position between before US treatment
transducer and artery wall is larger than 10.degree. (diagonal)
Distance <1 Catheter >1 Change GC * System alerts- short
measurement position position and distance during during complete *
System stops treatment treatment treatment excitation until
distance is changed according to criterion 0.7 < x < 1
Catheter >1 Consider to stop System alert- position excitation
and shortening distance during improve position treatment before
completing treatment 1 < x < 5 Catheter >1 Enable
excitation Enable excitation to position to end end during
treatment Decreasing Catheter >1 Possible blood System alert-
decreased distance position vessel constriction distance during due
to treatment- treatment consider stop and nitroglycerin infusion
>5 Catheter >1 System disabled Sudden position movement
during treatment Vessel blood Repetitive Pulsation Calculated blood
pulsation changes- detection pulsation: analysis Maximal before If
normal, enable position to treatment excitation minimal position No
differences Pulsation Possible no circulation: System alert-
between detection * Validate flow by no pulsation, Maximal before
contrast injection and possible position to treatment angiography
constriction minimal * If needed- infuse with position
nitroglycerin or cold saline distance >1 Pulsation >1 *
Validate flow by System alert- But no detection contrast injection
and no pulsation, pulsation before angiography possible detection
treatment * If needed- infuse with constriction nitroglycerin or
cold saline Distance 1.sup.st- <1 Artery Possible constriction:
System alert- measurement, 2.sup.nd- <1 diameter * Confirm by
contrast possible rotate 180.degree., evaluation injection and
constriction: distance angiography Disable measurement * If needed-
inject excitation nitroglycerin and treat Distance <3 Artery *
Check if US transducer System alert- measurement diameter is
located in the correct possible in 4 angles evaluation artery-
using contrast constriction: (90.degree.)- artery injection and
Disable diameter angiography excitation calculation * Check for
local constriction * Possible- Nitroglycerin injection 3 < x
< 8 Artery Enable excitation Enable diameter excitation
evaluation
[0406] In an exemplary embodiment of the invention, both kidneys
(e.g., renal arteries, renal nerves) are treated. However, this
need not be the case. For example, in a follow-up treatment,
possibly only a single kidney is treated. Optionally or
alternatively, if one kidney is known to be more diseased, that is
treated more (e.g., this is a reason for providing a treatment
which is asymmetrical between kidneys, this may be done for other
reasons as well). Optionally or alternatively, different kidneys
are treated a different amount. Optionally, one kidney is
intentionally undertreated so as to allow increasing treatment
thereof, at a later time.
Potential Advantages of Some Embodiments
[0407] Further details of the system described herein can be found
in the related applications. For example, "ULTRASOUND EMISSION
ELEMENT" (attorney docket no. 52344) describes an ultrasound
emission element. For example, "AN ULTRASOUND TRANSCEIVER AND USES
THEREOF" (attorney docket no. 52345) describes a method for
feedback and control. For example, "AN ULTRASOUND TRANSCEIVER AND
COOLING THEREOF" (attorney docket no. 52346) describes cooling of
the ultrasonic element. For example, "SEPARATION DEVICE FOR
ULTRASOUND ELEMENT" (attorney docket no. 52348) describes
preventing contract between the ultrasonic element and the blood
vessel wall. For example, "ULTRASOUND TRANSCEIVER AND USES IN
DETECTION" (attorney docket no. 52342) describes ultrasonic
imaging.
Some embodiments have one or more of the following exemplary
advantages: [0408] Relatively faster treatment, for example, a
treatment duration of 5-30 seconds per treatment region, or other
smaller, larger or intermediate ranges can be used. [0409]
Relatively small number of treatment regions per artery for renal
denervation, for example, 1 treatment region, 3 treatment regions,
4 treatment regions, 6 treatment regions, 8 treatment regions or
other smaller, intermediate or larger number of regions are used.
[0410] Remote and/or localized effect, for example, [0411] Accurate
control of the thermal effect and/or location, such as good control
on the location and/or size of the artery tissue damage by
therapeutic parameters. [0412] Ability to treat relatively large
continuous areas in the arterial wall. [0413] A treatment option
for short artery stumps and/or for short total treatment durations
(e.g., 5-10 minutes vs 20 minutes for RF treatments). [0414] The
thermal effect volume in the tissue is relatively far from the
transducer face (e.g, media, adventitia, vasa-vasorum,
peri-adventitia, adventitia nerves, peri-adventitia nerves,
peri-adventitia capillaries). [0415] Targeting tissues in varying
distances from the transducer face according to treatment
parameters. For example, applying the thermal effect in tissues
located about 5 mm or more from the lumen wall (e.g., intima
layer). A relatively far effect is relevant for example, for
achieving peripheral nerves blocks from inside the peripheral
arteries. [0416] Non-targeted tissues on the beam path to the
target tissue are not damaged and/or are selectively damaged (e.g.
according to a margin of safety), for example, the endothelium,
basal membrane and/or internal elastic lamina. [0417] Possibility
for varying levels of thermal modulation of the target tissue. For
example, partial damage to nerves and/or other target tissues, in a
controlled manner and different effect levels. Potentially, partial
nerve injury can be controlled, that might lead to nerve recovery,
either partially or entirely. [0418] Tissue selectivity, for
example, highly selective remote thermal effect in nerve bundles,
such as nerves that are covered with thick fat tissue. For example
as used in a Renal Denervation procedure in the Renal Artery
ostium. [0419] Treatment features suitable for Renal Denervation
include: [0420] The ability to work very close to the renal artery
ostium, for example, <10 [mm], or other smaller, intermediate or
larger values. [0421] The ability to work in short arteries, for
example, <20 [mm], or other smaller, intermediate or larger
values [0422] The ability to work in small arteries, for example,
4-3 [mm], or other smaller, intermediate or larger values [0423]
Safety issues [0424] Relatively safer treatment. [0425] The
temperature of the blood that flows over the ultrasonic transducer
can be controlled to not exceed a temperature threshold of 50
degrees Celsius (or other smaller, intermediate or larger numbers)
while working in the maximal allowed operation intensity level, for
example, 50 [W/cm 2], or other smaller, intermediate or larger
intensity levels. [0426] The temperature of the blood that flows
over the ultrasonic transducer can be controlled to not exceed a
temperature threshold of over 43 degrees Celsius (or other smaller,
intermediate or larger numbers), for example, while working in the
therapeutic operation intensity level 30 [W/cm 2], or other
smaller, intermediate or larger intensity levels. In some
embodiments, there is no need to add external cooling such as by
saline injection. [0427] The therapeutic treatment on the blood
vessel wall is done with no mechanical contact with the vessel
wall, thereby reducing or eliminating the danger of damaging the
vessel wall or disrupting any pathologies on the wall (e.g.,
atherosclerotic plaques). For example, reducing the risk of
arterial perforation and/or mechanical damage that might cause a
narrowing in the vessel, plaque tear and/or emboli. [0428]
Localized and/or controlled effects specifically in the targeted
treatment volume, preventing and/or reducing non-controlled energy
effects in other tissues. [0429] Blocking of the blood flow during
the treatment is optional, and in some embodiments, is not
required. [0430] Treatment of a single artery location (e.g.,
longitudinally) in one or more circumferential directions,
potentially, significantly reducing and/or preventing stenosis.
[0431] Preventing and/or reducing damage to the artery due to
repeating treatment 2-3 times (or more) at the same axial
position/radial direction, such as due to a mistake. [0432] Prevent
and/or reduce interference with implanted electronic medical
devices (e.g., pacemakers, defibrillators). [0433] Clinical
implications, for example, relatively lower pain during treatment
as a result of relatively faster blocking of nerves, with no
electric excitation of the target nerve and/or no effect on other
nerves. Potentially reducing sedation and/or anesthesia. [0434]
Relatively shallow learning curve, as leverages existing operator
skill sets. [0435] Many applications and/or ability to treat a wide
range of clinical disorders. [0436] Treatment option for a wide
range of patients, such as high risk populations, for example as
those suffering from vascular pathologies. Ability to treat in
arteries with plaques and/or stents. [0437] Ability to obtain a
partial clinical effect (vs. complete effect). Potentially suitable
for patients with milder disease, such as mild hypertension. [0438]
Feedback availability during treatment, such as information on the
direction and location of the applied energy, catheter and the
therapeutic catheter tip: [0439] Easy control capability and a
clear direction and location of the ultrasonic ray and/or catheter
location to carry out treatment, such as according to the
ultrasonic echo reflection analysis. [0440] Ability to control the
circumferential direction of the artery tissue damage. [0441]
Continues information (e.g., ultrasonic measurement) on the
position of the catheter tip, such as from the artery wall during
treatment. [0442] Automatic detection of unwanted and/or risky
movement of the catheter during treatment.
Alternative Ways to Determine Desirable Parameters
[0443] In some embodiments of the invention, trial and error is
used to figure out at least some parameters. For example, an
initial set of parameters estimated to cause a relatively small
area of thermal damage can be applied to the target tissue.
Alternatively, thermal damage is applied to a region that would not
be affected by the small area of thermal damage. Based on the
resulting area and/or volume of thermal damage caused by the
parameter settings (e.g., according to imaging), one or more
settings can be adjusted to achieve a desired effect in the target
tissues. Such a process can be followed iteratively until the
desired effect is achieved. Such a process is potentially useful in
certain situations, for example, if the rate of blood flow is
unclear.
[0444] In some embodiments of the invention, one or more equations
(e.g., a simplified physical and/or mathematical model) are
developed for obtaining at least some parameters, for example, as
described in detail in the sections "EXEMPLARY DEVELOPMENT OF AN
EQUATION" parts A and/or B. In some embodiments, the equations are
used to derive parameters according to experimental results. In
some embodiments, different equations are developed for different
experiments, such as for targeting different types of tissues in
different anatomical areas. In some embodiments, parameters are
extrapolated based on experimental results.
Exemplary Development of an Equation--Part A
[0445] Inventors followed the process as described in FIGS. 1A
and/or 1B to conduct experiments in 10 pigs (e.g., results
displayed with reference to FIG. 12A). Experiments were performed
using a catheter having a diameter of 3 mm. The data collected from
the process was analyzed and turned into parameters that affect
treatment; the intensity of ultrasound energy, the frequency of
ultrasound energy, and the flow rate of blood in the artery. An
equation was developed associating the parameters with the
resulting area of thermally damaged tissue, such as the minimum
radial distance from the artery wall.
[0446] The equation is based on the results of the conducted
experiments that showed the thermal effect initiating about 3 mm
from the intima, in the most distant location of the
peri-adventitia. As the acoustic intensity profile increased, the
thermal effect increased towards the intima. The experiments were
conducted for a period of about 30 seconds. The equation can be
adapted for other time periods in a similar manner.
[0447] The function that associates the radial distance (the
distance from the arterial wall to the start of the thermally
damaged area) to the ultrasound treatment parameters is:
x(f,I) [mm]=(C6+a*Exp(flow*b)-C2*log(C3*I [W/cm 2]))/(C4*f
[MHz]+C5)
[0448] Where:
[0449] I=Excitation intensity [w/cm 2]
[0450] f=Working excitation frequency [MHz]
[0451] x=Minimal radial distance from the artery wall [mm]
[0452] flow=blood flow rate in the artery [ml/min]
[0453] Calculated coefficients in order to adjust the model
assumptions, neglects and unknown variables to the experimental
results:
[0454] a=3.7 (2 . . . 4)
[0455] b=-1134(-2500 . . . 0)
[0456] C2=93 (90 . . . 100)
[0457] C3=2.2 (1 . . . 4)
[0458] C4=2.1 (1 . . . 4)
[0459] C5=47.4 (45 . . . 50)
[0460] C6=400 (0 . . . 1000)
[0461] *the numbers in ( . . . ) are the limits of the parameters
estimation based on the results of the experiments conducted.
[0462] The physical model (for parts A and/or B, below) is based on
several assumptions and/or simplifications. The Arrhenius thermal
damage equation was used as the basis for estimating the thermal
damage area in the artery wall, using a time value of 30 seconds
and an effective temperature higher than 55 degrees Celsius. The
blood flow in the artery was assumed to be exponentially related to
cooling of the artery wall by convection.
[0463] The equations were developed by plotting the experimental
results (e.g., as summarized in FIG. 12A for the renal arteries
(shown in FIG. 13A) and for the carotid arteries (shown in FIG.
13B). The plots graphically illustrate the extent of thermal damage
(e.g., the distance from the intima to the start of the damage on
the `y-axis) as a function of the intensity of the applied acoustic
energy (on the `x-axis) and as a function of the frequency of the
applied acoustic energy (on the `z-axis`). The coefficients of the
equation were adjusted in order to align the equation to the
plots.
Exemplary Development of an Equation--Part B
[0464] In another set of experiments, inventors followed the
process as described in FIGS. 1A and/or 1B to conduct experiments
in 12 pigs (e.g., results shown in FIGS. 12B-12D). Experiments were
performed using a catheter having a diameter of 2 mm, at
frequencies of 10 Mhz and/or 20 Mhz. Ultrasound was emitted at
intensities ranging from 10-35 watt/cm.sup.2, for time periods
ranging from 10-30 seconds. The anatomical target sites were the
left and/or right renal arteries.
[0465] FIG. 12B summarizes the experimental data for an ultrasound
emission frequency of 10 Mhz. FIG. 12C summarizes the experimental
data at 20 Mhz. FIG. 12D shows graphs visually displaying the data
of FIGS. 12B-12C.
[0466] FIG. 12E illustrates variables describing the resulting area
of thermally damaged tissue, useful in helping to understand the
results shown in FIGS. 12B-12D. The left side of the figure
illustrates a cross section of an artery (all measurements in
millimeters). `MED` represents the thickness of the media layer of
the arterial wall. `L` represents the minimum distance of the
thermally affected region from the lumen wall. `W` represents the
maximal width of the thermally effected region. `Th` represents the
thickness of the thermally affected region. `S` represents the
severity of the thermally affected region (e.g., as defined by a
trained professional), defined as: 0=no thermal damage, 0.5=thermal
damage to nerves only, 1=thermal damage to connective tissue in
surrounding artery, 2=thermal damage to media (represents possible
future risk of arterial stenosis).
[0467] Equations associating the parameters of ultrasound energy
(frequency and intensity) to the thermal effect in tissue were
developed by fitting the thermal damage parameters based on the
histological analysis. Exemplary graphs are shown in FIGS. 13C-13H.
Exemplary fitting coefficients (e.g., for duration of 30 seconds)
are shown in the table below. Although coefficients correspond to a
duration of 30 seconds, this is not intended to be limiting, and a
similar analysis can be conducted for any other data points. It is
emphasized that the coefficients in the table cannot be compared
with each other. Each coefficient is distinct with reference to
each formula. For example, the coefficient `b.sub.1` in formula 2
is different than the coefficient `b.sub.1` in formulas 3-7.
[0468] One possible function that associates the radial distance
`L` to the ultrasound treatment parameters of intensity
(watt/cm.sup.2) and frequency (Mhz) is shown as:
L ( I , f ) = c 1 - c 2 log ( c 3 I ) c 4 f + c 5 equation ( 1 )
##EQU00001##
[0469] Equation 1 contains 5 unknowns, but can be simplified to
only 3 independent values, such as shown in equation 2. Some
relationships represented by equation 2 are graphically illustrated
by FIG. 13C.
L ( I , f ) = b 1 - log ( I ) b 2 f + b 3 . equation ( 2 )
##EQU00002##
[0470] The relatively stronger flow of blood related to the
relatively smaller diameter catheter in this group of experiments
(2 mm vs 3 mm) is taken into consideration automatically by the
proper choice of the first parameter in equation (2).
[0471] One possible function that associates the width `W` to
intensity and frequency is represented by equation 3. Some
relationships represented by equation 3 are graphically illustrated
by FIG. 13D.
W(I,f)=(b.sub.1+b.sub.2f)I+(b.sub.3+b.sub.4f)I.sup.2 equation
(3)
[0472] One possible function that associates the severity of the
thermal effect `S` to intensity and frequency is represented by
equation 4. Some relationships represented by equation 4 are
graphically illustrated by FIG. 13F.
W(I,f)=(b.sub.1+b.sub.2f)I+(b.sub.3+b.sub.4f)I.sup.2 equation
(4)
[0473] Some possible functions that associate the standard
deviations of `L`, `W` and `S` to intensity and frequency include
respective equations 5-7. Some relationships represented by
equations 5-7 are graphically illustrated by respective FIGS.
13F-H.
.sigma. L ( I , f ) = b 1 + b 2 I b 3 f + b 4 . equation ( 5 )
.sigma. W ( I , f ) = b 1 + b 2 I b 3 f + b 4 . equation ( 6 )
.sigma. S ( I , f ) = b 1 + b 2 I 2 b 3 f + b 4 . equation ( 7 )
##EQU00003##
TABLE-US-00007 Parameter Formula b.sub.1 b.sub.2 b.sub.3 b.sub.4 L
(2) 6.22 0.080 0.665 -- W (3) 0.1374 -0.0044 -0.0065 0.00056 S (4)
-0.0082 0.0039 0.00014 -1.9 10.sup.b L (5) -0.069 0.012 -0.016 0.40
W (6) -1.87 0.45 -0.29 10.13 S (7) 1.66 0.0070 -0.53 18.18
Table of Exemplary Coefficients Corresponding to Exemplary
Equations 2-7
[0474] The equations (parts A and B) illustrate that the frequency
can be adjusted to control the area of thermal effect. For example,
a relative increase in frequency can result in one or more of: the
thermal effect being relatively closer to the wall edge, the width
of the thermal effect being relatively increased, the severity of
the thermal damage being relatively increased. The relative
decrease in frequency can result in one or more of: the thermal
effect being relatively further to the wall, the width is
relatively reduced, the severity of the thermal damage is
relatively reduced.
[0475] The equations further illustrate that the intensity can be
adjusted to control the area of thermal effect. For example, a
relatively increase in intensity can result in one or more of: the
thermal effect being relatively further closer to the wall edge,
the width of the thermal damage being relatively increased, the
severity of the thermal damage being relatively increased. The
relative decrease in intensity can result in one or more of: the
thermal effect being relatively further from the wall, the width is
relatively reduced, the severity of the thermal damage is
relatively reduced.
[0476] As can be seen, various application times can be used as
well.
[0477] In an exemplary embodiment of the invention equations can be
used to calibrate the system. For example, the system can use the
equations to provide an initial set of parameters. Optionally,
treatment is synchronized to adjustments. For example, a thermal
effect can be applied to a test region, or a small part of the
target region. Feedback such as imaging can be performed to
estimate the distance from the treated region to the arterial wall,
the width of the region and/or the severity of the thermal effect
(e.g., as described in co-filed PCT application with attorney
docket number 52342). The actual measured values can be compared to
the expected values. One or more parameters such as frequency
and/or intensity can be adjusted relatively higher or relatively
lower. The process can be repeated in a feedback-loop, thereby
achieving the desired thermal effect to the desired area of tissue
at the desired location.
Experimental Results
[0478] FIG. 12A is a table summarizing experimental results of
selective thermal effects (e.g., damage) to arterial wall tissues,
performed by the inventors, in accordance with some embodiments of
the invention.
[0479] Experiments were performed in a total of 10 pigs, with
multiple locations treated in the carotid and renal arteries. The
pigs were under general anesthesia. The frequencies of ultrasound
used were 10 Mhz, 15 Mhz and 20 Mhz. The intensity of acoustic
ultrasound applied to the target tissue ranged from 1-10
watts/square centimeter to over 71 watts/square centimeter. The
treatment duration was 30 seconds per location. The ultrasonic
catheter used had a transducer with dimensions of 1.5 mm.times.6
mm.times.0.8 mm. The size of the catheter was 9 French. The length
of the catheter was 55 cm when inserted into the renal artery, and
a catheter having a length of 95 cm was used for the carotid
artery.
[0480] In the set of experiments performed, the acoustic intensity
was applied for about 30 seconds.
[0481] In the set of experiments performed, the thermal damaged
initiated in the peri-adventitia, increasing towards the intima.
The tables illustrate that the area of damage from the
peri-adventitia inwards, for example, PA=damage localized to the
peri-adventitia, M=damage from the peri-adventitia to the media,
IEM=damage from the peri-adventitia to the internal elastic media.
The area damaged (e.g., on a cross sectional histological slide
through the artery) was summarized as S=small, M=medium and
L=large. The definition of the damage (S, M, L), reflects the
percentage of tissue with thermal effect in the relative sector
with the pathology; S=1-20% thermal effect, M=21-60% thermal
effect, L=>61% of thermal effect. The thermal effect was
localized by sectors in a clockwise manner. The percentage effect
represents the proportion of the thermal effect inside the defined
sector. For example, "S" represents a string-like thermal zone,
while "L" represents that most or all of the sector area was
affected.
[0482] In the experiments performed, nerves in the peri-adventitia
were thermally damaged, for example, Y=thermally damaged nerve,
N=no thermally damaged nerves. The extent of thermal damage and/or
the identification of thermally damaged nerves was conducted by a
trained pathologist. In the experiments performed, the location of
thermal damage in the arterial wall was selective. "Points" refers
to the location (e.g., center of a treatment region) in the
arterial wall by using an arbitrary clock as measurement, for
example, 12 o'clock=0 degrees, 6 o'clock=180 degrees. The
transducer was directed towards the affected sector.
[0483] In the experiments performed, multiple lesions were
selectively made in a single blood vessel in a pig.
Experiment in the Aorta #1
[0484] Study subject: a female domestic pig, 71.7 Kg had been
treated with an ultrasonic treatment system on its renal left
artery. Anatomical target: nerves in the surrounding of the ostium
of the right renal artery. Anatomical position of catheter: aorta
artery, proximity to the ostium of right renal artery. Length of
ultrasonic treatment catheter: 55 cm Transducer frequency: 20 MHz
Time component of intensity profile: 30 seconds Acoustic intensity
component of intensity profile: 52 Watts/cm 2 Results: mild thermal
effect was demonstrated at the peri adventitia. [0485] FIG. 14A
represents a 2.times. magnification of the location at the aorta
artery circumference that was treated with the ultrasonic system,
6.0 mm proximal from the renal right ostium artery. The marked area
represents the border of the thermal effect seen in the
priadventitia, which manifests in an irreversible tissue, and
vessels necrosis, (T=Thermal). [0486] FIG. 14B represents a
4.times. magnification of the thermal area.
[0487] Schematic Description of Pathology Analysis:
FIG. 14C represents a top view of all the artery layers (see index
box as follows), at the relevant depth (6.0 mm from the renal right
ostium). The artery is planned clockwise for the pathology
definition.
[0488] The thermal effect seen in the artery is represented by the
black area in the peri-adventitia, at sector 9.
Experiment in the Aorta #2
[0489] Study subject: a female domestic pig, 71.7 Kg had been
treated with an ultrasonic treatment system on its renal left
artery. Anatomical target: nerves in the surrounding of the ostium
of the right renal artery. Anatomical position of catheter: aorta
artery, proximity to the ostium of right renal artery. Length of
ultrasonic treatment catheter: 55 cm Transducer frequency: 20 MHz
Time component of intensity profile: 30 seconds Acoustic intensity
component of intensity profile: 67 Watts/cm 2 Results: nerves at
the ostium of the aorta were treated. [0490] FIG. 15A represents a
2.times. magnification of the location at the aorta artery
circumference that was treated with the ultrasonic system, 6.5 mm
proximal from the renal right ostium artery. The marked area
represents the border of the thermal effect seen in the
priadventitia, which manifests in an irreversible tissue, and
vessels necrosis, (T=Thermal). Furthermore the nerve which was
affected by the ultrasonic treatment is marked with XN, which
represents unviable nerves, expressed by necrosis of the nerve.
[0491] FIG. 15B represents a 4.times. magnification of the thermal
area and the localization of the thermal necrotic nerve. [0492]
FIG. 15C represents a 10.times. magnification of the necrotic nerve
surrounded by tissue with thermal effect.
Schematic Description of Pathology Analysis:
[0493] FIG. 15D represents top view of all the artery layers (see
index box as follows), at the relevant depth (6.5 mm from the renal
right ostium). The artery is planned clockwise for the pathology
definition.
[0494] The thermal effect seen in the artery is represented by the
black area in the peri-adventitia, at sector 9.
Experiment in the Carotid Artery #1
[0495] Study subject: a female domestic pig, 72.8 Kg had been
treated with an ultrasonic treatment system on its carotid left
artery. Anatomical target: nerves in the wall of the right common
carotid artery. Anatomical position of catheter: Right common
carotid artery. Length of ultrasonic treatment catheter: 95 cm
Transducer frequency: 20 MHz Time component of intensity profile:
30 seconds Acoustic intensity component of intensity profile: 34
Watts/cm 2 Results: thermal effect was demonstrated from the media
layer throughout the priadventitia of the right common carotid
artery. [0496] FIG. 16A represents a 2.times. magnification of the
location of the thermal effect at the circumference of the right
common carotid artery. The marked area represents the border of the
thermal effect seen in the media throughout the priadventitia
layer, which manifests in pyknosis of the smooth muscle cells and
focal collagen condensation. [0497] FIG. 16B represents a 4.times.
magnification of the thermal area
Schematic Description of Pathology Analysis:
[0498] FIG. 16C represents top view of all the artery layers (see
index box as follows), at the relevant depth. The artery is planned
clockwise for the pathology definition.
[0499] The thermal effect seen in the artery is represented by the
black area in the peri-adventitia, at sector 1-3.
Experiment in the Carotid Artery #2
[0500] Study subject: a female domestic pig, 78.0 Kg had been
treated with an ultrasonic treatment system on its carotid left
artery. Anatomical target: nerves in the wall of the left common
carotid artery. Anatomical position of catheter: left common
carotid artery. Length of ultrasonic treatment catheter: 95 cm
Transducer frequency: 20 MHz Time component of intensity profile:
30 seconds Acoustic intensity component of intensity profile: 13.2
Watts/cm 2 Results: nerves surrounding the left common carotid
artery were treated [0501] FIG. 17A represents a digital scan of
the 28.5 mm from the aorta arch slide. The thermal effect is
manifested in an irreversible tissue, and vessels necrosis in less
than 25% of the peri adventitia in the artery circumference.
Furthermore nerves which were affected by the ultrasonic treatment
are found to be necrotic.
Schematic Description of Pathology Analysis:
[0502] FIG. 17B represents top view of all the artery layers (see
index box as follows), at the relevant depth (6.5 mm depth from the
aorta). The artery is planned clockwise for the pathology
definition.
[0503] The thermal effect seen in the artery is represented by the
black area in the peri-adventitia, at sector 3.
Experiment in the Renal Artery #1
[0504] Study subject: a female domestic pig, 68.2 Kg had been
treated with an ultrasonic treatment system on its renal left
artery. Anatomical target: nerves in the wall of the left renal
artery. Anatomical position of catheter: left renal artery. Length
of ultrasonic treatment catheter: 55 cm Transducer frequency: 10
Mhz Time component of intensity profile: 30 seconds Acoustic
intensity component of intensity profile: 26 Watts/cm 2 Results:
nerves surrounding the left renal artery were treated [0505] FIG.
18A represents a 2.times. magnification of the 6.5 mm depth from
the aorta slide. The marked area represents the border of the
thermal effect seen in the priadventitia, which manifests in an
irreversible tissue, and vessels necrosis, (T=Thermal). Furthermore
the nerves which were affected by the ultrasonic treatment are
marked with XN, which represents unviable nerves. Both nerves in
the surrounding of thermal area are necrotic. [0506] FIG. 18B
represents a 4.times. magnification of the thermal area, and the
localization of the thermal necrotic nerves. [0507] FIG. 18C
represents a 10.times. magnification of the necrotic nerves inside
the thermal effect zone. [0508] FIG. 18D represents a 10.times.
magnification of the necrotic nerve outside the thermal effect
zone. Both nerves' necrosis caused by the thermal ultrasonic
treatment. [0509] FIG. 18E represents a 2.times. magnification of
the 6.5 mm depth from the aorta slide stained in PSR, before
applying the polarizer lens. [0510] FIG. 18G represent a 2.times.
magnification of the 6.5 mm depth from the aorta slide, examined
under polarizer light, representing a distinctive negative
birefringence caused by collagen denaturation as consequence of the
ultrasonic treatment. The marked area represents the border of the
thermal effect seen in the priadventitia.
Schematic Description of Pathology Analysis:
[0511] FIG. 18G represents top view of all the artery layers (see
index box as follows), at the relevant depth (6.5 mm depth from the
aorta). The artery is planned clockwise for the pathology
definition.
[0512] The thermal effect seen in the artery is represented by the
black area in the peri-adventitia, at sector 5.
Pathology Analysis: Pathology Report Prepared by a Trained
Pathologist
[0513] The table below represents the pathology report for the
experiment. The table contains columns with the artery layers,
different potential pathologies relevant to the artery layer, slide
ID with a categorical scoring of lesions (as detailed below), and a
sector (S) column for the localization of the pathology damage in
clockwise manner.
TABLE-US-00008 Slide ID: N05-R- PIG No. N05-R-L3 L3 + 0.5 Sector
Status Lumen Free thrombus 0 Endothelium Pyknosis 0 Endothelium
Attached thrombus 0 Endothelium Fibrin deposition 0 Endothelium
Erosion 4 1-12 Int. Elastic Distorted 0 Lamina Int. Elastic Rupture
1 11-1 Lamina Media Inflammation 0 Media Pyknosis* 1 11-1 Media
Necrosis 0 Media Damage width (%) 40- 11-1 Vasa-Vasorum Thrombus 0
Vasa-Vasorum Fibrin 0 Vasa-Vasorum Necrosis 0 Adventitia Pyknosis 0
Adventitia Necrosis 0 Adventitia Inflammation 0 P. Adventitia
Necrosis 1 5 THERMAL vessels P. Adventitia Thrombus 0 vessels Peri
Adventitia Inflammation 0 Peri Adventitia Necrosis 1 5 P.
Adventitia Degeneration/ 0 nerves vacuolation P. Adventitia
Inflammation 0 nerves P. Adventitia Necrosis 1 5 nerves
TABLE-US-00009 For lesion scoring: 0: Normal Media damage width (%,
maximum width given): 1: Minimal or X-: damage from the lumen
towards the involving 0-25% periphery of the vessel of the vessel
circumference 2: Mild or X+: damage from the periphery towards
involving 25-50% the lumen of the vessel of the vessel
circumference 3: Moderate or A: Artifact on histological processing
involving 50-75% of the vessel circumference 4: Marked/Severe or
S-Clockwise sector involving 75-100% of the vessel
circumference
Experiment in the Renal Artery #2
[0514] Study subject: a female domestic pig, 65.7 Kg had been
treated with an ultrasonic treatment system on its renal left
artery. Anatomical target: nerves in the wall of the right renal
artery. Anatomical position of catheter: right renal artery. Length
of ultrasonic treatment catheter: 55 cm Transducer frequency: 20
Mhz Time component of intensity profile: three times for a period
of 30 second each Acoustic intensity component of intensity
profile: 53 Watts/cm 2, 59 Watts/cm 2 and 66 Watts/cm 2
respectively. Results: thermal effect was demonstrated at the peri
adventitia of the right renal artery. [0515] FIG. 19A represent a
2.times. magnification of the 6.5 mm depth from the aorta slide.
The marked area represents the border of the thermal effect seen in
the priadventitia, which manifests in an irreversible tissue
necrosis, (T=Thermal). [0516] FIG. 19B represents a 4.times.
magnification of the thermal area. No nerves were affected at this
treatment.
Schematic Description of Pathology Analysis:
[0517] FIG. 19C represents top view of all the artery layers (see
index box as follows), at the relevant depth (6.5 mm depth from the
aorta). The artery is planned clockwise for the pathology
definition.
[0518] The thermal effect seen in the artery is represented by the
black area in the peri-adventitia, at sector 6-7.
Pathology Analysis: Pathology Report Prepared by a Trained
Pathologist
[0519] The table below represents the pathology report for the
experiment. The table contains columns with the artery layers,
different potential pathologies relevant to the artery layer, slide
ID with a categorical scoring of lesions (as detailed below), and a
sector (S) column for the localization of the pathology damage in
clockwise manner.
TABLE-US-00010 Slide ID: PIG No. N06-R-R4 N06-R-R4 + 0.5 Sector
Lumen Free thrombus 0 Endothelium Pyknosis 0 Endothelium Attached
thrombus 0 Endothelium Fibrin deposition 1 12 Endothelium Erosion 2
9-3 Int. Elastic Lamina Distorted 0 Int. Elastic Lamina Ruptured 1
12 Media Inflammation 0 Media Pyknosis* 1 12 Media Necrosis 0 Media
Damage width (%) <10- 12 Vasa-Vasorum Thrombus 0 Vasa-Vasorum
Fibrin 0 Vasa-Vasorum Necrosis 0 Adventitia Pyknosis 0 Adventitia
Necrosis 0 Adventitia Inflammation 0 P. Adventitia vessels Necrosis
0 P. Adventitia vessels Thrombus 0 Peri Adventitia Inflammation 0
Peri Adventitia Necrosis 1 6-7 P. Adventitia nerves Degeneration/ 0
vacuolation P. Adventitia nerves Inflammation 0 P. Adventitia
nerves Necrosis 0
TABLE-US-00011 For lesion scoring: 0: Normal Media damage width (%.
maximum width given): 1: Minimal or X-: damage from the lumen
towards the involving 0-25% periphery of the vessel of the vessel
circumference 2: Mild or X+: damage from the periphery towards the
involving 25-50% lumen of the vessel of the vessel circumference 3:
Moderate or A: Artifact on histological processing involving 50-75%
of the vessel circumference 4: Marked/Severe or involving 75-100%
of the vessel circumference
Experiment in the Renal Artery #3
[0520] Study subject: a female domestic pig, 65.7 Kg had been
treated with an ultrasonic treatment system on its renal left
artery. Anatomical target: nerves in the wall of the right renal
artery. Anatomical position of catheter: right renal artery. Length
of ultrasonic treatment catheter: 55 cm Transducer frequency: 20
MHz Time component of intensity profile: twice for a period of 30
second each Acoustic intensity component of intensity profile: 40
Watts/cm 2 and 53 Watts/cm 2 Results: nerves surrounding the right
renal artery were treated [0521] FIG. 20A represents a 2.times.
magnification of the 10.5 mm depth from the aorta slide. The marked
area represents the border of the thermal effect seen in the
priadventitia, which manifests in an irreversible tissue, and
vessels necrosis, (T=Thermal). Furthermore the nerves which were
affected by the ultrasonic treatment are marked with XN, which
represents unviable nerves, and VN, which represent viable nerves.
In the surrounding of thermal area are present 8 nerves, including
7 unviable. [0522] FIG. 20B represents a 4.times. magnification of
the thermal area. [0523] FIGS. 20C-E represents a 10.times.
magnification of the necrotic and/or vacuolated nerves inside the
thermal effect zone. [0524] FIGS. 20E-I represents a 10.times.
magnification of the necrotic and/or vacuolated and viable nerves
outside the thermal effect zone.
Schematic Description of Pathology Analysis:
[0525] FIG. 20J represents top view of all the artery layers (see
index box as follows), at the relevant depth (10.5 mm depth from
the aorta). The artery is planned clockwise for the pathology
definition.
[0526] The thermal effect seen in the artery is represented by the
black area in the peri-adventitia, at sector 4-5.
Renal Denervation Study
Goal:
[0527] Inventors performed a controlled study to evaluate the
clinical feasibility and/or safety of performing a renal
denervation procedure in a chronic swine model, in accordance with
some embodiments of the invention.
Study End Points
[0528] Primary: A significant decrease in norepinephrine levels at
30 days following the procedure, in the treatment group compared to
the control group. [0529] Secondary: Lack of procedure related
stenosis in the treated renal arteries at 30 days following the
procedure.
Experimental Materials
[0529] [0530] Equipment: An ultrasound emission element, catheter
and control system as described herein and/or in the related
applications was used to perform the treatments. A 10 Mhz
ultrasound emission element was used in the first set of
experiments. A 20 Mhz element was used in the second set of
experiments. [0531] Animals and preparation: All aspects of the
study were approved by the Animal Research Committee. A total of 10
Yorkshire domestic swine (weight 70-75 Kg) were used for the first
set of experiments, 4 underwent the renal denervation procedure and
6 served as control. 5 additional pigs were used for the second set
of experiments, all underwent the procedure. [0532] Animal
preparation: Anatomic eligibility was confirmed by angiography
prior to the treatment. No animals were disqualified. The
experiment was performed under general anesthesia. Intravenous
heparin was administered to achieve an intraprocedural activated
clotting time (ACT)>250 seconds. At the end of the procedure the
animals were euthanized.
Experimental Protocol
Ultrasonic Treatment:
[0533] In the experimental swine group, the catheter was advanced
via a femoral approach to access the renal arteries. Ultrasound
treatment, in accordance with some embodiments of the invention,
was administered at the main arterial trunks in one or more
locations. In each location, the ultrasound energy was directed in
up to 4 angles of the arterial circumference (e.g., 0.degree.,
90.degree., 180.degree., 270.degree.--equivalent to 12, 3, 6, 9
hours in a clock model). Ablation of neural tissue was performed by
ultrasonic excitation of 10 or 30 seconds in each treatment
location. In actual practice, a smaller or larger number of angle
may be used.
[0534] The catheter distance from the artery wall was measured
using ultrasonic imaging of the system, prior to ultrasonic
excitation, in accordance with some embodiments of the invention.
If needed, a distancing device (e.g., as described with reference
to co-filed PCT application "Separation device for ultrasound
transducer", attorney docket number 52348) was deployed, such as a
part of the safety mechanism.
[0535] Control:
[0536] No ultrasonic energy was applied to the 6 swines in the
control group. One control animal was cannulated and the catheter
was introduced to the renal arteries without ultrasonic energy
delivery.
[0537] Angiography:
[0538] Angiography was performed during three time periods; prior
to the procedure, immediately at the end of procedure, and at 30
days+2 days. Under angiography, each renal artery was examined by a
trained physician for stenosis, constriction and/or any
abnormalities in blood flow.
[0539] Biopsy:
[0540] All experimental and control animals were biopsied. In vivo,
open bilateral renal cortex biopsies were conducted in order to
perform a norepinephrine (NE) quantitative analysis. The biopsy was
taken from the cranial and caudal poles of the kidney under direct
vision. Samples were sent to analysis of NE levels in the tissue
using HPLC.
[0541] Histology:
[0542] The renal arteries and kidneys were perfused, dissected and
immersed in 4% formalin prior to histological processing.
Pathological examination for any thermal or mechanical damage to
the renal arteries and connective tissue, including nerves.
Procedure Parameters
[0543] Procedure parameters are described for the first set of
experiments.
[0544] An average of about 6.5+0.5 ultrasonic treatments were
performed in the right renal artery in two locations along the
artery, and about 4.5+1.0 ultrasonic treatments were performed in
the left artery, in 1-2 focal locations along the artery. In an
exemplary embodiment of the invention, a number of treatments can
be performed in a number of locations. For example, 1, 2, 4, 8 or
other smaller, intermediate or larger treatment locations are
available. For example, 1, 2, 4, 6, 8, 12 or other smaller,
intermediate or larger numbers of treatments can be performed in an
artery.
[0545] Ultrasonic ablations were applied in one of two time
durations, 10 seconds or 30 seconds. In an exemplary embodiment of
the invention, the treatment time is about 1 second, about 5, 10,
15, 20, 25, 30, 35, 50, 60, 100 seconds or other smaller,
intermediate or larger time periods are used.
[0546] The average total procedure time was about 35.2+13.3
minutes. The maximal temperature measured by the sensor close to
the ultrasonic transducer was about 44.25+1.0 degrees Celsius in
the right renal artery, and about 45.2+3.4 degrees Celsius in the
left renal artery. The temperatures are considered safe.
Table Summarizing the Treatment Parameters
TABLE-US-00012 [0547] Number of Number of Number of treated Number
of treated excitations locations excitations locations in right in
right in left in left Duration of Animal renal renal renal renal
treatment ID artery artery artery artery (seconds) 7917 6 2 4 1 30
7918 7 2 6 2 30 7920 6 2 4 1 10 7921 7 2 4 1 10
Results
[0548] Norepinephrine (NE):
[0549] Renal tissue NE content was used as a chemical marker of the
sympathetic nervous system activity. Denervation of the sympathetic
nervous system potentially causes a reduction in NE release from
the sympathetic nerves terminals, indicating reduced sympathetic
activity.
[0550] The mean reduction in NE concentration (normalized and
averaged over different parts of the kidney) in renal tissue in the
treated animals in comparison to the control group was, on the
average, greater than 50% after 30 days. Longer treatment durations
generally caused a greater reduction.
[0551] Angiography:
[0552] Neither perfusion defects nor artery constriction were
depicted in the treatment group of animals, neither at the
treatment time point, nor at the 30 day follow up. Mild spasm had
occurred coincidentally during the treatment, with no sign of
permanent spasm or abnormalities remaining or forming de-novo in
the 30 days following treatment.
[0553] Histopathology:
[0554] There was no stenosis in any of the renal artery vessels in
all levels. All vessels were potent in all levels.
CONCLUSION
[0555] As illustrated by the decrease in NE levels, all 10 pigs
were successfully treated by renal denervation using ultrasound
energy, in accordance with some embodiments of the invention. A
relatively longer treatment (e.g., 30 seconds vs. 10 seconds)
resulted in a relatively larger decrease of NE levels, suggesting
that longer treatment times disrupt a larger number of nerves
and/or nerves to a greater degree. Furthermore, some embodiments as
described herein have been shown to be safe, as no abnormalities
occurred to the renal arties during and immediately post treatment,
as well as at 30 days.
[0556] Although the invention has been described in conjunction
with specific embodiments thereof, it is evident that many
alternatives, modifications and variations will be apparent to
those skilled in the art. Accordingly, it is intended to embrace
all such alternatives, modifications and variations that fall
within the spirit and broad scope of the appended claims.
[0557] All publications, patents and patent applications mentioned
in this specification are herein incorporated in their entirety by
reference into the specification, to the same extent as if each
individual publication, patent or patent application was
specifically and individually indicated to be incorporated herein
by reference. In addition, citation or identification of any
reference in this application shall not be construed as an
admission that such reference is available as prior art to the
present invention. To the extent that section headings are used,
they should not be construed as necessarily limiting.
GENERAL
[0558] It is expected that during the life of a patent maturing
from this application many relevant ultrasound transducers will be
developed and the scope of the term transducer is intended to
include all such new technologies a priori.
[0559] As used herein the term "about" refers to .+-.10%
[0560] The terms "comprises", "comprising", "includes",
"including", "having" and their conjugates mean "including but not
limited to".
[0561] The term "consisting of" means "including and limited
to".
[0562] The term "consisting essentially of" means that the
composition, method or structure may include additional
ingredients, steps and/or parts, but only if the additional
ingredients, steps and/or parts do not materially alter the basic
and novel characteristics of the claimed composition, method or
structure.
[0563] As used herein, the singular form "a", "an" and "the"
include plural references unless the context clearly dictates
otherwise. For example, the term "a compound" or "at least one
compound" may include a plurality of compounds, including mixtures
thereof.
[0564] Throughout this application, various embodiments of this
invention may be presented in a range format. It should be
understood that the description in range format is merely for
convenience and brevity and should not be construed as an
inflexible limitation on the scope of the invention. Accordingly,
the description of a range should be considered to have
specifically disclosed all the possible subranges as well as
individual numerical values within that range. For example,
description of a range such as from 1 to 6 should be considered to
have specifically disclosed subranges such as from 1 to 3, from 1
to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as
well as individual numbers within that range, for example, 1, 2, 3,
4, 5, and 6. This applies regardless of the breadth of the
range.
[0565] Whenever a numerical range is indicated herein, it is meant
to include any cited numeral (fractional or integral) within the
indicated range. The phrases "ranging/ranges between" a first
indicate number and a second indicate number and "ranging/ranges
from" a first indicate number "to" a second indicate number are
used herein interchangeably and are meant to include the first and
second indicated numbers and all the fractional and integral
numerals therebetween.
[0566] It is appreciated that certain features of the invention,
which are, for clarity, described in the context of separate
embodiments, may also be provided in combination in a single
embodiment. Conversely, various features of the invention, which
are, for brevity, described in the context of a single embodiment,
may also be provided separately or in any suitable subcombination
or as suitable in any other described embodiment of the invention.
Certain features described in the context of various embodiments
are not to be considered essential features of those embodiments,
unless the embodiment is inoperative without those elements.
[0567] Reference is now made to the following examples, which
together with the above descriptions illustrate some embodiments of
the invention in a non limiting fashion.
* * * * *