U.S. patent application number 14/651009 was filed with the patent office on 2015-10-29 for methods and apparatus for treating a cervix with ultrasound energy.
This patent application is currently assigned to ARIZONA BOARD OF REGENTS ON BEHALF OF ARIZONA STATE UNIVERSITY. The applicant listed for this patent is ARIZONA BOARD OF REGENTS ON BEHALF OF ARIZONA STATE UNIVERSITY. Invention is credited to Robert E. Garfield, Shao-Qing Shi, Bruce C. Towe.
Application Number | 20150306429 14/651009 |
Document ID | / |
Family ID | 50934889 |
Filed Date | 2015-10-29 |
United States Patent
Application |
20150306429 |
Kind Code |
A1 |
Towe; Bruce C. ; et
al. |
October 29, 2015 |
Methods and Apparatus for Treating a Cervix with Ultrasound
Energy
Abstract
Methods and apparatuses for speeding the softening of the cervix
(cervical ripening) by way of application of ultrasound energy. A
vaginal transducer may be used to emit pulse-modulated ultrasound
energy directed to the cervix. Focused ultrasound energy may be
applied trans-abdominally and directed at the cervix. Ultrasound
energy is widely used in medical applications such as diagnostic
imaging, therapeutic heating and noninvasive surgery.
Inventors: |
Towe; Bruce C.; (Mesa,
AZ) ; Garfield; Robert E.; (Goodyear, AZ) ;
Shi; Shao-Qing; (Goodyear, AZ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ARIZONA BOARD OF REGENTS ON BEHALF OF ARIZONA STATE
UNIVERSITY |
Scottsdale |
AZ |
US |
|
|
Assignee: |
ARIZONA BOARD OF REGENTS ON BEHALF
OF ARIZONA STATE UNIVERSITY
Scottsdale
AZ
|
Family ID: |
50934889 |
Appl. No.: |
14/651009 |
Filed: |
December 10, 2013 |
PCT Filed: |
December 10, 2013 |
PCT NO: |
PCT/US13/74106 |
371 Date: |
June 10, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61735306 |
Dec 10, 2012 |
|
|
|
Current U.S.
Class: |
601/2 |
Current CPC
Class: |
A61N 2007/0043 20130101;
A61B 8/08 20130101; A61B 2090/378 20160201; A61N 7/00 20130101 |
International
Class: |
A61N 7/00 20060101
A61N007/00 |
Claims
1. A method of promoting cervical ripening comprising: applying
pulsed ultrasound energy to a cervix at a frequency, pulse
duration, pulse repetition rate and peak pulse power sufficient to
promote cervical ripening.
2. The method according to claim 1, wherein the frequency range of
the ultrasound energy is 100 kHz to 10 MHz.
3. The method according to claim 1, wherein the frequency range of
the ultrasound energy is about 680 kHz.
4. The method according to claim 1, wherein the pulse duration is
in the range of 1-50 milliseconds.
5. The method according to claim 1, wherein the pulse duration is
in the range of 2-10 milliseconds.
6. The method according to claim 1, wherein the pulse repetition
rate is within the range of 5-100 pulses per second.
7. The method according to claim 1, wherein the instantaneous peak
pulse power (I.sub.PPP) is in the range of 10-190 W/cm.sup.2.
8. The method according to claim 1, wherein the instantaneous peak
pulse power (I.sub.PPP) is about 40 W/cm.sup.2.
9. The method according to claim 1, wherein the average power
delivered is less than 720 m W/cm.sup.2.
10. The method according to claim 1, wherein the ultrasound energy
is applied from 10 minutes to 60 minutes.
11. The method according to claim 1, wherein the pulse duration is
in the range of 10 microseconds to 300 microseconds and delivered
in trains of 10-100 milliseconds bursts and the repetition rate is
5-200 Hz; and the mechanical index (MI) is less than or equal to
1.9 and the Ispta.3 is less than 720 m W/cm.sup.2.
12. The method according to claim 1, wherein the ultrasound energy
is applied to the face of the cervix via an intra-vaginal
transducer.
13. The method according to claim 1, wherein the ultrasound energy
is applied trans-abdominally using a focused transducer, wherein
the focal zone encompasses the cervix.
14. The method according to claim 13, wherein 60% of the cervix is
within the focal zone.
15. The method according to claim 1, wherein the ultrasound energy
is applied transabdominally using a scanning ultrasound beam so as
to progressively cover the cervical area through a process of
continuous or interrupted advancement over the tissue volume.
16. The method according to claim 1, further comprising visualizing
the cervix by ultrasound applied either transabdominally or
vaginally.
17. The method according to claim 1, further comprising treatment
with prostaglandin or other drugs to promote cervical ripening.
18. The method of claim 1, further comprising applying high
frequency sound waves for ultrasound imaging.
19. A method of promoting cervical ripening comprising: applying
ultrasound energy to a cervix, wherein the parameters of the
ultrasound energy are selected to promote cervical ripening, the
parameters being selected from the group comprising: pulse
frequency, pulse duration, pulse repetition frequency, and
instantaneous peak pulse power.
20. The method of claim 19, wherein the step of applying pulsed
ultrasound energy comprises directing a focal zone of a focused
ultrasound energy transducer towards a cervix.
21. The method of claim 19, wherein the step of applying pulsed
ultrasound energy comprises directing a vaginal transducer towards
a cervix.
22. A method of treating a cervix, comprising: applying pulsed
ultrasound energy to a cervix, wherein a frequency of the pulsed
ultrasound energy is 100 kHz to 10 MHz, a pulse duration of the
pulsed ultrasound energy is 1-50 milliseconds; a pulse repetition
rate of the pulsed ultrasound energy is 10-100 pulses per second;
and a peak pulse power of the pulsed ultrasound energy is in the
range of 10-300 W/cm.sup.2.
23. The method according to claim 22, wherein the frequency, pulse
duration, pulse repetition rate, and peak pulse power promote
cervical ripening.
24. The method according to claim 23, wherein the frequency is
about 680 kHz, the pulse duration is about 2-4 milliseconds, and
the pulse repetition rate is about 25 Hz.
25. The method according to claim 22, wherein the average power
delivered is less than 720 m W/cm.sup.2.
26. The method according to claim 22, wherein the ultrasound energy
is applied from 10 minutes to 60 minutes.
27. An apparatus for delivering ultrasound energy, comprising: an
ultrasound transducer; and a signal generator coupled to the
ultrasound transducer to generate ultrasound energy, wherein the
signal generator is adapted to generate pulsed ultrasound energy
with a frequency of 100 kHz to 10 MHz, a pulse duration of 1-50
milliseconds; a pulse repetition rate of 5-100 pulses per second;
and a peak pulse power of 10-190 W/cm.sup.2.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional
Patent Application No. 61/735,306 entitled "Methods and Apparatuses
for Treating a Cervix With Ultrasound Energy," filed on Dec. 10,
2012, which is specifically incorporated herein by reference
without disclaimer in its entirety.
BACKGROUND
[0002] 1. Field of the Invention
[0003] This disclosure relates generally to methods and apparatus
for the practice of medical obstetrics. More particularly, this
disclosure relates to methods and apparatus for treating a cervix
using ultrasound energy.
[0004] 2. Description of Related Art
[0005] Ultrasound energy is widely used in medical applications
such as diagnostic imaging, therapeutic heating and noninvasive
surgery. Ultrasound diagnostic imaging employs sound power levels
and pulse protocols considered safe for use in obstetrics. Its long
history of use in the clinic supports this conclusion. At much
higher ultrasound power levels, the vibration of tissue can produce
warmth and heating which is useful in the treatment of soft tissue
injuries and certain arthritic conditions. There are also
ultrasound based devices that use relatively high intensity focused
energy for thermal treatment of cancers.
[0006] Ultrasound energy levels used in medical imaging are
characterized by their mechanical effects where avoidance of
cavitation is important and also by their thermal effects on
tissues. The mechanical effects of ultrasound absorption are also
known as non-thermal effects and are represented by the mechanical
index (MI), which is a relative measure. The mechanical index (MI)
is defined as the maximal value of the peak negative pressure of
the ultrasound wave measured in milliPascals divided by the square
root of the acoustic center frequency of the ultrasound wave.
Regulatory standards in the United States require the MI to be
below 1.9 to avoid cavitation. The ultrasound power delivery known
as I.sub.SPTA.3 is a derated spatial peak temporal average. There
are different permissible values of this depending on the target
organ exposed to ultrasound. The most commonly cited value is 720 m
W/cm.sup.2 I.sub.SPTA.3 and 190 W/cm.sup.2 I.sub.SPPA.3 for
exposure to the body (US FDA, Guidance for Industry and FDA Staff:
Information for Manufacturers Seeking Marketing Clearance of
Diagnostic Ultrasound Systems and Transducers, Document issued on:
Sep. 9, 2008). This value is lower for direct ultrasound exposure
of the fetus. Another measure of thermal effects is the thermal
index (TI), which is a calculated estimate of temperature increase
with tissue absorption of ultrasound and is defined as the ratio of
the emitted acoustic power to the power required to raise the
temperature of tissue by 1.degree. C. Regulatory standards in the
United States require the TI to be below 1.0.
[0007] Ultrasound imaging machines emit microsecond-order pulses
into tissues at a repetition rate that typically does not exceed 4
kHz and thus the duty cycle of the ultrasound energy is relatively
low, on the order of less than one percent. In addition, ultrasound
imaging examinations are conducted over short intervals of time,
typical minutes, and the overall ultrasound integrated dose to a
patient is relatively low. Ultrasound imaging is briefly described
below.
[0008] Ultrasound imaging (sonography) uses high-frequency sound
waves to view soft tissues such as muscles and internal organs.
Because ultrasound images are captured in real-time, they can show
movement of the body's internal organs as well as blood flowing
through blood vessels.
[0009] In an ultrasound exam, a hand-held transducer is placed
against the skin. The transducer sends out high frequency sound
waves that reflect off of body structures. The returning sound
waves, or echoes, are displayed as an image on a monitor. The image
is based on the frequency and strength (amplitude) of the sound
signal and the time it takes to return from the patient to the
transducer. Unlike with an x-ray, there is no ionizing radiation
exposure with this procedure.
[0010] Ultrasound imaging is used in many types of examinations and
procedures. Some examples include: [0011] a) Doppler ultrasound (to
visualize blood flow through a blood vessel); [0012] b) bone
sonography (to diagnose osteoporosis); [0013] c) echocardiogram (to
view the heart); [0014] d) fetal ultrasound (to view the fetus in
pregnancy); [0015] e) ultrasound imaging of the cervix during
pregnancy (short cervix is risk factor for preterm birth) [0016] f)
ultrasound-guided biopsies; and [0017] g) Doppler fetal heart rate
monitors (to listen to the fetal heart beat).
[0018] Ultrasound imaging has been used for over 20 years and has
an excellent safety record. It is non-ionizing radiation, so it
does not have the same risks as x-rays or other types of ionizing
radiation. Even though there are no known risks of ultrasound
imaging, it can produce effects on the body. When ultrasound enters
the body, it heats the tissues slightly. In some cases, it can also
produce small pockets of gas in body fluids or tissues
(cavitation). Because of the particular concern for fetal
exposures, national and international organizations have advocated
prudent use of ultrasound imaging. Furthermore, the use of
diagnostic ultrasound for non-medical purposes such as fetal
keepsake videos has been discouraged. Ultrasound imaging is used
routinely in obstetrics to visualize the cervix in pregnant
patients. Transvaginal ultrasound imaging has now established that
the shorter the sonographic cervical length in the mid-trimester,
the higher the risk of preterm delivery. Indeed, it is possible to
assign an individualized risk for preterm delivery using
sonographic cervical length and other maternal risk factors, such
as maternal age, ethnic group, body mass index and previous
cervical surgery. Among these factors, sonographic cervical length
is thought to be one of the most powerful predictors for preterm
birth in the index pregnancy, and is more informative than a
history of previous preterm birth.
[0019] Pulses of longer duration ultrasound, on the order of
milliseconds and at repetition rates much lower while still
emitting power levels within MI and I.sub.SPTA.3 safety limits can
produce bioelectrical stimulatory and in some cases inhibitory
effects on the central nervous system. See, e.g., Tyler, W. J.,
Tufail, Y., Finsterwald, M., Tauchmann, M. L., Olsen, E. J.,
Majestic, C., Remote Excitation of Neuronal Circuits Using Low
Intensity, Low Frequency Ultrasound, PLoS One, 3(10):e3511;
Bystritsky, A., Korb, A., Douglas, P., Cohen, M., Melega, W.,
Mulgaonkar, A., DeSalles, A., Min, B., Yoo, S. S., A Review of Low
Intensity Focused Ultrasound Pulsation, Brain Stimulation, vol. 4,
no. 3, pp. 125-136, (July 2011); Yoo, S. S., Bystritsky, A., Lee,
J. H., Zhang, Y., Fischer, K., Min, B. K., McDannold, N. J.,
Pascual-Leone, A., Jolesz, F. A., Focused Ultrasound Modulates
Region-Specific Brain Activity, NeuroImage, 56(3), 1267-75, (June
2011)). However, ultrasound is not known to produce significant
effects on the peripheral nervous system sufficient to produce
action events. See, e.g., Gavrilov L R, Geshuni G V, Il'iniskii O
B, Popova L A, Sirotyuk M G, Tsirul'nikov E. M., Stimulation Of
Human Peripheral Neural Structures By Focused Ultrasound, Sov Phys
Acoust, 19(4):332-334 (1974); Colucci, V., Strichartz, G., Jolesz,
F., Vykhodtseva, N., Hynynen, K., Focused Ultrasound Effects on
Nerve Action Potential, Ultrasound in Medicine and Biology, Vol.
35. #10, pp. 1737-1747 (2009). Additionally it is well known that
ultrasound passes through muscle tissue, even at elevated power
levels, without producing direct stimulatory effects. There are,
however, medical therapeutic applications that would be well served
if ultrasound could be applied to the body in a method that would
evoke physiologic changes.
[0020] The control of events during pregnancy and labor are
generally understood to be under hormonal control, but there are
certain bioelectrical effects associated with labor and delivery.
For example, the underlying electrical activity of the uterine
muscle produce the contractions associated with labor. However,
bioelectric events are not thought to be associated with the
progress of labor associated with changes in the cervix and
cervical softening. Early changes in tensile strength during
cervical softening result in part from changes in the number and
type of collagen cross-links and are associated with a decline in
expression of two matricellular proteins thrombospondin 2 and
tenascin C.
[0021] Throughout early pregnancy, the cervix is rigid and thereby
helps to maintain pregnancy by protecting the growing fetus within
the uterine cavity. Normally, during the last one-half of
pregnancy, the cervix slowly softens in preparation for birth at
term. This process is generally termed cervical ripening. At term,
the softened cervix is then capable of effacement and dilation to
allow the baby to pass through the cervix and vagina during birth.
Early cervical ripening often leads to premature birth (i.e., birth
of the baby before the 37th week of gestation) and serious problems
related to prematurity. On the other hand, delay in cervical
ripening can result in still birth and seriously jeopardize the
health of the baby or mother.
[0022] Presently, drugs such as prostaglandins and oxytocin are
used to stimulate cervical ripening and labor near the end of
gestation. It is estimated that about 40 to 60% of pregnant
patients are treated with various prostaglandin agents to ripen the
cervix and prepare patients for delivery. Thus, there is a large
market for procedures which will ripen the cervix effectively. In
the year 2000, the total sales for prostaglandins used to ripen the
cervix was estimated to be $123 million in the USA. There are no
present estimates but the total market today could approach well
over $200 million dollars.
[0023] Remodeling of the cervix involves enzymatic dissolution of
collagen fibrils, increase in water content, and chemical changes.
These changes are known to be induced by hormones (estrogen,
progesterone, relaxin), as well as cytokines, prostaglandins, and
nitric oxide synthesis enzymes.
SUMMARY
[0024] According to an exemplary embodiment, a method of promoting
cervical ripening comprises applying pulsed ultrasound energy to a
cervix at a frequency, pulse duration, pulse repetition rate and
peak pulse power sufficient to promote cervical ripening. In
certain embodiments, the frequency range of the ultrasound energy
is from 100 kHz to 10 MHz, the pulse duration is in the range of
1-50 milliseconds, the pulse repetition rate is in the range of
10-100 pulses per second, and the instantaneous peak pulse power
(I.sub.PPP) is in the range of 10-300 W/cm.sup.2. The average power
delivered is less than 720 m W/cm.sup.2 and the ultrasound energy
is applied from 10 minutes to 60 minutes.
[0025] According to another embodiment, the pulse duration is in
the range of 10 microseconds to 300 microseconds and delivered in
trains of 10-100 milliseconds bursts, the repetition rate is 1-25
Hz and the mechanical index (MI) is less than or equal to 1.9 and
the I.sub.SPTA.3 is less than 720 m W/cm.sup.2.
[0026] In some embodiments, the ultrasound energy is applied to the
face of the cervix via an intra-vaginal transducer. Alternatively,
the ultrasound energy may be applied trans-abdominally to the
cervix using a focused transducer, wherein the focal zone
encompasses the cervix. The focal zone may encompass 60% of the
cervix.
[0027] In accordance with other embodiments, other treatments, such
as prostaglandin or other drugs to promote cervical ripening, may
also be used, or ultrasound imaging using high frequency sound
waves may be used to visualize the cervix before or following
application of ultrasound energy that will soften (ripen) the
cervix.
[0028] In other embodiments, a method of promoting cervical
ripening comprises applying ultrasound energy to a cervix, wherein
the parameters of the ultrasound energy are selected to promote
cervical ripening. The parameters are selected from the group
comprising: pulse frequency, pulse duration, pulse repetition
frequency, and instantaneous peak pulse power. The pulsed
ultrasound energy may be delivered by directing a focal zone of a
focused ultrasound energy transducer towards a cervix or by
directing a vaginal transducer towards a cervix.
[0029] In certain embodiments, a method of treating a cervix
comprises applying pulsed ultrasound energy to a cervix, wherein a
frequency of the pulsed ultrasound energy is 100 kHz to 10 MHz, a
pulse duration of the pulsed ultrasound energy is 1-50
milliseconds; a pulse repetition rate of the pulsed ultrasound
energy is 10-100 pulses per second; and a peak pulse power of the
pulsed ultrasound energy is in the range of 10-300 W/cm.sup.2. The
frequency, pulse duration, pulse repetition rate, and peak pulse
power may be selected to promote cervical ripening. The average
power delivered may be less than 720 m W/cm.sup.2, and the
ultrasound energy may be applied from 10 minutes to 60 minutes.
[0030] In accordance with another embodiment, an apparatus for
delivering ultrasound energy comprises an ultrasound transducer and
a signal generator coupled to the ultrasound transducer to generate
ultrasound energy. The signal generator is adapted to generate
pulsed ultrasound energy with a frequency of 100 kHz to 10 MHz, a
pulse duration of 1-50 milliseconds; a pulse repetition rate of
10-100 pulses per second; and a peak pulse power of 10-300
W/cm.sup.2.
BRIEF DESCRIPTION OF THE DRAWINGS
[0031] The following drawings form part of the present
specification and are included to further demonstrate certain
aspects of the present invention. The invention may be better
understood by reference to one or more of these drawings in
combination with the detailed description of specific embodiments
presented herein.
[0032] FIG. 1 is a schematic view of an apparatus for applying
ultrasound energy to a cervix in accordance with an exemplary
embodiment;
[0033] FIG. 2 is a schematic view of an apparatus used to construct
and deliver pulsed ultrasound waveforms;
[0034] FIG. 3 is a graph showing focal zone power distribution;
[0035] FIG. 4 is an exemplary low frequency ultrasound stimulus
waveform;
[0036] FIG. 5 is a graph of daily light-induced fluorescence (LIF)
measurement during gestation in treated rats versus control
rats;
[0037] FIG. 6 is a graph showing changes in LIF after focused
ultrasound application as a function of exposure time;
[0038] FIG. 7 is a graph showing changes in LIF after focused
ultrasound application as a function of power level;
[0039] FIG. 8 is a graph showing stretch test results showing the
effect of ultrasound on a cervix; and
[0040] FIG. 9 is a comparison of fetal delivery weights of
ultrasound treated and control groups.
DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0041] In the following detailed description, reference is made to
the accompanying drawings, in which are shown exemplary but
non-limiting and non-exhaustive embodiments of the invention. These
embodiments are described in sufficient detail to enable those
having skill in the art to practice the invention, and it is
understood that other embodiments may be used, and other changes
may be made, without departing from the spirit or scope of the
invention. The following detailed description is, therefore, not to
be taken in a limiting sense, and the scope of the invention is
defined only by the appended claims.
[0042] FIG. 1 shows a system 10 for applying pulsed ultrasound
energy which may be used in accordance with an exemplary embodiment
of the present invention. The system 10 includes a signal generator
12 which is coupled to a transducer 14 by a cable 16. The
transducer 14 may be a focused transducer or an intra-vaginal
transducer which uses, for example, a piezoelectric transducer to
generate mechanical vibrations from electrical signals. The signal
generator 10 generates a signal to drive the transducer to generate
pulsed ultrasound and may include a power supply, a function
generator, and an oscilloscope to generate and monitor a signal.
The signal generator 10 has controls 18 to adjust the parameters
(such as pulse frequency, pulse duration, pulse repetition
frequency, and instantaneous peak pulse power) of the generated
signal in accordance with the values described in further detail
below. The system may be compact and implemented as a portable
intra-vaginal applicator. The system may also be incorporated with
or implemented by a ultrasound imaging system.
[0043] In accordance with an exemplary embodiment, ultrasound
energy is applied to a cervix to promote cervical ripening. The
ultrasound energy is applied with a specific pulse protocol that is
selected to promote cervical ripening. The power level is
comparable to that used in ultrasound imaging. However, it differs
from ultrasound imaging in that the ultrasound pulses are emitted
at a lower repetition rate, have a longer duration than used in
imaging, and are applied for overall a longer period of time than
typical of imaging.
[0044] The application of ultrasound is directed so as to apply
energy to the cervix while minimizing application of energy to
surrounding tissue. One method of doing so is by using a focused
ultrasound transducer that applies energy through the abdominal
wall. The focused ultrasound transducer is positioned such that the
focal zone encompasses the cervix.
[0045] Preferably, at least 60% of the cervix is within the focal
zone. However, the positioning of the beam is not critical, as
evidenced by the testing described below. Another method of
applying ultrasound energy is to use an intra-vaginal device to
apply energy at the face of the cervix.
[0046] In one embodiment, ultrasound at 30-300 W/cm.sup.2 is
applied in the range of 1 to 50 millisecond pulses with a pulse
repetition rate of 5 to 100 Hz such that the overall power level
applied to tissue is less than 720 m W/cm.sup.2 and therefore
within generally accepted safe levels of ultrasound power. This
power level is applied for a suitable duration, such as 10-60
minutes. Preferably, the power is applied for approximately 15
minutes.
[0047] In accordance with another embodiment, ultrasound pulses
with a relatively shorter duration, 50 microseconds to 300
microseconds, are delivered in trains of 10-100 milliseconds
bursts. The repetition rate is then 1-25 Hz, which is chosen to
maintain an overall safe power delivery level. In this embodiment,
the shorter duration pulses can use higher peak power values yet
still remain within the range of safe MI and I.sub.SPTA.3.
[0048] Additional therapies may be used in combination with
ultrasound to promote the ripening of the cervix. For example, the
ultrasound treatment may be combined with prostaglandin treatment
or other drugs to promote cervical ripening.
[0049] The ultrasound ripening technique may also be performed in
combination with traditional ultrasound imaging (i.e., applying
high frequency sound waves).
EXAMPLE
[0050] A study was undertaken to characterize the effect of focused
ultrasound (FUS) stimulation on a rat cervix as a means to produce
ripening during pregnancy. Rat models are routinely used in studies
of drugs used in humans for obstetrics and gynaecology
applications. Timed-pregnant Sprague-Dawley rats (Charles River
Laboratories, Wilmington, Mass., USA) were housed separately. The
rats were maintained on a constant 12 hours light and 12 hour dark
cycle. The pregnant rats have a 22 day gestation cycle, day 1 being
the day on which the sperm plug is observed. While undergoing
focused ultrasound (FUS) treatment, the animals were anaesthetized
with a combination of xylazine and ketamine based on their weight 1
.mu.l/g. They were sacrificed by surgical dislocation for cervical
tissue collection.
[0051] A custom made ultrasound instrumentation set-up was
constructed as illustrated in FIG. 2 to study the effects of FUS on
cervix. A function generator 20 (Stanford Research Systems DS-345)
provided the excitation waveform as shown in FIG. 4. An ultrasound
power amplifier 22 was built to drive a transducer 24 made from a 5
cm PZT disk (Steminc Inc.) with a fundamental frequency of 0.682
MHz. The transducer was coupled to a spherically focused epoxy
(West System Inc.) lens, having a 6.5 cm radius. The FWHM (full
width at half maximum) of the output beam was approximately 5 mm
diameter as measured by hydrophone (Precision Acoustics,
Devonshire, UK). FIG. 3 shows the focal zone power distribution. A
thermocouple 26 was used to measure temperature.
[0052] The ultrasound energy was applied through a water coupling
column and acoustic coupling gel to the rat's abdominal skin
surface over the cervix region as determined by palpation of an
internal probe placed at the cervical entrance. The ultrasound beam
passed through the annulus of the cervix in a parallel incidence to
the plane of the cervix.
[0053] The experiment tested a range of ultrasound pulse widths at
680 KHz ultrasound using 25 Hertz pulse repetition rate as shown in
FIG. 4.
[0054] As shown in Table 1, the I.sub.SPPA used in this experiment
was measured at 40 W/cm.sup.2 using continuous mode ultrasound and
a force balance. The I.sub.SPTA varied from 1 W/cm.sup.2 to 4
W/cm.sup.2 by way of pulse durations from 1 millisecond to 4
milliseconds. The duration of ultrasound exposure time was in the
range of 30 minutes to 1 hour.
TABLE-US-00001 TABLE 1 Day of gestation Stimulation Frequency
I.sub.SPTA N = number when applied time (hour) (KHz)
(Watts/cm.sup.2) of rats D15 1 -- 0 10 D15 1 680 4 9 D15 0.5 680 4
2 D14 0.5 -- 0 5 D14 0.5 680 4 4 D14 0.5 680 2 4 D14 0.5 680 1 4
Total 38
[0055] On day 14 or 15 of gestation, a focused ultrasound (FUS)
system was placed on the abdominal surface of ketamine/xylazine
anesthetized rats at the level of the internal cervix. In control
rats, the FUS system was placed on the animals but no energy was
applied. In treated rats, 680 kHz ultrasound at 25 Hertz repetition
rate, 2-4 millisecond pulse duration was directed to the cervix
from the skin for 0.5 to 1 hour. I.sub.SPPA.3 was 40 W/cm.sup.2,
which is less than used in imaging (190 W/cm.sup.2). The mechanical
index (MI) of the ultrasound pulse was calculated to be 0.2 and so
within safe regulatory limits (1.9).
[0056] A light-induced fluorescence (LIF) Collascope (Reproductive
Research Technologies Inc., Houston, Tex.) was used to evaluate the
changes in the elasticity of the cervix over time during gestation.
LIF measurements were made on both experimental and control groups
prior to ultrasound exposure. One hour after the beginning the FUS
ultrasound treatment, the LIF test was performed again. LIF
measurements were made on rats every 24 hours until their
spontaneous delivery. The average of 16 measurements of fluorescent
intensity at 390 nm wavelength was used to evaluate cervical
ripening for each animal. Lower numerical values represent greater
cervical ripening. After FUS, the cervix of animals was examined
for mechanical changes and visually by endoscopic camera. Delivery
times, fetal weights and fetal viability were made following
delivery of both control and FUS-treated animals.
[0057] The effects of focused ultrasound on the cervix mechanical
stretching and compliance were tested using a universal Tissue
Organ Bath System (750TOBS, DMT, Inc.). The cervix is defined as
the least vascular tissue with two parallel lumina between the
uterine horns and the vagina. Connective tissue and fat were
removed and the cervix was suspended with its longitudinal axis
vertically in a tissue bath chamber for tension recording. The
chamber was filled with physiological Kreb's solution, bubbled with
a mixture of 95% 02 and 5% CO2, and maintained at 37.degree. C. The
isolated cervix was elongated incrementally at the rate of 0.015
mm/s and tension continuously recorded. The slope of the regression
line through the linear portion of the length-tension curve was
employed as an indication of the cervical extensibility. The slope
of the length-tension curve is linearly related to cervical
resistance.
[0058] Statistical comparisons between two group data were
estimated by unpaired student's t-test analysis. A 2-tailed
probability value of P<0.05 was considered to be statistically
significant different. Results are expressed as means.+-.SEM.
[0059] A total of 38 rats were used in the study according to Table
1 where the day of gestation is listed on the left.
[0060] FIG. 5 plots the cervical ripening as determined by the LIF
for ultrasound treated (n=9) animals and for untreated control
(n=10) animals and for treatment duration of 1 hour at 4
milliseconds ultrasound pulse width. This plot starts at gestation
day 15 when FUS stimulation was applied until spontaneously
delivery on day 22.
[0061] The time of delivery of controls and treated groups were
determined as hours after 8 AM of day 22 of gestation. The
expulsion of 1 pup was defined as delivery. In control animals as
seen in FIG. 5 the cervical LIF values drop with the normal
progressive ripening from day 15 of gestation to day 21.
[0062] In the ultrasound treated group LIF values dropped faster
from the control value of 2064.+-.116 on day 15 and continued to
decline after treatment to delivery at 637.+-.133 which is lower
than control.
[0063] The ultrasound treatment produced LIF values significantly
lower (P<0.01) in FUS treated animals on days 16 and 17 that are
immediately after ultrasound treatment when compared to controls
(day 16: 700.+-.237 versus control 1319.+-.241 day 17: 503.+-.231
versus control 1000.+-.178). The LIF values for the treated group
remain low until delivery.
[0064] A series of experiments were performed on day 15 for both 30
minute and 1 hour at 4 W/cm.sup.2. After 24 hours and LIF tests,
the rat cervix was collected and mechanical tests of cervical
resistance were performed. FIG. 6 shows this result. Ultrasound had
a strong cervical ripening effect measured at 1 hour after the
beginning of stimulation compared to control (1 hour: 806.+-.90,
0.5 hour: 897.+-.99, compared to control: 2059.+-.122) and this was
sustained over the 24 hour observation interval. The amount of
ripening produced by ultrasound at this stage of pregnancy was
greater than that of control. Additionally, longer 1 hour exposures
compared to 30 minutes did not appear to produce an additional
ripening effect. Further testing has shown that ripening is
initiated with durations of 20 minutes, and some trial data
suggests 10 minutes may be sufficient.
[0065] An additional series of experiments were directed to
measuring the effects of power level. This series consisted of 30
minute ultrasound exposure commencing on day 14 using three
different power levels (1 W/cm.sup.2, 2 W/cm.sup.2, 4 W/cm.sup.2).
FIG. 7 shows a large and significant cervical change (P<0.01) at
power levels of 1 W/cm.sup.2: 1454.+-.349, 2 W/cm.sup.2:
1458.+-.103, 4 W/cm.sup.2: 1119.+-.89 compared to control of
2467.+-.126 at one hour after exposure.
[0066] FIG. 8 shows the stretch test result for cervical ripening
for treated and control groups. Confirming the result above, there
is significantly increased cervical extensibility of the ultrasound
treated group compared to the control group.
[0067] FIG. 9 shows that the FUS treated groups have no change in
the average weight (grams) of fetus of control and treated groups
(FUS: 5.81.+-.0.43 VS Control: 5.41.+-.0.25). We observed no
preterm births in the treated group. All fetuses were delivered
within 24 hours after 8 am of day 22.
[0068] These studies show that focused ultrasound of the listed
pulse characteristics produced a significant effect on the rat
cervix to produce early softening or ripening. The physical basis
of this effect is unclear and unexpected in view of the scientific
literature of ultrasound bioeffects.
[0069] The softening of the cervix normally is a gradual and
progressive process occurring during the last half of gestation
cycle. This finds that the process of cervical ripening can be
substantially accelerated by application of ultrasound and
comparable to a level to animals during normal spontaneous that of
delivery at term.
[0070] In this study 680 kHz ultrasound effects occur after as
little as 30 minutes exposure and at power levels as low as 1
W/cm.sup.2. The lower threshold of this ultrasound cervical
bioeffect was not determined in this study, and lower values may be
satisfactorily used. The effects at 4 W/cm.sup.2 were statistically
the same as 1 W/cm.sup.2 and power levels below this were not
tested.
[0071] By comparison, ultrasound imaging systems typically use 3-6
MHz frequencies and microsecond-order pulse widths at kilohertz
repetition rate. The difference in pulse characteristics is likely
the reason for the physiologic effects of FUS on cervical ripening
since ultrasound imaging systems are not known to produce
physiologic changes.
[0072] The largest of the ultrasound induced physiologic change is
seen within tens of minutes after stimulation. This is in contrast
to the much slower process of ripening occurring over the last
seven to eight days during normal pregnancy. The ultrasound induced
cervical ripening was verified by a mechanical stretch test of
extensibility.
[0073] Experiments show that ultrasound decreased the time course
of cervical ripening which was then sustained over the 8 days prior
to delivery and did not reverse back to a rigid state. The induced
cervical ripening appears to be irreversible. We note that the
early cervical ripening did not produce preterm birth or delay
birth even though the treated group had a cervix soft enough to
allow delivery.
[0074] The relatively rapid ripening of the cervix by ultrasound is
much faster than the typical application of prostaglandins that
need 12 hours to promote cervical ripening in the clinic with women
as is conventional treatment. This could be a substantial advantage
of the ultrasound technique in that it could be applied clinically
to achieve ripening before delivery. The ultrasound energy in these
experiments was focused to the cervix and this would suggest little
or no effects on other body systems.
Acoustic Intensity Calculation
[0075] The pulse characteristics of ultrasound in this study were
long compared to imaging systems but slow in repetition rate. The
total ultrasound dose was comparable to imaging systems and to safe
regulatory guidelines. Ultrasound power level is a function of both
its intensity and time of application. Spatial-peak pulse-average
intensity (I.sub.sPPA) is defined as:
I SPPA = PII PD ##EQU00001##
Where PD is the pulse duration defined as (t).
[0076] The I.sub.SPPA was tested through force balance to be 40
W/cm.sup.2. Spatial-peak temporal-average intensity (I.sub.SPTA) is
defined as:
I.sub.SPTA=PII(PRF)
Where PRF is pulse repetition frequency, which is represented in
Hertz.
[0077] The pulse intensity integral (PII) is defined as:
PII = .intg. .rho. 2 ( t ) z 0 t ##EQU00002##
Where .rho..sub.c is the instantaneous peak pressure, Z.sub.0 is
the characteristic acoustic impedance in Pas m-1 defined as .rho.c,
where .rho. is the density of the medium and c is the speed of
sound in the medium. .rho. was estimated to be 1028 kg m-3 and c to
be 1515 m s-1 for tissue on the basis of previous reports.
.rho..sub.r was calculated to be 158 KPa.
[0078] The mechanical index (MI) was calculated by:
MI = .rho. r f ##EQU00003##
[0079] where .mu..sub.r is the peak rare-factional pressure and f
is the acoustic frequency.
[0080] From these relationships the I.sub.SPPA is calculated at 40
W/cm.sup.2 while the FDA regulatory limit is 190 W/cm.sup.2 for
both the body periphery as well as the fetus. The mechanical index
is calculated at 0.2 and so within the FDA limitation of 1.9. FDA
regulations define ultrasound power levels in terms of power at the
target organ I.sub.SPPA.3 where the 0.3 indicates the derated
power. Currently the FDA I.sub.SPTA.3 regulatory limit on
diagnostic imaging systems to organs in the body periphery is
presently 720 m W/cm.sup.2 (ODRH, 2008). The I.sub.SPTA.3 was
unknown in this study but would be less than 1 W/cm.sup.2 because
of transducer coupling losses and attenuation of ultrasound as its
passes through the tissues of the rat body.
[0081] As recognized by one skilled in the art, there are many
variables that might be optimized in an effort to achieve lower yet
effective ultrasound power. The lowest effective power is likely to
be below that tested in this study since even 1 W/cm.sup.2 was as
effective as the highest tested power at 4 W/cm.sup.2.
[0082] The mechanism of action for ripening of the cervix by the
application of ultrasound energy is not generally understood at
this time. Without being bound by any particular theory, it has
been postulated that FUS may include activation of neural and
biochemical pathways or direct fragmenting collagen X-bridges.
[0083] One theory is that ultrasound does not directly affect the
collagenous structure of the cervix but rather triggers a
bioelectrical activation that then causes a cascade of events that
affect it indirectly. Another theory is that ultrasound may trigger
the release of cytokines that then result in the ripening
process.
[0084] Another theory depends on the known stretch sensitivity of
the cervix. Mechanical stretching actuates natural physiologic
responses and this may initiate cervical maturation. For example,
Takemura et al. (M. Takemural, H. Itoh, N. Sagawa, S. Yura, D.
Korita, K. Kakuil, M. Kawamural, N. Hirota, H. Maeda and S. Fujii,
"Cyclic mechanical stretch augments hyaluronan production in
cultured human uterine cervical fibroblast cells", Molecular Human
Reproduction Vol. 11, No. 9 pp. 659-665, 2005) report that
mechanical stretching of cervical cells in culture causes a
biochemical cascade of events that ultimately releases hyaluron, a
biochemical associated with cervical collagen.
[0085] Pulses of ultrasound in the repetition range of 5-200 Hz as
practiced by this invention, create a periodic radiation pressure
at the pulse repetition rate. Soft tissue at the beam focus is
stretched at this pulse rate compared to the ultrasound carrier
wave. In the above described study, for example, the data was
generated using a modulation frequency of 25 Hz. Thus pulsed
ultrasound may initiate a cascade of biochemical events by way of
the stretch sensitivity of cervical tissue and thus promote
cervical maturation.
[0086] A further theory is that most physiological processes within
the body have bioelectrical correlates and processes can be
modulated in their function by application of small electrical
currents. Ultrasound energy is known to affect bioelectrical events
in the CNS and have some effects on the PNS. Thus the observed
effects of ultrasound on the cervix may be through interaction with
a local nerve plexus that then promotes the local or more distant
release of endogenous prostaglandin.
[0087] Furthermore, although bioelectrical events are not known to
be associated with cervical ripening, that there is the possibility
and that the effects of ultrasound could be through a known
bioelectrical interaction with nerves (see, e.g., Gavrilov L R,
Geshuni G V, Il'iniskii O B, Popova L A, Sirotyuk M G, Tsirul'nikov
E. M. , Stimulation Of Human Peripheral Neural Structures By
Focused Ultrasound, Sov Phys Acoust, 19(4):332-334 (1974); Mihran,
R., Barnes, F., Wachtel, H., Temporally Specific Modification of
Myelinated Axon Excitability In-Vitro Following a Single Ultrasound
Pulse, Ultrasound in Med. Biol. vol. 16, No. 3., pp. 297-309
(1990); Colucci, V., Strichartz, G., Jolesz, F., Vykhodtseva, N.,
Hynynen, K., Focused Ultrasound Effects on Nerve Action Potential,
Ultrasound in Medicine and Biology, Vol. 35. #10, pp. 1737-1747
(2009)) and these may trigger cervical hormonal release.
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