Patent Application
20180093112
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.
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 wamith 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.
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 ISPTA.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/cm2 ISPTA.3 and 190 W/cm2 ISPPA.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° C. Regulatory standards in the United States require the TI to be below 1.0.
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.
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.
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.
Ultrasound imaging is used in many types of examinations and procedures. Some examples include:
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.
Pulses of longer duration ultrasound, on the order of milliseconds and at repetition rates much lower while still emitting power levels within MI and ISPTA.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.
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.
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.
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.
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.
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 (IPPP) is in the range of 10-300 W/cm2. The average power delivered is less than 720 m W/cm2 and the ultrasound energy is applied from 10 minutes to 60 minutes.
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 ISPTA.3 is less than 720 m W/cm2.
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 transabdominally to the cervix using a focused transducer, wherein the focal zone encompasses the cervix. The focal zone may encompass 60% of the cervix.
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.
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.
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/cm2. 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/cm2, and the ultrasound energy may be applied from 10 minutes to 60 minutes.
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/cm2.
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.
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.
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.
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. 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.
In one embodiment, ultrasound at 30-300 W/cm2 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/cm2 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.
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 ISPTA.3.
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.
The ultrasound ripening technique may also be performed in combination with traditional ultrasound imaging (i.e., applying high frequency sound waves).
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 gynecology 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 μl/g. They were sacrificed by surgical dislocation for cervical tissue collection.
A custom made ultrasound instrumentation set-up was constructed as illustrated in
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.
The experiment tested a range of ultrasound pulse widths at 680 KHz ultrasound using 25 Hertz pulse repetition rate as shown in
As shown in Table 1, the ISPPA used in this experiment was measured at 40 W/cm2 using continuous mode ultrasound and a force balance. The ISPTA varied from 1 W/cm2 to 4 W/cm2 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.
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. ISPPA.3 was 40 W/cm2, which is less than used in imaging (190 W/cm2). The mechanical index (MI) of the ultrasound pulse was calculated to be 0.2 and so within safe regulatory limits (1.9).
A light-induced florescence (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.
The effects of focused ultrasound on the cervix mechanical stretching and compliance were tested using a universal Tissue Organ Bath System (750TOBS, DMT, 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% O2 and 5% CO2, and maintained at 37° C. The isolated cervix was elongated incrementally at 0.10 the rate of 0.0.15 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.
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.
A total of 38 rats were used in the study according to Table 1 where the day of gestation is listed on the left.
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
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.
The ultrasound treatment produced LIF values significantly lower (P<0.01) in FUS treated animals on days 16 and 0.17 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.
A series of experiments were performed on day 15 for both 30 minute and 1 hour at 4 W/cm2. After 24 hours and LIF tests, the rat cervix was collected and mechanical tests of cervical resistance were performed.
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 (0.1 W/cm2, 2 W/cm2, 4 W/cm2).
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.
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.
In this study 680 kHz ultrasound effects occur after as little as 30 minutes exposure and at power levels as low as 1 W/cm2. 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/cm2 were statistically the same as 1 W/cm2 and power levels below this were not tested.
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.
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.
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.
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.
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 (ISPPA) is defined as:
Where PD is the pulse duration defined as (t).
The ISPPA was tested through force balance to be 40 W/cm2. Spatial-peak temporal-average intensity (ISPTA) is defined as:
I
SPTA=PII(PRF)
Where PRF is pulse repetition frequency, which is represented in Hertz.
The pulse intensity integral (PII) is defined as:
Where ρc is the instantaneous peak pressure, Z0 is the characteristic acoustic impedance in Pa·s m-1 defined as ρc, where ρ is the density of the medium and c is the speed of sound in the medium. ρ was estimated to be 0.1028 kg m-3 and c to be 1515 in s-1 for tissue on the basis of previous reports. ρr was calculated to be 158 KPa.
The mechanical index (MI) was calculated by:
where ρr is the peak rare-factional pressure and f is the acoustic frequency.
From these relationships the ISPPA is calculated at 40 W/cm2 while the FDA regulatory limit is 190 W/cm2 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 ISPPA.3 where the .3 indicates the derated power. Currently the FDA ISPTA.3 regulatory limit on diagnostic imaging systems to organs in the body periphery is presently 720 m W/cm2 (ODRH, 2008). The ISPTA.3 was unknown in this study but would be less than 1 W/cm2 because of transducer coupling losses and attenuation of ultrasound as its passes through the tissues of the rat body.
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/cm2 was as effective as the highest tested power at 4 W/cm2.
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 Vii-bridges.
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.
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.
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.
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.
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, Soy 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.
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.
| Number | Date | Country | |
|---|---|---|---|
| 61735306 | Dec 2012 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 14651009 | Jun 2015 | US |
| Child | 15820838 | US |
