Selective reduction of multifetal pregnancy using high-intensity focused ultrasound in the rabbit model.

OBJECTIVE: High-order multifetal pregnancies carry a significant risk of obstetric complications and poor pregnancy outcome. Selective reduction has traditionally been performed using transabdominal and transvaginal ultrasound-guided intracardiac injection of potassium chloride. We have previously shown that high-intensity focused ultrasound (HIFU) can create a coagulative tissue necrosis in the sheep fetus. The objective of this study was to investigate the feasibility of non-invasive selective fetal reduction using HIFU in a rabbit model. METHODS: A protocol for HIFU-induced tissue coagulation was developed in the rabbit model. The fetal heart was targeted with ultrasound-guided tissue ablation by a HIFU beam. Five time-mated does between 20-29 days' gestation underwent transabdominal fetal cardiac ablation in a total of 11 fetuses. The HIFU system consisted of a 7-MHz high-power transducer, operated at 2000 W/cm2. The fetal heart rate was observed using real-time ultrasound with Doppler flow velocimetry. All lesions were assessed macroscopically and by histological analysis. RESULTS: Severe bradycardia leading to asystole was observed in all targeted fetuses with ultrasound examination. Dissection of fetuses demonstrated a necrotic intrathoracic lesion similar in size to the HIFU focus (approximately 1 x 9 mm). None of the surrounding fetuses was found to have bradycardia during the procedure or a macroscopic lesion on dissection. CONCLUSION: In this pilot study HIFU seems promising to ablate even highly vascularized tissue in the fetus.

Color Doppler detection of acoustic streaming in a hematoma model.

Accurate differentiation between stagnant blood and soft tissue or clotted and unclotted blood has potential value in managing trauma patients with internal hemorrhage. Determination by regular ultrasound (US) imaging is sometimes difficult because the sonographic appearance of blood, clots and soft tissue may be similar. A hematoma model was developed to investigate the use of acoustic streaming for hematoma diagnosis in an in vivo environment. The results showed that a derated spatial peak temporal average (SPTA) intensity of 30 W/cm(2) was needed to generate color-Doppler-detectable streaming in stirred blood. The streaming velocity increased in proportion to the derated intensity. Streaming was also detected in stagnant blood, but at higher intensities. In clots, streaming was not detected even at high intensities. The streaming detection may be a valuable tool for improving the distinction between liquid blood and clots or soft tissue in hematoma diagnosis.

Image-guided acoustic therapy.

The potential role of therapeutic ultrasound in medicine is promising. Currently, medical devices are being developed that utilize high-intensity focused ultrasound as a noninvasive method to treat tumors and to stop bleeding (hemostasis). The primary advantage of ultrasound that lends the technique so readily to use in noninvasive therapy is its ability to penetrate deep into the body and deliver to a specific site thermal or mechanical energy with submillimeter accuracy. Realizing the full potential of acoustic therapy, however, requires precise targeting and monitoring. Fortunately, several imaging modalities can be utilized for this purpose, thus leading to the concept of image-guided acoustic therapy. This article presents a review of high-intensity focused ultrasound therapy, including its mechanisms of action, the imaging modalities used for guidance and monitoring, some current applications, and the requirements and technology associated with this exciting and promising field.

High intensity focused ultrasound: a method of hemostasis.

Acoustic hemostasis is a new field of ultrasound research in which high intensity focused ultrasound (HIFU) is used to induce hemostasis in actively bleeding, injured solid organs and blood vessels. In animal studies, moderate to profuse bleeding from parenchymal and vascular injuries has been arrested within approximately 1 minute of HIFU application, even when a large dose of heparin was administered. Moreover, acoustic hemostasis has shown promise in cauterizing large regions of liver, providing a method for bloodless resectioning of abnormal tissue. Two distinct physical mechanisms of HIFU appear to contribute to hemostasis: (1) a thermal mechanism in which absorption of sound leads to temperature elevations, and (2) mechanical mechanisms (acoustic cavitation) in which gas and vapor-filled voids oscillate with large displacement amplitudes. While the thermal mechanism results in a temperature increase in excess of 70 degrees C in about 1 second, the mechanical mechanism appears to result in structural disruption of tissue and possible release of coagulation-inducing tissue factors. Of utmost importance in further development of HIFU as a clinical tool is targeting and monitoring of the HIFU treatment. We have obtained initial success in integrating HIFU with ultrasound imaging so as to develop an image-guided therapy system. Image-guided acoustic hemostasis may provide a valuable method of hemostasis in surgical and prehospital settings with applications in trauma and elective surgery.

Use of overpressure to assess the role of bubbles in focused ultrasound lesion shape in vitro.

Overpressure--elevated hydrostatic pressure--was used to assess the role of gas or vapor bubbles in distorting the shape and position of a high-intensity focused ultrasound (HIFU) lesion in tissue. The shift from a cigar-shaped lesion to a tadpole-shaped lesion can mean that the wrong area is treated. Overpressure minimizes bubbles and bubble activity by dissolving gas bubbles, restricting bubble oscillation and raising the boiling temperature. Therefore, comparison with and without overpressure is a tool to assess the role of bubbles. Dissolution rates, bubble dynamics and boiling temperatures were determined as functions of pressure. Experiments were made first in a low-overpressure chamber (0.7 MPa maximum) that permitted imaging by B-mode ultrasound (US). Pieces of excised beef liver (8 cm thick) were treated in the chamber with 3.5 MHz for 1 to 7 s (50% duty cycle). In situ intensities (I(SP)) were 600 to 3000 W/cm(2). B-mode US imaging detected a hyperechoic region at the HIFU treatment site. The dissipation of this hyperechoic region following HIFU cessation corresponded well with calculated bubble dissolution rates; thus, suggesting that bubbles were present. Lesion shape was then tested in a high-pressure chamber. Intensities were 1300 and 1750 W/cm(2) ( +/- 20%) at 1 MHz for 30 s. Hydrostatic pressures were 0.1 or 5.6 MPa. At 1300 W/cm(2), lesions were cigar-shaped, and no difference was observed between lesions formed with or without overpressure. At 1750 W/cm(2), lesions formed with no overpressure were tadpole-shaped, but lesions formed with high overpressure (5.6 MPa) remained cigar-shaped. Data support the hypothesis that bubbles contribute to the lesion distortion.

Attenuation coefficient and sound speed in human myometrium and uterine fibroid tumors.

OBJECTIVE: To develop a noninvasive method for treatment of uterine fibroid tumors using high-intensity focused ultrasound. Optimal high-intensity focused ultrasound treatment would be dependent on quantitative information about ultrasonic tissue characteristics. METHODS: Ultrasonic attenuation and the sound speed of fresh human fibroid tumors and myometrium were measured as a function of frequency (1-3 MHz) by using a pulse transmission technique before and after in vitro high-intensity focused ultrasound treatment (3.5 MHz at an intensity of 2,000 W/cm2). RESULTS: The ranges of the attenuation coefficients, before and after high-intensity focused ultrasound treatment, were 0.9 to 2.2 and 1.8 to 3.9 dB/cm2, respectively, for fibroid tumors and 0.5 to 1.6 and 1.7 to 3.3 dB/cm2, respectively, for myometrium. Although the sound speed appeared to be independent of frequency (1,611 to 1,616 m/s at 1 to 3 MHz) in both types of tissues, a slight increase of approximately 4 to 14 m/s was observed after high-intensity focused ultrasound treatment. CONCLUSIONS: The results of this study represent our first reported values of the attenuation coefficient and sound speed in fibroid tumors and myometrium before and after high-intensity focused ultrasound treatment.

A new high intensity focused ultrasound applicator for surgical applications.

Improved high-intensity focused ultrasound (HIFU) surgical applicators are required for use in a surgical environment. We report on the performance and characteristics of a new solid-cone HIFU applicator. Previous HIFU devices used a water-filled stand-off to couple the ultrasonic energy from the transducer to the treatment area. The new applicator uses a spherically-focused element and a solid aluminum cone to guide and couple the ultrasound to the tissue. Compared with the water-filled applicators, this new applicator is simpler to set up and manipulate, cannot leak, prevents the possibility of cavitation within the coupling device, and is much easier to sterilize and maintain during surgery. The design minimizes losses caused by shear wave conversion found in tapered solid acoustic velocity transformers operated at high frequencies. Computer simulations predicted good transfer of longitudinal waves. Impedance measurements, beam plots, Schlieren images, and force balance measurements verified strong focusing and suitable transfer of acoustic energy into water. At the focus, the -3 dB beam dimensions are 1.2 mm (axial) x 0.3 mm (transverse). Radiation force balance measurements indicate a power transfer efficiency of 40%. In vitro and in vivo tissue experiments confirmed the applicator's ability to produce hemostasis.

Real-time visualization of high-intensity focused ultrasound treatment using ultrasound imaging.

High-intensity focused ultrasound (HIFU) and conventional B-mode ultrasound (US) imaging were synchronized to develop a system for real-time visualization of HIFU treatment. The system was tested in vivo in pig liver. The HIFU application resulted in the appearance of a hyperechoic spot at the focus that faded gradually after cessation of HIFU exposure. The duration of HIFU exposure needed for a hyperechoic spot to appear, was inversely related to the HIFU intensity. The threshold intensity required to produce a hyperechoic spot in liver in < 1 s was 970 W/cm(2), in situ. At this HIFU dose, no immediate cellular damage was observed, providing a potential for pretreatment targeting. The real-time visualization method was used in hemostasis of actively bleeding internal pelvic vessels, allowing targeting and monitoring of successful treatment. Real-time US imaging may provide a useful tool for image-guided HIFU therapy.

Treatment of uterine fibroid tumors in a nude mouse model using high-intensity focused ultrasound.

OBJECTIVE: The purpose of this study was to investigate the potential efficacy of high-intensity focused ultrasound for the treatment of uterine fibroid tumors in a nude mouse model. STUDY DESIGN: A total of 60 female athymic nude mice were inoculated subcutaneously with 3 to 5 x 10(6) ELT-3 cells, a uterine fibroid tumor cell line. Tumor size was monitored with transcutaneous caliper measurements. The high-intensity focused ultrasound probe was a concave, single-element, high-power transducer that operated at a frequency of 3.5 MHz. The tumors were treated for 30 to 60 seconds using a high-intensity focused ultrasonic intensity of 2000 W/cm(2), depending on the tumor size. RESULTS: A single high-intensity focused ultrasonic treatment resulted in an average reduction in tumor volume of 91% within 1 month of the treatment. Histologic analysis of tumors treated with high-intensity focused ultrasound showed coagulation necrosis and nuclear fragmentation of tumor cells. CONCLUSION: High-intensity focused ultrasound effectively reduced uterine fibroid tumor size in a nude mouse model. Further studies are needed to assess the in situ response of uterine fibroids to high-intensity focused ultrasonic treatment.

Control of splenic bleeding by using high intensity ultrasound.

BACKGROUND: High-intensity focused ultrasound (HIFU) has been shown to control bleeding from liver incisions, and blood vessel punctures and incisions. The objective of the current study was to investigate the capability of HIFU to stop bleeding from splenic injuries in a pig model. METHODS: Surgical incisions, 25 to 50 mm in length and 2 to 8 mm in depth, were made in the spleens of five anesthetized pigs. HIFU with a frequency of 5 MHz was applied within 5 seconds of making the incision. A total of 39 incisions and HIFU treatments were performed. RESULTS: Bleeding from all incisions was stopped completely after HIFU treatment. The average times to control and completely arrest the hemorrhage were 28 and 55 seconds, respectively. The mechanisms of hemostasis appeared to be thermally induced coagulation necrosis of splenic tissue and occlusion of blood vessels by a mechanically induced homogenized splenic tissue. CONCLUSION: HIFU may provide a useful method of hemostasis for actively bleeding spleen. Because of its ability to induce hemostasis at adjustable depth, HIFU may prove to be a useful cauterization method both in the operating room and for patients who are managed nonoperatively.

Detection of high-intensity focused ultrasound liver lesions using dynamic elastometry.

A novel ultrasound technique was developed for detecting the distribution of stiffness in biological tissue. The method, which we call 'dynamic elastometry,' involves applying a low-frequency vibration (< or = 5 Hz) to the tissue and measuring the resulting velocity pattern within the sample using Doppler spectral analysis. Based upon the velocity differences, an elastically stiff region can be differentiated from surrounding soft tissue. Dynamic elastometry was used to both detect and quantify lesions produced by high-intensity focused ultrasound (HIFU) in porcine livers. Measurements of the lesion position and length agreed well with independent geometric measurements. The mean and standard deviation of the differences between the two types of measurement were -0.01 cm and 0.10 cm for lesion position, and -0.05 cm and 0.12 cm for lesion length, respectively. The relative stiffness between lesions and normal liver tissue was estimated by the velocity gradient ratio. Results were compared with the Young's modulus ratios between lesion and normal liver tissue obtained from mechanical measurement. The dynamic elastometric estimates had a strong linear correlation with the mechanical measurements (r = 0.93) but were smaller than the latter by 26%.

Hemostasis of punctured vessels using Doppler-guided high-intensity ultrasound.

The use of Doppler ultrasound was investigated to determine if it would aid in guiding the application of high-intensity focused ultrasound (HIFU) to stop bleeding from punctured vessels. Major vessels (abdominal aorta, illiac, carotid, common femoral and superficial femoral arteries and the jugular vein) were surgically exposed, punctured and treated in anesthetized pigs. Treatment was applied when the Doppler sounds indicated the focus coincided with the bleeding site. In 89 treatment trials, the average time to achieve major hemostasis (a point where bleeding was reduced to a level of only oozing) was 8 s, and for complete hemostasis was 13 s. These times were significantly shorter than those of an identical former study in which only visual guidance was used. In that study, the average times for major and complete hemostasis were 40 and 62 s, respectively. The advantage of Doppler guidance in applying HIFU in treating bleeding vessels was demonstrated.

Hemostasis using high intensity focused ultrasound.

High intensity focused ultrasound (HIFU) has been shown to be an effective method of hemostasis, in animal studies, for both solid organs and blood vessels. Two distinct effects of HIFU, thermal and mechanical, appear to contribute to hemostasis. Acoustic hemostasis may provide an effective method in surgery and prehospital settings for treating trauma and elective surgery patients. A review of the methodology is given.

Use of high-intensity focused ultrasound to control bleeding.

OBJECTIVE: High-intensity focused ultrasound (HIFU) has been shown to be effective in controlling hemorrhage from punctures in blood vessels. The objective of the current study was to investigate the capability of HIFU to stop bleeding after a more severe type of vascular injury, namely longitudinal incisions of arteries and veins. METHODS: The superficial femoral arteries, common femoral arteries, carotid arteries, and jugular veins of four anesthetized pigs were exposed surgically. A longitudinal incision, 2 to 8 mm in length, was produced in the vessel. HIFU treatment was applied within 5 seconds of the onset of the bleeding. The HIFU probe consisted of a high-power, 3.5-MHz, piezoelectric transducer with an ellipsoidal focal spot that was 1 mm in cross section and 9 mm in axial dimension. The entire incision area was scanned with the HIFU beam at a rate of 15 to 25 times/second and a linear displacement of 5 to 10 mm. A total of 76 incisions and HIFU treatments were performed. RESULTS: Control of bleeding (major hemosatsis) was achieved in all 76 treatments, with complete hemostasis achieved in 69 treatments (91%). The average treatment times of major and complete hemostasis were 17 and 25 seconds, respectively. After the treatment, 74% of the vessels in which complete hemostasis was achieved were patent with distal blood flow and 26% were occluded. The HIFU-treated vessels showed a consistent coagulation of the adventitia surrounding the vessels, with a remarkably localized injury to the vessel wall. Extensive fibrin deposition at the treatment site was observed. CONCLUSION: HIFU may provide a useful method of achieving hemostasis for arteries and veins in a variety of clinical applications.

Hemostasis of punctured blood vessels using high-intensity focused ultrasound.

The hemorrhagic complications of vascular injury can be significant. We report on the use of high-intensity focused ultrasound (HIFU) to stop the hemorrhage of punctured blood vessels in pigs. Two HIFU transducers with frequencies of 3.5 and 2.0 MHz, each equipped with a water-filled conical housing, were used. Major blood vessels (femoral artery and vein, axillary artery, carotid artery and jugular vein), 2-10 mm in diameter, of anesthetized pigs were exposed surgically and punctured with 14- and 18-gauge needles to produce moderate to profuse bleeding. Complete hemostasis was achieved in less than 3 min of HIFU treatment in most blood vessels, and all vessels were patent after the treatment. Both HIFU frequencies were effective in producing hemostasis. Gross examination of the HIFU-treated vessels showed a consistent hardening of the soft tissue surrounding the blood vessels, providing a seal for the puncture hole. Microscopic examination of the vessels showed a remarkably localized HIFU treatment, resulting in coagulation of the adventitia, and an extensive fibrin network around the vessels and in the puncture hole. The vessel walls exhibited focal swelling, without evidence of irreversible injury. HIFU may provide a useful method for achieving hemostasis of punctured and traumatized blood vessels in a variety of clinical settings.

Estimation of the human liver volume and configuration using three-dimensional ultrasonography: effect of a high-caloric liquid meal.

The aim of this study was to investigate whether or not a magnetic position sensing system for free-hand acquisition of 3-D ultrasound images could be used to estimate liver volumes, and to study the effect of a high-caloric meal on these volumes in healthy subjects. In vitro accuracy was evaluated by scanning porcine and rabbit livers. Ten healthy subjects were examined fasting and 30 min after ingesting a high-caloric liquid meal. Portal and hepatic vein blood flow were measured by 2-D duplex sonography. The 3-D system yielded a strong correlation (r = 0.99) between true and estimated volumes in vitro. No significant increase in liver volume in response to the meal was seen. However, portal and hepatic vein flow volume increased significantly. Experience in human subjects suggests that a complete 3-D study of liver volumes can be obtained from multiple acoustic windows. In healthy subjects, no significant increase in liver volume was seen in response to ingestion of a high-caloric liquid meal.

Liver hemostasis using high-intensity focused ultrasound.

Liver hemorrhage, the major cause of death in hepatic trauma, is notoriously difficult to control. We report on the use of high-intensity focused ultrasound (HIFU) to arrest the bleeding from incisions made in rabbit livers. A HIFU transducer, with a spherically curved aperture of 6.34 cm2 area, a focal length of 4 cm and a frequency of 3.3 MHz was used. In approximately 94% of the incisions, the hemorrhage was reduced to a slow oozing of blood in less than 2 min. The maximum temperature of liver tissue around the incision area, during HIFU application, was measured to be 86 degrees C. The mechanism of hemostasis, confirmed by histological examination, appears to be coagulative necrosis of a volume of liver tissue around the incision. We believe that acoustic hemostasis, with the unique characteristic of "volume cauterization," offers a novel method for the management of liver hemorrhage and, thus, has major clinical implications.

Two-dimensional fourier analysis of electron micrographs of human skin for quantification of the collagen fiber organization in the dermis.

Two-dimensional (2-D) Fourier analysis was used to quantify the structural organization of collagen fibers in the dermis of the human skin. The 2-D Fourier spectra of electron micrographs of collagen fibers contained large amplitude Fourier components (1 fundamental and 3 harmonic peaks), representing the predominant structural parameter of the fibers, the center-to-center spacing of collagen fibrils. The average center-to-center spacing of the collagen fibrils was found from the position of the peaks. For a normal fiber of reticular dermis, this spacing was 116 nm. The fibril diameter appeared to modulate the peak heights.

Characterization of the cellular microstructure of ocular lens using 2D power law analysis.

Power law analysis provides a quantitative method for characterization of spatial fluctuations in the cellular microstructure of the ocular lens. In the power law analysis, Fourier components of the spatial fluctuations are computed, and the relationship between the amplitude, A, and spatial frequency, f, of the components is defined by a power law function: [formula, see text]. The exponent of the function, beta, defines the scaling of the amplitude of the Fourier components as a function of spatial frequency. We performed two-dimensional power law analysis on electron micrographs of lens cells ranging from transparent to opaque. We identified two values of power law exponent, beta, for the spatial fluctuations of all lens cells, one for low- and a second for high-spatial frequencies. In the low-spatial frequency region, the value of beta was in the range of 0.53 to 1.33, for transparent and opaque cells. In the high-spatial frequency region, the value of beta increased from 2.78 for transparent lens cells to 3.60 for opaque lens cells. The power law analysis provides a new method for quantitative characterization of the spatial fluctuations in the microstructure of transparent and opaque lens cells.

Quantitative analysis of the lens cell microstructure in selenite cataract using a two-dimensional Fourier analysis.

Using two-dimensional (2-D) Fourier methods, we analysed the cellular microstructure of three rat lenses: normal transparent, selenite-induced cataractous and selenite-treated plus a phase separation inhibitor (PSI) to prevent cataract. 2-D Fourier analysis of electron micrographs of the lens cells quantified the dimensions of the spatial fluctuations in electron density of the lens cell microstructure. The 2-D Fourier spectra of the transparent normal and PSI-treated lens cells were remarkably similar while those of the opaque selenite-treated lens cells were dramatically different. In the opaque cells the contributions of large Fourier components (larger than half the wavelength of light) in the 2-D Fourier spectra were much greater than in the transparent cells. The results of the 2-D Fourier analysis of electron micrographs are consistent with the theory of transparency of the eye.