Comparison Between Clinically Available Low-Intensity Pulsed Ultrasound (LIPUS) and a Novel Bimodal Acoustic Signal System for Accelerating Fracture Healing.

Low-intensity pulsed ultrasound (LIPUS) accelerates fracture healing by stimulating the production of bone callus and the mineralization process. This study compared a novel bimodal acoustic signal (BMAS) device for bone fracture healing to a clinical LIPUS system (EXOGEN; Bioventus, Durham, NC, USA). Thirty rabbits underwent a bilateral fibular osteotomy. Each rabbits' legs were randomized to receive 20-min treatment daily for 18 days with BMAS or LIPUS. The latter utilizes a longitudinal ultrasonic mode only, while the former employs ultrasound-induced shear stress to promote bone formation. Power Doppler imaging (PDI) was acquired days 0, 2, 4, 7, 11, 14, and 18 post-surgery to monitor treatment response and quantified off-line. X-rays were acquired to evaluate fractures on days 0, 14, 18, and 21. Seventeen rabbits completed the study and were euthanized day 21 post-surgery. The fibulae were analyzed to determine maximum torque, initial torsional stiffness, and angular displacement at failure. ANOVAs and paired t-tests were used to compare pair-wise outcome variables for the two treatment modes on a per rabbit basis. The BMAS system induced better fracture healing with greater stiffness (BMAS 0.21 ± 0.19 versus LIPUS 0.16 ± 0.19 [Formula: see text]cm/°, p = 0.050 ) and maximum torque (BMAS 7.84 ± 5.55 versus LIPUS 6.26 ± 3.46 [Formula: see text]cm, p = 0.022 ) than the LIPUS system. Quantitative PDI assessments showed a higher amount of vascularity with LIPUS than BMAS on days 4 and 18 ( ). In conclusion, the novel BMAS technique achieved better bone fracture healing response than the current Food and Drug Administration (FDA)-approved LIPUS system.

In vitro mitral chordal cutting by high intensity focused ultrasound.

Mitral regurgitation, when it arises from functional restriction of mitral leaflet closure, can be relieved by surgical cutting of the mitral tendineae chordae. We hypothesized that high intensity focused ultrasound (HIFU) might be useful as a noninvasive extracorporeal technique for cutting mitral chordae. As a pilot study to test this hypothesis, we examined the in vitro feasibility of using HIFU to cut calf mitral chordae with diameters from 0.2 to 1.6 mm. Sixty-seven percent of chordae were completely cut with HIFU, operated at 4.67 MHz and 45 W acoustic power, with up to 120 pulses of 0.3-s duration at 2-s intervals. Forty-five percent were completely cut when the pulse duration was reduced to 0.2 s. The average diameter of those chordae, which were completely cut, was significantly smaller than that of incompletely cut chordae (0.59 +/- 0.30 versus 1.14 +/- 0.30 mm with a pulse duration of 0.2 s, p < 0.0001; 0.68 +/- 0.29 versus 1.32 +/- 0.20 mm with a pulse duration of 0.3 s, p < 0.0001). For each pulse duration, the number of pulses required for complete cutting exhibited a strong positive correlation with the chordae diameter. In conclusion, in vitro feasibility of mitral chordal cutting by HIFU depended on the diameter of chordae but was controllable by HIFU settings. (E-mail: abeyukio@aol.com).

Improved visualization of high-intensity focused ultrasound lesions.

Spectral parameter imaging in both the fundamental and harmonic of backscattered radio-frequency (RF) data were used for immediate visualization of high-intensity focused ultrasound (HIFU) lesion sites. A focused 5-MHz HIFU transducer with a coaxial 9-MHz focused single-element diagnostic transducer was used to create and scan lesions in chicken breast and freshly excised rabbit liver. B-mode images derived from the backscattered RF signal envelope were compared with midband fit (MBF) spectral parameter images in the fundamental (9-MHz) and harmonic (18-MHz) bands of the diagnostic probe. Images of HIFU-induced lesions derived from the MBF to the calibrated spectrum showed improved contrast (approximately 3 dB) of tumor margins versus surround compared with images produced from the conventional signal envelope. MBF parameter images produced from the harmonic band showed higher contrast in attenuated structures (core, shadow) compared with either the conventional envelope (3.3 dB core; 11.6 dB shadow) or MBF images of the fundamental band (4.4 dB core; 7.4 dB shadow). The gradient between the lesion and surround was 3.4 dB/mm, 6.9 dB/mm and 17.2 dB/mm for B-mode, MBF-fundamental mode and MBF-harmonic mode, respectively. Images of threshold and "popcorn" lesions produced in freshly excised rabbit liver were most easily visualized and boundaries best-defined using MBF-harmonic mode.

In vitro ablation of cardiac valves using high-intensity focused ultrasound.

The purpose of this study was to evaluate the possibility of using high-intensity focused ultrasound (US), or HIFU, to create lesions in cardiac valves in vitro. Calf mitral valves and aortic valves were examined. Focused US energy was applied with an operating frequency of 4.67 MHz at a nominal acoustic power of 58 W for 0.2, 0.3 and 0.4 s at 4-s intervals. Mitral valve perforation was achieved with 20.8 +/- 3.7 exposures of 0.2 s, 15.4 +/- 2.1 exposures of 0.3 s or 11.2 +/- 2.3 exposures of 0.4 s. Aortic valve perforation was achieved with 13.3 +/- 2.4 exposures of 0.2 s, 10.3 +/- 2.2 exposures of 0.3 s or 8.4 +/- 1.8 exposures of 0.4 s. The mean diameter of the perforated area was 1.09 +/- 0.11 mm. The lesions were slightly discolored and coagulation of tissue around the perforation was observed. HIFU was successful in perforating cardiac valves. With further refinement, HIFU may prove useful for valvulotomy or valvuloplasty.

Radiation-force technique to monitor lesions during ultrasonic therapy.

This report describes a monitoring technique for high-intensity focused ultrasound (US), or HIFU, lesions, including protein-denaturing lesions (PDLs) and those made for noninvasive cardiac therapy and tumor treatment in the eye, liver and other organs. Designed to sense the increased stiffness of a HIFU lesion, this technique uniquely utilizes the radiation force of the therapeutic US beam as an elastographic push to detect relative stiffness changes. Feasibility was demonstrated with computer simulations (treating acoustically induced displacements, concomitant heating, and US displacement-estimation algorithms) and pilot in vitro experimental studies, which agree qualitatively in differentiating HIFU lesions from normal tissue. Detectable motion can be induced by a single 5 ms push with temperatures well below those needed to form a lesion. Conversely, because the characteristic heat diffusion time is much longer than the characteristic relaxation time following a push, properly timed multiple therapy pulses will form lesions while providing precise control during therapy.

The Journal of Therapeutic Ultrasound: broadening knowledge in a rapidly growing field.

The Journal of Therapeutic Ultrasound has been established to provide an open access, online venue for the exponentially growing body of work in biomedical ultrasound therapy.

In vitro atrial septal ablation using high-intensity focused ultrasound.

BACKGROUND: High-intensity focused ultrasound (HIFU) has been applied clinically as a noninvasive therapeutic tool. Atrial septostomy is a palliative treatment for pulmonary artery hypertension. The purpose of this study was to assess the feasibility of atrial septal ablation in vitro using HIFU. METHODS: Fourteen sections of atrial septum from pig hearts were treated. Focused ultrasound energy was applied with an operating frequency of 5.25 MHz at the nominal focal point intensity of 4.0 kW/cm(2) for 0.4 sec in 1-sec intervals. RESULTS: Lesions were created with ultrasonic exposures ranging from 40 to 120 pulses. There were significant relationships between HIFU exposure time and lesion area on the exposed site (R(2) = 0.3389, P < .0001) and lesion volume (R(2) = 0.6161, P < .0001). CONCLUSIONS: HIFU has the potential to create focal perforations without direct tissue contact. This method may prove useful for noninvasive atrial septostomy.

High-intensity focused ultrasound ablation of ex vivo bovine achilles tendon.

Small tears in tendons are a common occurrence in athletes and others involved in strenuous physical activity. Natural healing in damaged tendons can result in disordered regrowth of the underlying collagen matrix of the tendon. These disordered regions are weaker than surrounding ordered regions of normal tendon and are prone to re-injury. Multiple cycles of injury and repair can lead to chronic tendinosis. Current treatment options either are invasive or are relatively ineffective in tendinosis without calcifications. High-intensity focused ultrasound (HIFU) has the potential to treat tendinosis noninvasively. HIFU ablation of tendons is based on a currently-used surgical analog, viz., needle tenotomy. This study tested the ability of HIFU beams to ablate bovine tendons ex vivo. Two ex vivo animal models were employed: a bare bovine Achilles tendon (deep digital flexor) on an acoustically absorbent rubber pad, and a layered model (chicken breast proximal, bovine Achilles tendon central and a glass plate distal to the transducer). The bare-tendon model enables examination of lesion formation under simple, ideal conditions; the layered model enables detection of possible damage to intervening soft tissue and consideration of the possibly confounding effects of distal bone. In both models, the tissues were degassed in normal phosphate-buffered saline. The bare tendon was brought to 23 degrees C or 37 degrees C before insonification; the layered model was brought to 37 degrees C before insonification. The annular array therapy transducer had an outer diameter of 33 mm, a focal length of 35 mm and a 14-mm diameter central hole to admit a confocal diagnostic transducer. The therapy transducer was excited with a continuous sinusoidal wave at 5.25 MHz to produce nominal in situ intensities from 0.23-2.6 kW/cm(2). Insonification times varied from 2-10 s. The focus was set over the range from the proximal tendon surface to 7 mm deep. The angle of incidence ranged from 0 degrees (normal to the tissue surface) to 15 degrees . After insonification, tendons were dissected and photographed, and the dimensions of the lesions were measured. Transmission electron micrographs were obtained from treated and untreated tissue regions. Insonification produced lesions that mimicked the shape of the focal region. When lesions were produced below the proximal tendon surface, no apparent damage to overlying soft tissue was apparent. The low intensities and short durations required for consistent lesion formation, and the relative insensitivity of ablation to small variations in the angle of incidence, highlight the potential of HIFU as a noninvasive treatment option for chronic tendinosis.

Extracardiac ablation of the left ventricular septum in beating canine hearts using high-intensity focused ultrasound.

BACKGROUND: High-intensity focused ultrasound (HIFU) produces immediate focal lesions without direct tissue contact. Previously, we reported the HIFU potential for cardiac ablation. The purpose of this study was to evaluate the possibility of myocardial ablation in the left ventricle of beating dog hearts with monitoring by 2-dimensional echocardiography. METHODS: The operating frequency and the acoustic intensity were 5.25 MHz and 23 kW/cm(2), and the focal length and diameter were 3.3 mm axial and 0.37 mm wide at a distance of 35 mm from the transducer. Three dogs underwent a left-sided thoracotomy. The right ventricular surface was coupled with the transducer. The timing of the HIFU exposure was set during the early systolic phase using an electrocardiographic triggering system. The focal point was set in the left ventricular septum using 2-dimensional echocardiography mounted in the HIFU transducer. Ultrasound energy was delivered for 0.2 seconds. For each dog, we created 18 lesions. Exposures were performed 20, 30, or 40 times. Lesion size was assessed by manually measuring its length and width. RESULTS: All lesions except one were clearly visible. The histologic lesion area was 18.7 +/- 8.3, 26.3 +/- 8.7, and 35.5 +/- 15.7 mm(2) (20, 30, and 40 times, respectively). The intraclass correlation coefficients were found to be 0.72, 0.63, 0.75, and 0.73 for lesion length, width, area, and depth, respectively. CONCLUSION: HIFU can be used to create targeted, well-demarcated thermal lesions in the ventricular septum myocardium during cardiac contraction.

Myocardial lesion formation using high-intensity focused ultrasound.

BACKGROUND: The potential therapeutic uses of ultrasound energy in cardiac disease have not been extensively studied. We have developed a means to deliver high-intensity focused ultrasound (HIFU) to myocardial tissue. Unlike other therapy modalities such as radiofrequency catheter ablation, this system has the advantages of not requiring direct tissue contact and the ability to focus intense energy within a small volume. METHODS: Sections of left and right ventricles from freshly excised canine hearts were treated in vitro with HIFU pulses. Lesions were created using 1-second HIFU pulses with ultrasonic powers ranging from 19.8 to 45.8 W. RESULTS: There was a dose-response relationship between the applied HIFU energy and lesion size (r = 0.70, P < .001). Myocardial lesion formation with HIFU was also performed in vivo in a canine open-chest beating heart model. With 200-millisecond HIFU pulses gated to the electrocardiogram, focal myocardial lesions were created ranging in length from 2 to 6 mm depending on the dose used. Furthermore, both in vitro and in vivo, focal lesions were successfully formed in the midmyocardial wall that spared both the endocardial and epicardial surfaces. CONCLUSION: HIFU is a novel means to create focal myocardial lesions without direct tissue contact. HIFU energy delivery can be gated to the electrocardiogram in an in vivo model, and lesions can be formed intramyocardially. Further application of this technology may prove to be useful for the ablation of myocardial lesions such as arrhythmogenic foci and the hypertrophic ventricular septum in hypertrophic cardiomyopathy. The potential therapeutic uses of ultrasound energy in cardiac diseases have not been well studied. We tested a novel system to deliver high-intensity focused ultrasound energy in vitro and in vivo to canine myocardial samples without direct contact with the target tissue. Focal myocardial lesions were formed in a dose-dependent manner, and myocardial lesions were created. This technology may prove useful for ablation of focal intramyocardial lesions such as arrhythmogenic foci and the hypertrophic left ventricular septum in hypertrophic cardiomyopathy.

Effects of ultrasonic exposure parameters on myocardial lesions induced by high-intensity focused ultrasound.

OBJECTIVE: This study evaluated variables relevant to creating myocardial lesions using high-intensity focused ultrasound (HIFU). Without an effective means of tracking heart motion, lesion formation in the moving ventricle can be accomplished by intermittent delivery of HIFU energy synchronized by electrocardiographic triggering. In anticipation of future clinical applications, multiple lesions were created by brief HIFU pulses in calf myocardial tissue ex vivo. METHODS: Experiments used f-number 1.1 spherical cap HIFU transducers operating near 5 MHz with in situ spatial average intensities of 13 and 7.4 kW/cm2 at corresponding depths of 10 and 25 mm in the tissue. The distance from the HIFU transducer to the tissue surface was measured with a 7.5-MHz A-mode transducer coaxial and confocal with the HIFU transducer. After exposures, fresh, unstained tissue was dissected to measure visible lesion length and width. Lesion dimensions were plotted as functions of pulse parameters, cardiac structure, tissue temperature, and focal depth. RESULTS: Lesion size in ex vivo tissue depended strongly on the total exposure time but did not depend strongly on pulse duration. Lesion width depended strongly on the pulse-to-pulse interval, and lesion width and length depended strongly on the initial tissue temperature. CONCLUSIONS: High-intensity focused ultrasound creates well-demarcated lesions in ex vivo cardiac muscle without damaging intervening or distal tissue. These initial studies suggest that HIFU offers an effective, noninvasive method for ablating myocardial tissues to treat several important cardiac diseases.