High Intensity Focused Ultrasound Intensity Research Articles

Effect of ultrasonic intensity and intervals of ultrasonic exposure on efficiency of sonochemiluminescence in gel phantom for sonodynamic therapy

Sonodynamic treatment (SDT) is one of the non-invasive modalities for cancer treatment. In SDT, ultrasound, reactive oxygen species (ROS) generated from cavitation bubbles, and a sonosensitizer are used in combination. In this study, high-intensity focused ultrasound (HIFU) was employed as ultrasound to generate and oscillate cavitation bubbles. When cavitation bubbles oscillate and collapse, the gas inside the bubble is extremely compressed and heated, inducing ROS generation. The disadvantage of SDT is a long treatment time because of its smallness of a treatment region by a shot of HIFU. To overcome this, the effect of the intensity and interval of HIFU for oscillating cavitation bubbles was investigated by using luminol sonochemiluminescence and high-speed imaging. The results showed that a HIFU exposure sequence with an interval of 300 ms and a burst-wave intensity of 0.25 kW cm−2 improve the energy efficiency of ROS generation.

The feasibility of a noise elimination method using continuous wave response of therapeutic ultrasound signals for ultrasonic monitoring of high-intensity focused ultrasound treatment

PurposeIn this study, the robustness and feasibility of a noise elimination method using continuous wave response of therapeutic ultrasound signals were investigated when tissue samples were moved to simulate the respiration-induced movements of the different organs during actual high-intensity focused ultrasound (HIFU) treatment. In addition to that, the failure conditions of the proposed algorithm were also investigated.MethodsThe proposed method was applied to cases where tissue samples were moved along both the lateral and axial directions of the HIFU transducer to simulate respiration-induced motions during HIFU treatment, and the noise reduction level was investigated. In this experiment, the speed of movement was increased from 10 to 40 mm/s to simulate the actual movement of the tissue during HIFU exposure, with the intensity and driving frequency of HIFU set to 1.0–5.0 kW/cm2 and 1.67 MHz, respectively. To investigate the failure conditions of the proposed algorithm, the proposed method was applied with the HIFU focus located at the boundary between the phantom and water to easily cause cavitation bubbles. The intensity of HIFU was set to 10 kW/cm2.ResultsAlmost all HIFU noise was constantly able to be eliminated using the proposed method when the phantom was moved along the lateral and axial directions during HIFU exposure. The noise reduction level (PRL in this study) at an intensity of 1.0, 3.0, and 5.0 kW/cm2 was in the range of 28–32, 38–40, and 42–45 dB, respectively. On the other hand, HIFU noise was not basically eliminated during HIFU exposure after applying the proposed method in the case of cavitation generation at the HIFU focus.ConclusionsThe proposed method can be applicable even if homogeneous tissues or organs move axially or laterally to the direction of HIFU exposure because of breathing. A condition under which the proposed algorithm failed was when instantaneous tissue changes such as cavitation bubble generation occurred in the tissue, at which time the reflected continuous wave response became less steady.

High intensity focused ultrasound responsive release behavior of metallo-supramolecular block PPG-PEG copolymer micelles.

An amphiphilic metallo-supramolecular poly(propylene glycol)-block-poly(ethylene glycol) block copolymer containing a bis(2,2':6',2″-terpyridine) ruthenium (II) complex as a supramolecular connection between the two constituting blocks was used to prepare stable aqueous micelles which displayed a high intensity focused ultrasound (HIFU) triggered release behavior. By adjusting the HIFU time and intensity, the novel modality of HIFU triggered release allows for fine-tuning of the release kinetics of the encapsulants from the micelles in a remote and controlled way. Nuclear magnetic resonance spectroscopy, ultraviolet spectroscopy, and matrix-assisted laser desorption/ionization-time of flight mass spectrometry confirmed that the degradation of the micelles was due to the cleavage of the ether bond connected to the pyridine ring. This well controlled HIFU-copolymer micelle drug delivery system has considerable potential in targeted therapy.

Effect of shear wave propagation on estimation of heating distribution by high-intensity focused ultrasound using acoustic radiation force imaging

In a high-intensity focused ultrasound (HIFU) treatment, to predict a HIFU heat source is important for the safety and efficiency. Acoustic radiation force impulse imaging using a HIFU burst is known as a method for the prediction from the distribution of the tissue displacement in a homogeneous tissue. However, the distribution induced by HIFU radiation force expands as the shear wave propagates. In this study, the effect of the shear wave propagation on the estimation of the heat source distribution was investigated by changing the burst duration and intensity of HIFU. The results showed that a shorter HIFU burst provided the higher accuracy of the prediction, improving the spatial resolution. It is concluded that the estimation method has the potential to estimate in a wide range of HIFU energy and requires one to obtain the distribution of displacements immediately after the start of HIFU burst exposure.

Theoretically Estimating the Acoustic Intensity of High-Intensity Focused Ultrasound (HIFU) Using Infrared Thermography.

High-intensity focused ultrasound (HIFU) has been used successfully in clinics for the treatment of a variety of cancerous and benign tumors. Characterization of the focused acoustic field is of importance in the planning of the ablation procedure and further development of HIFU technology. Quantitative estimation of acoustic intensity is feasible using the infrared (IR) thermography on an absorber. However, the current approach is limited to low power output. In this study, a theoretical model was established to describe the acoustic field and absorbed energy in the absorber with the presence of harmonics in the HIFU pressure waveform at the focus and then to calculate the temperature elevations during the HIFU heating, from which the acoustic intensities could be derived. The absolute difference between the derived and incident acoustic intensities in a 2-mm absorber at the varied acoustic power output (up to 80 W) and attenuation of the absorber (up to 346 Np/m/MHz) is <6%. In addition, the proposed approach was found to also work well for the absorber with a varied thickness because of the monotonic decrease of the temperature elevation. The effects of pulse duration and duty cycle of pulsed HIFU ablation on the estimation accuracy were also investigated. It is found that the estimation accuracy is good for short pulse duration using the equivalent acoustic intensity. Overall, the proposed approach could estimate the acoustic intensity and harmonic distribution of HIFU at the high power output using IR thermography for a large parametric range of absorber and HIFU output in the numerical investigation.

Nanoparticle-Mediated Acoustic Cavitation Enables High Intensity Focused Ultrasound Ablation Without Tissue Heating.

While thermal ablation of various solid tumors has been demonstrated using high intensity focused ultrasound (HIFU), the therapeutic outcomes of this technique are still unsatisfactory because of common recurrence of thermally ablated cancers and treatment side effects due to the high ultrasound intensity and acoustic pressure requirements. More precise ablation of tumors can be achieved by generating cavitating bubbles in the tissue using shorter pulses with higher acoustic pressures, which induce mechanical damage rather than thermal. However, it has remained as a challenge to safely deliver the acoustic pressures required for mechanical ablation of solid tumors. Here, we report a method to achieve mechanical ablation at lower acoustic pressures by utilizing phospholipid-stabilized hydrophobic mesoporous silica nanoparticles (PL-hMSN). The PL-hMSNs act as seeds for nucleation of cavitation events and thus significantly reduce the peak negative pressures and spatial-average temporal-average HIFU intensities needed to achieve mechanical ablation. Substantial mechanical damage was observed in the red blood cell or tumor spheroid containing tissue mimicking phantoms at PL-hMSN concentrations as low as 10 μg mL-1, after only 5 s of HIFU treatment with peak negative pressures ∼11 MPa and duty cycles ∼0.01%. Even the application of HIFU (peak negative pressure of 16.8 MPa and duty cycle of 0.017%) for 1 min in the presence of PL-hMSN (200 μg mL-1) did not cause any detectable temperature increase in tissue-mimicking phantoms. In addition, the mechanical effects of cavitation promoted by PL-hMSNs were observed up to 0.5 mm from the center of the cavitation events. This method may thus also improve delivery of therapeutics or nanoparticles to tumor environments with limited macromolecular transport.

The impact of gestational sac size on the effectiveness and safety of high intensity focused ultrasound combined with ultrasound-guided suction curettage treatment for caesarean scar pregnancy

Objective: To evaluate the correlation between the gestational sac size and the effect and safety of high intensity focused ultrasound (HIFU) combined with ultrasound-guided suction curettage for caesarean scar pregnancy (CSP).Methods: Seventy-six patients with CSP were enrolled. Based on their gestational sac size, patients were divided into three groups: Group 1 (n = 16, 10–20 mm), Group 2 (n = 28, 21–30 mm) and Group 3 (n = 32, >30 mm). All of them were treated by HIFU combined with ultrasound-guided suction curettage. Baseline characteristics, parameters and adverse events of HIFU, and intraoperative hemorrhage during ultrasound-guided suction curettage were recorded.Results: The median treatment time and average treatment intensity of HIFU in Group 3 were significantly higher than Group 1 (p < .05); the median HIFU treatment power in Group 2 and Group 3 were both significantly higher than that of Group 1 (p < .05). The median sonication time of HIFU in Group 3 was significantly longer than patients in the other two groups (p < .05). The size of the gestational sac had a positive correlation with all the above-mentioned parameters of HIFU and blood loss during ultrasound-guided suction curettage (p < .05). No statistically significant differences were observed among the three groups in the duration of vaginal bleeding post-curettage and the time necessary for serum β-hCG to return to normal levels (p > .05).Conclusions: HIFU combined with ultrasound-guided suction curettage is a safe and effective clinical approach for CSP. Gestational sac size is a meaningful factor for predicting the efficacy and safety of HIFU treatment and hemorrhage during ultrasound-guided suction curettage.

Usefulness of modified BRB technique in treatment to ablate uterine fibroids with magnetic resonance image-guided high-intensity focused ultrasound.

ObjectiveIf bowels and other structures are in the pathway of high-intensity focused ultrasound (HIFU) beam during magnetic resonance image-guided HIFU (MRgFUS) therapy, filling to the bladder and the rectum and then emptying the bladder (i.e., the BRB technique) is used to avoid them. A modified BRB technique might be useful method to using a uterine elevator method or by inducing uterus downward traction to lower the position of the uterus.MethodsA total of 156 patients who had undergone MRgFUS surgery treatment for uterine fibroids from March 2015 to February 2016 were included in this retrospective study. Of the 156 patients, 40 were treated using a uterine elevator while 29 were treated using downward traction of uterus. HIFU was performed using Philips Achieva 1.5 Tesla MR and Sonalleve HIFU system.ResultsMRgFUS surgery was feasible with modified BRB technique in 69 cases. Using uterine elevator method, the intensity of HIFU for group with antefletxio uteri was significantly lower than that for the group without antefletxio uteri (105.37±17.62 vs. 118.71±26.88 W). The group with downward traction of uterus induced was found to have significantly lower intensity of HIFU compared to the group without downward traction of uterus induced (110.26±22.60 vs. 130.51±27.81 W).ConclusionModified BRB technique was useful in avoiding bowels and other structures located in HIFU beam pathway during MRgFUS treatment to ablate uterine fibroids.

Acute effects of sono-activated photocatalytic titanium dioxide nanoparticles on oral squamous cell carcinoma

Sonodynamic therapy (SDT) is a new treatment modality using ultrasound to activate certain chemical sensitizers for cancer therapy. In this study, effects of high intensity focused ultrasound (HIFU) combined with photocatalytic titanium dioxide (TiO2) nanoparticles on human oral squamous cell line HSC-2 were investigated. Viability of HSC-2 cells after 0, 0.1, 1, or 3s of HIFU irradiation with 20, 32, 55 and 73Wcm−2 intensities in the presence or absence of TiO2 was measured immediately after the exposures in vitro. Immediate effects of HIFU (3s, 73Wcm−2) combined with TiO2 on solid tumors were also examined by histological study. Cytotoxic effect of HIFU+TiO2in vitro was significantly higher than that of TiO2 or HIFU alone with the tendency to increase for higher HIFU intensity, duration, and TiO2 concentration in the suspension. In vivo results showed significant necrosis and tissue damage in HIFU and HIFU+TiO2 treated samples. However, penetration of TiO2 nanoparticles into the cell cytoplasm was only observed in HIFU+TiO2 treated tissues. In this study, our findings provide a rational basis for the development of an effective HIFU based sonodynamic activation method. This approach offers an attractive non-invasive therapy technique for oral cancer in future.

Clinical Consideration of Treatment to Ablate Uterine Fibroids with Magnetic Resonance Imaging-guided High Intensity Focused Ultrasound (MRgFUS): Sonalleve.

ObjectivesMagnetic resonance imaging (MRI)-guided high intensity focused ultrasound surgery (MRgFUS) is a newly emerging non-invasive technique for the treatment of uterine fibroids. The purpose of this study is to review the clinical impact of MRgFUS.MethodsThis study examined 157 patients. The high intensity focused ultrasound (HIFU) utilized in this study was Philips Achieva 1.5 Tesla MR (Philips Healthcare, Best, the Netherlands) and Sonalleve HIFU system. The patients were followed in post-operative Month 1, Month 3, and Month 6 to investigate any change. Then, these were further classified according to the use of uterine stimulant (oxytocin) in parallel, Funaki Type of uterine fibroid, HIFU intensity, and non-perfused volume (NPV) ratio.ResultsWhen the uterine stimulant was utilized, the HIFU intensity was measured at significantly lower levels, compared with the group not using uterine stimulant, and treatment duration was significantly. The NPV ratio was found significantly higher in the group using uterine stimulant. Concerning the correlation between Funaki Type of uterine fibroid and average sonication power, it was found that the closer to Type I, the lower the sonication power, the shorter the treatment duration, and the higher the NPV ratio significantly.ConclusionsIn this study, it was found that the lower the Funaki Types of uterine fibroids, and the higher the NPV ratio immediately after the operation, the larger the uterine fibroid volume decrease and SSS change were. Also, if uterine stimulant was used in parallel in treatment, treatment duration and HIFU intensity could become shorter and lower.

A Multifunctional Theranostic Nanoagent for Dual-Mode Image-Guided HIFU/Chemo- Synergistic Cancer Therapy.

High-intensity focused ultrasound (HIFU) is deemed to be a promising noninvasive therapeutic modality for cancers as well as non-neoplastic diseases. However, the accuracy of the technique in the diagnosis and treatment of tumors remains unsatisfactory. HIFU, when combined with multifunctional synergistic agents (SAs), has the potential to be of greater diagnostic and therapeutic efficacy. Here we describe a smart and multifunctional hollow mesoporous Prussian blue (HMPBs) theranostic nanoplatform, the hollow structure of which is capable of encapsulating doxorubicin (DOX) and perfluorohexane (HMPBs-DOX/PFH). In vitro and in vivo studies validated that HMPBs-DOX/PFH can be used as an amplifiable dual-mode imaging contrast agent, which can simultaneously enhance ultrasound (US) and photoacoustic (PA) imaging for guiding and monitoring tumor therapy. When exposed to HIFU, this versatile HMPBs-DOX/PFH agent could increase the cavitation effect and use lower HIFU intensity to achieve coagulative necrosis. Furthermore, it significantly accelerated the release of DOX thereby enhancing chemotherapeutic efficacy and avoiding systemic side effects of the drug. Such a novel theranostic nanoplatform is expected to integrate dual-mode guided imaging with greater therapeutic efficacy and fewer side effects and is very promising for the noninvasive synergistic tumor therapy.

Abstract 12973: High-Intensity Focused Ultrasound (HIFU) Promotes Angiogenesis in a Rat Model of Peripheral Arterial Disease

Shock wave therapy (SWT) delivers single pulses of pressure to tissue, and promotes angiogenesis in animal models and humans with PAD and CAD. HIFU applies pulses of multiple pressure waves, which may be more efficient. We hypothesized that setting HIFU intensity to replicate peak negative pressures (-6 MPa) typically used for SWT would lead to greater angiogenesis. Eight week-old female Sprague-Dawley rats underwent left femoral artery excision to induce hindlimb ischemia, and the right hindlimb was used as an internal control. Rats were randomized to three groups (n=10 each): SWT (0.10 mJ/mm2), HIFU (1.054 MHz, 1 ms pulse duration), and sham therapy. Both treatments were applied at a pulse repetition frequency of 5 Hz, 200 pulses per spot, for six spots along the hindlimb. Rats were treated three times weekly for two weeks, and hindlimb perfusion was assessed with a Moor LDI Laser Doppler scanner. Compared with pre-treatment baseline (Fig 1A), HIFU improved the ratio of left:right perfusion by 23.6 ± 4.5% (mean ± SEM; Fig 1B), SWT by 17.0 ± 5.9%, and sham by 4.7 ± 3.4% (Fig 1C). Immunohistochemistry of gastrocnemius muscle was performed using anti-CD31 (PECAM) antibody, and microvascular density was quantified using ImageJ software. Both HIFU and SWT increased microvascular density in the left hindlimb (223 ± 4 and 217 ± 5 vessels/hpf, respectively) compared with sham (196 ± 7, p = 0.0001 for HIFU, p = 0.01 for SWT), but there was no significant difference between HIFU and SWT. RT-PCR was performed to examine the level of VEGF mRNA. HIFU increased left:right VEGF mRNA compared with sham (2.98 ± 0.69 vs 1.17 ± 0.23, p = 0.03), whereas SWT did not exhibit a significant change compared with sham (0.75 ± 0.20, p = 0.19). In conclusion, HIFU may be a potential non-invasive therapy for promotion of angiogenesis and reperfusion for PAD patients. Further research is needed to define a dose-response relationship of HIFU-mediated angiogenesis, and to elucidate its pro-angiogenic mechanisms.

First successful case of non‐invasive in‐utero treatment of twin reversed arterial perfusion sequence by high‐intensity focused ultrasound

High-intensity focused ultrasound (HIFU) has excellent potential as a non-invasive therapeutic tool in various fields of medicine. We present a case of twin reversed arterial perfusion sequence, in which non-invasive blood flow occlusion in the acardiac fetus was successfully achieved by means of HIFU exposure from outside the maternal abdomen. HIFU was applied to blood vessels of the acardiac fetus at the point at which the umbilical cord entered the body in a series of four procedures at 3-day intervals starting at 13 weeks' gestation, and in a final procedure with higher power at 17 weeks. The HIFU intensity was set at approximately 2300 W/cm(2) for the initial series of procedures and at 4600 W/cm(2) for the final procedure, with exposure periods of 10 s. As color Doppler examination revealed absence of blood flow to the acardiac fetus after the second round of HIFU exposure, we concluded that complete occlusion of target vessels had been achieved. Delivery was by Cesarean section at 37 weeks' gestation. A male neonate (the pump fetus) was born weighing 1903 g with Apgar scores of 8 and 9 at 1 and 5 min, respectively. At the time of writing, the baby was healthy and growing normally, with the exception of congenital pseudarthrosis.

High Intensity Focused Ultrasound Triggered Shape Memory and Drug Release from Biodegradable Polyurethane

AbstractA shape memory biodegradable polyurethane composite is prepared and shape recovery and simultaneous release of embedded copper sulfate are realized by high intensity focused ultrasound (HIFU). The composite shows an excellent HIFU‐controlled shape recovery performance, wherein temporal and spatial control can be realized by switching the HIFU on/off or selecting the place where the ultrasound is focused. The composite shows an excellent HIFU switchable drug release function. The release process of a model payload can be tuned by adjusting the HIFU intensity and time. The shape memory polyurethane shows a rapid enzymatic biodegradation rate. This polyurethane composite has potential applications in minimally invasive interventional therapy devices.magnified image

Estimating dynamic changes of tissue attenuation coefficient during high-intensity focused ultrasound treatment.

BackgroundThis study investigated the dynamic changes of tissue attenuation coefficients before, during, and after high-intensity focused ultrasound (HIFU) treatment at different total acoustic powers (TAP) in ex vivo porcine muscle tissue. It further assessed the reliability of employing changes in tissue attenuation coefficient parameters as potential indicators of tissue thermal damage.MethodsTwo-dimensional pulse-echo radio frequency (RF) data were acquired before, during, and after HIFU exposure to estimate changes in least squares attenuation coefficient slope (Δβ) and attenuation coefficient intercept (Δα0). Using the acquired RF data, Δβ and Δα0 images, along with conventional B-mode ultrasound images, were constructed. The dynamic changes of Δβ and Δα0, averaged in the region of interest, were correlated with B-mode images obtained during the HIFU treatment process.ResultsAt a HIFU exposure duration of 40 s and various HIFU intensities (737–1,068 W/cm2), Δβ and Δα0 increased rapidly to values in the ranges 1.5–2.5 dB/(MHz.cm) and 4–5 dB/cm, respectively. This rapid increase was accompanied with the appearance of bubble clouds in the B-mode images. Bubble activities appeared as strong hyperechoic regions in the B-mode images and caused fluctuations in the estimated Δβ and Δα0 values. After the treatment, Δβ and Δα0 values gradually decreased, accompanied by fade-out of hyperechoic spots in the B-mode images. At 10 min after the treatment, they reached values in ranges 0.75–1 dB/(MHz.cm) and 1–1.5 dB/cm, respectively, and remained stable within those ranges. At a long HIFU exposure duration of around 10 min and low HIFU intensity (117 W/cm2), Δβ and Δα0 gradually increased to values of 2.2 dB/(MHz.cm) and 2.2 dB/cm, respectively. This increase was not accompanied with the appearance of bubble clouds in the B-mode images. After HIFU treatment, Δβ and Δα0 gradually decreased to values of 1.8 dB/(MHz.cm) and 1.5 dB/cm, respectively, and remained stable at those values.ConclusionsΔβ and Δα0 estimations were both potentially reliable indicators of tissue thermal damage. In addition, Δβ and Δα0 images both had significantly higher contrast-to-speckle ratios compared to the conventional B-mode images and outperformed the B-mode images in detecting HIFU thermal lesions at all investigated TAPs and exposure durations.

The Localized Elasticity Measurement for Coagulation Detection during HIFU Therapy

High Intensity Focused Ultrasound (HIFU) treatment is one of minimally invasive treatment methods for cancer. To control a beam position and dose amount of HIFU, visualizing inside of the body during treatment is essentially required. Our objective is to develop an ultrasound monitoring system for thermally induced coagulation. Localized Motion Imaging (LMI) is a monitoring method to detect a localized mechanical response depending on stiffness change caused by thermal coagulation. In LMI, amplitude modulated HIFU causes oscillation of tissues in the HIFU focal area. Because an elastic modulus at coagulated area will increase, coagulated area will be detected as a decreased area of oscillation amplitude. To increase detection sensitivity for small coagulated area, a localization control of oscillation by changing modulation frequency were tested in experiments of porcine liver. A 2MHz transducer for HIFU and 7.5MHz transducer for imaging were used. The amplitude modulation frequency was ranging from 50 to 200Hz. Acoustic intensity of HIFU was 2000 w/cm2 at the focus and HIFU exposure time was 45 s. Amplitude decrease of tissues oscillation at focal point was detected in 5-10 s HIFU exposure at the highest modulation frequency. Detected amplitude was decrease to 0.2. This suggested that in LMI, high modulation frequency is suited to detection for small coagulation area or begging of coagulation.

High‐intensity focused ultrasound treatment for twin reversed arterial perfusion sequence

Twin reversed arterial perfusion (TRAP) sequence is a serious complication of monochorionic twin pregnancies, in which arterioarterial anastomoses allow blood flow from a 'pump' fetus to an acardiac fetus via reversed flow in the latter's umbilical artery. Several trial treatments for TRAP sequence have been reported, but all of these have been invasive. We present a case of TRAP sequence in which high-intensity focused ultrasound (HIFU) was applied to the umbilical artery of the anomalous twin at 26 weeks as a non-invasive fetal therapy. The HIFU intensity was set at approximately 2300 W/cm(2) with exposure periods of 10 s. Color Doppler ultrasound showed a decrease in blood supply to the anomalous twin, although complete occlusion of the targeted vessel was not achieved. Delivery was by Cesarean section at 29 weeks' gestation and the pump twin survived, without severe clinical complications at 6 months.

WE‐C‐220‐01: Histotripsy without Cavitation

Purpose: Histotripsy is an exciting new mechanism for ablating tissue in that it completely emulsifies tissue, leaving nothing behind but a liquid‐like slurry. Although clinical applications of this approach are still to be tested, it offers high promise for the use of High Intensity Focused Ultrasound (HIFU) for therapy. Accordingly to the conventional approach, short (microsecond‐length) pulses of very high amplitude ultrasound are used to induce intense cavitation, which mechanically disrupts the tissue. We have developed an approach that involves longer (millisecond‐length) pulses. These high amplitude pulses develop into shock waves that induce superheated boiling in the tissue, resulting in very efficient tissue emulsification. Methods. Experiments have been undertaken in a variety of tissues and tissue phantoms; we particularly prefer transparent tissue mimicking materials that permit high‐speed photography. Histotripsy lesions (essentially holes in tissue) were generated in these materials under acoustic exposures that have been reported in clinical applications. Imaging modalities include MR, ultrasound, and high‐speed photography. Results. When ultrasound imaging is used to examine HIFU‐induced, thermal‐lesion formation, the appearance of hyperechogenicity often occurs. Although this hyperechogenicity has typically been associated with the occurrence of cavitation, we have determined that cavitation seldom generates enough backscatter to be detectable; rather, hyperechogenicity is more often associated with boiling. In particular, we have observed that when the HIFU intensity is sufficiently high that shock formation occurs, boiling can occur in milliseconds. The appearance of a hyperechoic echo is an accurate focus monitoring technique. Modeling, using weak shock theory, supports this occurrence of boiling. The time‐to‐boil can accurately be predicted by modeling and is very reproducible. Conclusions: Histotripsy can be generated by shock‐wave‐induced boiling, an approach that offers many attractive features.

Induction of Luciferase Activity under the Control of an hsp70 Promoter Using High-Intensity Focused Ultrasound: Combination of Bioluminescence and MRI Imaging in Three Different Tumour Models

The in vivo temporal changes of luciferase activity were investigated under the control of an hsp70 promoter in three tumour models after the application of different intensities of high-intensity focused ultrasound (HIFU). Three cell lines, SCCVII, NIH3T3 and M21 were stably transfected with a plasmid containing the hsp70 promoter and luciferase reporter gene, and tumours were subcutaneously initiated into mice. At a size of 1300 ± 234 mm(3), the tumours were exposed to five intensities of continuous HIFU (802-1401-2157-3067-4133 W/cm(2)) for 20 sec. Bioluminescence and MR imaging were performed to assess luciferase activity and signal intensity changes in the tissue. The MRI scan protocol was pre- and post-contrast T1-wt-SE, T2-wt-FSE, DCE-MRI, diffusion-wt STEAM sequence, T2 relaxation time determination obtained on a 1.5-T GE MRI scanner. The NIH3T3 tumours showed the highest luciferase activity of 328.1 ± 7.1 fold at 24 h at a HIFU intensity of 3067 W/cm(2), the M21 tumours of 3.2 ± 0.6 fold 8 hours and the SCCVII tumours 2.9 ± 0.9 fold 4 hours post-HIFU at 2157 W/cm(2). The greatest increase in T2 signal intensity and T2 relaxation time of 20.7 ± 3.4% was seen in the SCCVII tumours. The highest contrast medium uptake of 10.1 ± 1.1% was noted in the M21 tumours, and 14.8 ± 1.9% in the SCCVII tumours. In all tumours, a significant increase in the diffusion coefficient was seen with increased HIFU intensity, the highest of which was 40.3 ± 4.1% in the SCCVII tumours. The three tumour cell lines stably transfected with the hsp70/luciferase gene showed differential luciferase activity, which peaked at different times after the application of HIFU and was dependant on tumour type and HIFU energy deposition.

Enhancing targeted focused ultrasound therapy using light, sound, and nanoparticles.

The use of targeted nanoparticles for both imaging and therapeutic applications shows significant promise. Photoacoustic tomography is a non‐invasive imaging technique based on the detection of broad‐band acoustic emissions generated by the absorption of laser light in tissue. The introduction of light‐absorbing gold nanoparticles can improve signal emission levels and, if functionalized, can promote the targeting of specific cell populations, thereby enhancing both contrast and the ability to delineate tissue types. For a sufficiently high laser fluence, a transient vapor cavity is formed which collapses inertially, generating a broadband emission and even greater contrast enhancement. However, the fluence required typically exceeds the maximum permissible exposure for tissue. By combining ultrasonic and optical pulses, the light and sound thresholds required to repeatedly generate inertial cavitation (IC) can be significantly reduced, thus reducing both the laser fluence and acoustic pressures required to generate images from these acoustic emissions. The presence of IC in continuous wave high intensity focused ultrasound (HIFU) exposures can locally enhance the heating resulting in effective tissue ablation at lower HIFU intensities. [Work supported by a Boston University COE Dean’s Catalyst Award and the Gordon Center for Subsurface Sensing and Imaging Systems (NSF ERC Award No. EEC‐9986821).]