High Intensity Focused Ultrasound Pulses Research Articles

Optical method for direct temperature measurement of high intensity focused ultrasound heating

The acoustic pressure field or heat deposition from the passage of an ultrasonic wave can produce a perceptible alteration in the medium’s optical refractive index. With proper placement of the light source and imaging camera, the optical effect can be recorded. This talk describes an optical temperature measurement methodology dubbed laser-ray-bundle (LRB) of the heat deposition from a high intensity focused ultrasound (HIFU) transducer in a transparent tissue phantom. The method does not require calibration, and directly converts the thermo-optic signal to temperature without recourse to any iterative computations. LRB boasts of excellent temporal and spatial resolutions and high temperature sensitivity better than any fine wire thermocouple. Furthermore, it is completely non-invasive. The LRB method is demonstrated with the heat deposition from single millisecond long HIFU pulses in a PDMS tissue phantom or from a train of single pulses with very good performance. The method represents a new capability for quickly assess a HIFU transducer output, and for laboratory and preclinical studies of heating near tissue interfaces including bone, air, or fat. A preliminary experimental setup for measuring the acoustic pressure field is presented.

Real-time cavitation monitoring based on the entropic analysis of ultrasound RF signals

The violent inertial cavitation activity generated in high intensity focused ultrasound (HIFU) treatment has a risk of damaging healthy tissues around the target area, so that it is necessary to monitor the degree of cavitation during the treatment. Entropy, as a non-model-based statistical parameter, can effectively characterize the effect of cavitation on the structure of scatters within tissues. Thus, a real-time cavitation monitoring system was established based on the entropy analysis of ultrasound radio frequency (RF) signals, and the degree of cavitation was evaluated through entropy images. Based on the two-dimensional average filtering method, we achieved real-time monitoring of cavitation through the reconstruction of entropy image and the binarization of cavitation regions, breaking the inherent limitation of current systems that can only perform cavitation monitoring between HIFU pulses. The results showed that the entropy image retained more frequency components, which could determine the time and location of cavitation earlier and display cavitation areas. Moreover, as the acoustic pressure increased, the advance of cavitation indication in the entropy images became earlier. This method might provide a feasible evaluation scheme for improving real-time cavitation monitoring during HIFU treatment and was expected to become an effective reference index for imaging in HIFU surgery.

Control of the dynamics of a boiling vapour bubble using pressure-modulated high intensity focused ultrasound without the shock scattering effect: A first proof-of-concept study

Boiling histotripsy is a promising High-Intensity Focused Ultrasound (HIFU) technique that can be used to induce mechanical tissue fractionation at the HIFU focus via cavitation. Two different types of cavitation produced during boiling histotripsy exposure can contribute towards mechanical tissue destruction: (1) a boiling vapour bubble at the HIFU focus and (2) cavitation clouds in between the boiling bubble and the HIFU source. Control of the extent and degree of mechanical damage produced by boiling histotripsy is necessary when treating a solid tumour adjacent to normal tissue or major blood vessels. This is, however, difficult to achieve with boiling histotripsy due to the stochastic formation of the shock scattering-induced inertial cavitation clouds. In the present study, a new histotripsy method termed pressure-modulated shockwave histotripsy is proposed as an alternative to or in addition to boiling histotripsy without inducing the shock scattering effect. The proposed concept is (a) to generate a boiling vapour bubble via localised shockwave heating and (b) subsequently control its extent and lifetime through manipulating peak pressure magnitudes and a HIFU pulse length. To demonstrate the feasibility of the proposed method, bubble dynamics induced at the HIFU focus in an optically transparent liver tissue phantom were investigated using a high speed camera and a passive cavitation detection systems under a single 10, 50 or 100 ms-long 2, 3.5 or 5 MHz pressure-modulated HIFU pulse with varying peak positive and negative pressure amplitudes from 5 to 89 MPa and −3.7 to −14.6 MPa at the focus. Furthermore, a numerical simulation of 2D nonlinear wave propagation with the presence of a boiling bubble at the focus of a HIFU field was conducted by numerically solving the generalised Westervelt equation. The high speed camera experimental results showed that, with the proposed pressure-modulated shockwave histotripsy, boiling bubbles generated by shockwave heating merged together, forming a larger bubble (of the order of a few hundred micron) at the HIFU focus. This coalesced boiling bubble then persisted and maintained within the HIFU focal zone until the end of the exposure (10, 50, or 100 ms). Furthermore, and most importantly, no violent cavitation clouds which typically appear in boiling histotripsy occurred during the proposed histotripsy excitation (i.e. no shock scattering effect). This was likely because that the peak negative pressure magnitude of the backscattered acoustic field by the boiling bubble was below the cavitation cloud intrinsic threshold. The size of the coalesced boiling bubble gradually increased with the peak pressure magnitudes. In addition, with the proposed method, an oval shaped lesion with a length of 0.6 mm and a width of 0.1 mm appeared at the HIFU focus in the tissue phantom, whereas a larger lesion in the form of a tadpole (length: 2.7 mm, width: 0.3 mm) was produced by boiling histotripsy. Taken together, these results suggest that the proposed pressure-modulated shockwave histotripsy could potentially be used to induce a more spatially localised tissue destruction with a desired degree of mechanical damage through controlling the size and lifetime of a boiling bubble without the shock scattering effect.

WITHDRAWN: Combination technique for tattoo removal by Q switching Nd: YAG laser and high intensity focused ultrasound

For decades, nanosecond lasers (NSLs) have been used to remove tattoos is Neodymium‐doped yttrium aluminum garnet (Nd: YAG) 1064‐nm. High‐intensity focused ultrasound (HIFU) is new and potentially applicable to ablative tattoo removal. This research presents a new quick hybrid technique for removing blue-black mature tattoos. The combination of high intensity focusing ultrasound (HIFU) on the treatment area is used to produce acoustic media inside the skin during laser application. A study on 11 subjects were treated with (Nd: YAG) 1064‐nm, with a fluence of (450–850) mJ, spot size of 5 mm, and pulse width 3–5 ns. Some tattoo areas are treated with 1064 nm laser only by multiple pulses in a single session and others are treated between the laser pulses with a Nd: YAG nanosecond laser and HIFU pulse, treatments were limited to 450 mJ only for laser and a maximum frequency of 10 MHz and 0.25 joul and 14 mm depth for ultrasound. Then the percentage of tattoo removing was detected using FCM-based image segmentation method. This method can help dermatologist to set the amount of removal at each session, making it easier to predict the number of sessions that might be needed for full removal. The treated area divided into 3 parts. Each part treated with certain type of technique: 450 mJ + 450 mJ, 450 mJ + 850 mJ and 450 + HIFU + 450 mJ. There was a significant difference between the 450 mJ + 450 mJ and 450 mJ + 850 mJ also for 450 mJ + 450 mJ & 450 mJ + HIFU + 450 mJ at 1, 3 and 4 sessions but not for the second session. No significant differences found in comparison between 450 mJ + 850 mJ & 450 mJ + HIFU + 450 mJ for any session. The tattoo pigments removed by 33%, 47% and 50% at energy 450 mJ + 850 mJ and 450 mJ + HIFU + 450 mJ respectively at the end of the 4th session. The use of HIFU in combination with Nd: YAG laser reduces the pain and scars. Transient side effects were observed first area because of high energy, but neither area had significant adverse reactions. In conclusion, the use of HIFU in combination with laser gives the better response comparing to the low or high energy laser due to a smaller number of sessions required for tattoo removal, fewer or no scars remains after treatment and less pain effect.

Use of Speckle Tracking Echocardiography to Detect Induced Regional Strain Changes in the Murine Myocardium by Acoustic Radiation Force.

BACKGROUNDIt is difficult to simulate the abnormal myocardial strain patterns caused by ischemic coronary artery disease (CAD) which are a precursor to heart failure (HF) within an animal model. Simulation of these strain changes could contribute to better understanding of the early formative stages of HF. This is especially important in investigating the poorly understood pathogenesis of heart failure with preserved ejection fraction (HFpEF). Here, we discuss delivery of high intensity focused ultrasound (HIFU) in a murine model to alter left ventricular (LV) regional longitudinal strain (RLS), and use of speckle tracking echocardiography to detect these changes.METHODSHIFU pulses (pressure amplitude 1.7 MPa) were generated by amplifying a sinusoidal waveform from a function generator into a piezoelectric transducer. These pulses were then directed extracorporeally towards the anterior LV surface of C57BI6 mice during three time periods (early, mid, and late diastole). Speckle tracking echocardiography was then used to quantify changes in RLS within six segments of the LV.RESULTSWe observed an increase in LV RLS with acoustic augmentation during all three time periods. This augmentation was most prominent near the anterior apical region in early diastole and near the posterior basilar region during late diastole.CONCLUSIONSOur findings demonstrate the application of HIFU to non-invasively induce changes in RLS within a murine model. Our results also reflect the capability of speckle tracking echocardiography to analyze and quantify these changes. These findings represent the first demonstration of ultrasound-induced augmentation in LV RLS within a small animal model.

Efficacy and safety assessment of an ultrasound-based thermal treatment of varicose veins in a sheep model

Purpose Varicose veins are a common pathology that can be treated by endovenous thermal procedures like radiofrequency ablation (RFA). Such catheter-based techniques consist in raising the temperature of the vein wall to 70 to 120 °C to induce vein wall coagulation. Although effective, this treatment option is not suited for all types of veins and can be technically challenging. Materials and methods In this study, we used High-Intensity Focused Ultrasound (HIFU) as a non-invasive thermal ablation procedure to treat varicose veins and we assessed the long-term efficacy and safety of the procedure in a sheep model. In vivo experiments were first conducted on two saphenous veins to measure the temperature rise induced at the vein wall during HIFU ablation and were compared with reported RFA-induced thermal rise. Thermocouples were inserted in situ to perform 20 measurements during 8-s ultrasound pulses at 3 MHz. Eighteen saphenous veins of nine anesthetized sheep (2–2.5 % Isoflurane) were then exposed to similar pulses (85 W acoustic, 8 s). After treatments, animals recovered from anesthesia and were followed up 30, 60 and 90 days post-treatment (n = 3 animals per group). At the end of the follow-up, vein segments and perivenous tissues were harvested and histologically examined. Results Temperatures induced by HIFU pulses were found to be comparable to reported RFA treatments. Likewise, histological findings were similar to the ones reported after RFA and laser-based coagulation necrosis of the vein wall, thrombotic occlusions and vein wall fibrosis. Conclusion These results support strongly the effectiveness and safety of HIFU for ablating non-invasively veins.

An MRI-guided HIFU-triggered wax-coated capsule for supertargeted drug release: a proof-of-concept study

BackgroundExternally controlling and monitoring drug release at a desired time and location is currently lacking in the gastrointestinal tract. The aim of the study was to develop a thermoresponsive wax-coated capsule and to trigger its release upon applying a magnetic resonance imaging (MRI)-guided high-intensity focused ultrasound (HIFU) pulse.MethodsCapsules containing a lyophilised gadolinium-based contrast agent (GBCA) were coated with a 1:1 (mass/mass) mixture of lanolin and cetyl alcohol (melting point ≈43 °C) and exposed to simulated gastric and intestinal fluids (United States Pharmacopoeia) at 37 °C for 2 and 24 h, respectively. In a HIFU gel phantom, wax-coated capsules (n = 3) were tracked based on their T1- and T2-hypointensity by 1.5-T T1- and T2-weighted MRI pre- and post-exposure to an MRI-guided HIFU pulse.ResultsLanolin/cetyl alcohol-coated capsules showed high resistance to simulated gastrointestinal fluids. In a gel phantom, an MRI-guided HIFU pulse punctured the wax coating, resulting in the hydration and release of the encapsulated lyophilised GBCA and yielding a T1-hyperintense signal close to the wax-coated capsule.ConclusionWe provide the proof-of-concept of applying a non-invasive MRI-guided HIFU pulse to actively induce the disintegration of the wax-coated capsule, and a method to monitor the release of the cargo via T1-weighted MRI based on the hydration of an encapsulated lyophilised GBCA. The wax-coated capsule platform enables temporally and spatially supertargeted drug release via the oral route and promises to address a currently unmet clinical need for personalised local therapy in gastrointestinal diseases such as inflammatory bowel diseases and cancer.

Gold nanoparticle nucleated cavitation for enhanced high intensity focused ultrasound therapy

High intensity focused ultrasound (HIFU) or focused ultrasound surgery is a non-invasive technique for the treatment of cancerous tissue, which is limited by difficulties in getting real-time feedback on treatment progress and long treatment durations. The formation and activity of acoustic cavitation, specifically inertial cavitation, during HIFU exposures has been demonstrated to enhance heating rates. However, without the introduction of external nuclei its formation an activity can be unpredictable, and potentially counter-productive.In this study, a combination of pulse laser illumination (839 nm), HIFU exposures (3.3 MHz) and plasmonic gold nanorods (AuNR) was demonstrated as a new approach for the guidance and enhancement of HIFU treatments. For imaging, short duration HIFU pulses (10 μs) demonstrated broadband acoustic emissions from AuNR nucleated cavitation with a signal-to-noise ranging from 5–35 dB for peak negative pressures between 1.19–3.19 ± 0.01 MPa. In the absence of either AuNR or laser illumination these emissions were either not present or lower in magnitude (e.g. 5 dB for 3.19 MPa). Continuous wave (CW) HIFU exposures for 15 s, were then used to generate thermal lesions for peak negative pressures from 0.2–2.71 ± 0.01 MPa at a fluence of 3.4 mJ . Inertial cavitation dose (ICD) was monitored during all CW exposures, where exposures combined with both laser illumination and AuNRs resulted in the highest level of detectable emissions. This parameter was integrated over the entire exposure to give a metric to compare with measured thermal lesion area, where it was found that a minimum total ICD of a.u. was correlated with the formation of thermal lesions in gel phantoms. Furthermore, lesion area (mm2) was increased for equivalent exposures without either AuNRs or laser illumination.Once combined with cancer targeting AuNRs this approach could allow for the future theranostic use of HIFU, such as providing the ability to identify and treat small multi-focal cancerous regions with minimal damage to surrounding healthy tissue.

Numerical and Experimental Study of Mechanisms Involved in Boiling Histotripsy

The aim of boiling histotripsy is to mechanically fractionate tissue as an alternative to thermal ablation for therapeutic applications. In general, the shape of a lesion produced by boiling histotripsy is tadpole like, consisting of a head and a tail. Although many studies have demonstrated the efficacy of boiling histotripsy for fractionating solid tumors, the exact mechanisms underpinning this phenomenon are not yet well understood, particularly the interaction of a boiling vapor bubble with incoming incident shockwaves. To investigate the mechanisms involved in boiling histotripsy, a high-speed camera with a passive cavitation detection system was used to observe the dynamics of bubbles produced in optically transparent tissue-mimicking gel phantoms exposed to the field of a 2.0-MHz high-intensity focused ultrasound (HIFU) transducer. We observed that boiling bubbles were generated in a localized heated region and cavitation clouds were subsequently induced ahead of the expanding bubble. This process was repeated with HIFU pulses and eventually resulted in a tadpole-shaped lesion. A simplified numerical model describing the scattering of the incident ultrasound wave by a vapor bubble was developed to help interpret the experimental observations. Together with the numerical results, these observations suggest that the overall size of a lesion induced by boiling histotripsy is dependent on the sizes of (i) the heated region at the HIFU focus and (ii) the backscattered acoustic field by the original vapor bubble.

Numerical Study of Bubble Area Evolution During Acoustic Droplet Vaporization-Enhanced HIFU Treatment.

Acoustic droplet vaporization has the potential to shorten treatment time of high-intensity focused ultrasound (HIFU) while minimizing the possible effects of microbubbles along the propagation path. Distribution of the bubbles formed from the droplets during the treatment is the major factor shaping the therapeutic region. A numerical model was proposed to simulate the bubble area evolution during this treatment. Using a linear acoustic equation to describe the ultrasound field, a threshold range was defined that determines the amount of bubbles vaporized in the treated area. Acoustic parameters, such as sound speed, acoustic attenuation coefficient, and density, were treated as a function of the bubble size distribution and the gas void fraction, which were related to the vaporized bubbles in the medium. An effective pressure factor was proposed to account for the influence of the existing bubbles on the vaporization of the nearby droplets. The factor was obtained by fitting one experimental result and was then used to calculate bubble clouds in other experimental cases. Comparing the simulation results to these other experiments validated the model. The dynamic change of the pressure and the bubble distribution after exposure to over 20 pulses of HIFU are obtained. It is found that the bubble area grows from a grainlike shape to a "tadpole," with comparable dimensions and shape to those observed in experiments. The process was highly dynamic with the shape of the bubble area changing with successive HIFU pulses and the focal pressure. The model was further used to predict the shape of the bubble region triggered by HIFU when a bubble wall pre-exists. The results showed that the bubble wall helps prevent droplet vaporization on the distal side of the wall and forms a particularly shaped region with bubbles. This simulation model has predictive potential that could be beneficial in applications, such as cancer treatment, by parametrically studying conditions associated with these treatments and designing treatment protocols.

Phospholipid Capped Mesoporous Nanoparticles for Targeted High Intensity Focused Ultrasound Ablation.

The mechanical effects of cavitation can be effective for therapy but difficult to control, thus potentially leading to off-target side effects in patients. While administration of ultrasound active agents such as fluorocarbon microbubbles and nanodroplets can locally enhance the effects of high intensity focused ultrasound (HIFU), it has been challenging to prepare ultrasound active agents that are small and stable enough to accumulate in tumors and internalize into cancer cells. Here, this paper reports the synthesis of 100 nm nanoparticle ultrasound agents based on phospholipid-coated, mesoporous, hydrophobically functionalized silica nanoparticles that can internalize into cancer cells and remain acoustically active. The ultrasound agents produce bubbles when subjected to short HIFU pulses (≈6 µs) with peak negative pressure as low as ≈7 MPa and at particle concentrations down to 12.5 µg mL-1 (7 × 109 particles mL-1 ). Importantly, ultrasound agents are effectively uptaken by cancer cells without cytotoxic effects, but HIFU insonation causes destruction of the cells by the acoustically generated bubbles, as demonstrated by (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) and lactate dehydrogenase assays and flow cytometry. Finally, it is showed that the HIFU dose required to effectively eliminate cancer cells in the presence of ultrasound agents causes only a small temperature increase of ≈3.5 °C.

Real-time feedback control of high-intensity focused ultrasound thermal ablation using echo decorrelation imaging

The feasibility of controlling high-intensity focused ultrasound (HIFU) thermal ablation in real time using echo decorrelation imaging feedback was investigated in ex vivo bovine liver. Sonication cycles (5.0 MHz, 0.7 s per HIFU pulse, 20-24% duty, 879-1426 W/cm2 spatial-peak, and temporal peak intensity) performed by a linear image-ablate array were repeated until the minimum cumulative echo decorrelation within the focal region of interest exceeded a predefined threshold. Based on preliminary experiments (N = 13), a threshold of −2.7 for the log10-scaled echo decorrelation per millisecond was defined, corresponding to 90% specificity of local ablation prediction. Controlled HIFU thermal ablation experiments (N = 10) were compared with uncontrolled experiments employing 2, 5, or 9 sonication cycles. Controlled trials showed significantly smaller average lesion area (4.78 mm2), lesion width (1.29 mm), and treatment time (5.8 s) than 5-cycle (7.02 mm2, 1.89 mm, 14.5 s) or 9-cycle (9.31 mm2, 2.4 mm, 26.1 s) uncontrolled trials. Prediction of local ablation using echo decorrelation was assessed using receiver operator characteristic (ROC) curve analysis, in which controlled trials showed significantly greater prediction capability (area under the ROC curve AUC = 0.956) compared to 2-cycle uncontrolled trials (AUC = 0.722). These results suggest that ablation control using echo decorrelation may improve the precision, reliability, and duration of ultrasound-guided HIFU treatments.

Morphometric analysis of high-intensity focused ultrasound-induced lipolysis on cadaveric abdominal and thigh skin.

Non-focused ultrasound and high-intensity focused ultrasound (HIFU) devices induce lipolysis by generating acoustic cavitation and coagulation necrosis in targeted tissues. We aimed to investigate the morphometric characteristics of immediate tissue reactions induced by 2MHz, 13-mm focused HIFU via two-dimensional ultrasound images and histologic evaluation of cadaveric skin from the abdomen and thigh. Acoustic fields of a 2MHz, 38-mm HIFU transducer were characterized by reconstruction of the fields using acoustic intensity measurement. Additionally, abdominal and thigh tissues from a fresh cadaver were treated with a HIFU device for a single, two, and three pulses at the pulse energy of 130J/cm2 and a penetration depth of 13mm. Acoustic intensity measurement revealed characteristic focal zones of significant thermal injury at the depth of 38mm. In both the abdomen and thigh tissue, round to oval ablative thermal injury zones (TIZs) were visualized in subcutaneous fat layers upon treatment with a single pulse of HIFU treatment. Two to three HIFU pulses generated larger and more remarkable ablative zones throughout subcutaneous fat layers. Finally, experimental treatment in a tumescent infiltration-like setting induced larger HIFU-induced TIZs of an oval or columnar shape, compared to non-tumescent settings. Although neither acoustic intensity measurement nor cadaveric tissue exactly reflects in vivo HIFU-induced reactions in human tissue, we believe that our data will help guide further in vivo studies in investigating the therapeutic efficacy and safety of HIFU-induced lipolysis.

Direct nanodroplet and microbubble comparison for high intensity focused ultrasound ablation enhancement and safety

High intensity focused ultrasound (HIFU) surgery often requires hours of ablation in order to treat an entire tumor. Both perfluorocarbon gaseous microbubbles and vaporized liquid droplets are known enhancers of HIFU thermal ablation. Microbubbles, however, often lead to surface or skin lesions. Furthermore, they have a relatively short half-life in vivo (minutes) rendering them insufficiently stable for an entire HIFU surgery, which can last several hours. Many droplet formulations require very high pressures to activate. Our aim was to design an agent that could shorten ablation procedures without sacrificing safety. We designed and investigated a perfluorocarbon nanodroplet composed of a 1:1 ratio of dodecafluoropentane and decafluorobutane. These are tuned to change phase and activate at only 2 MPa peak negative pressure with common HIFU pulse lengths, enabling focused and targeted activation. Additionally, they are stable at body temperature.

Transsclera Drug Delivery by Pulsed High-Intensity Focused Ultrasound (HIFU): An Ex Vivo Study

Purpose/aim of study: Drug delivery to the ocular posterior segment is of importance, but it is a challenge in the treatment of irreversible blindness disease, such as age-related macular degeneration. Although some methods (i.e. intraocular injection, sustained release by polymer and iontophoresis) have been applied, some technical drawbacks, such as slow rate and damage to the eye, need to be overcome for wide use.Materials and methods: In this study, the feasibility of high-intensity focused ultrasound (HIFU) to enhance the transsclera drug delivery was tested for the first time. One-hundred HIFU pulses with the driving frequency of 1.1 MHz, acoustic power of 105.6 W, pulse duration of 10–50 ms and pulse repetition frequency of 1 Hz were delivered to the fresh ex vivo porcine sclera specimen.Results: In comparison to the passive diffusion (control), 50-ms HIFU can increase the penetration depth by 2.0 folds (501.7 ± 126.4 µm versus 252.4 ± 29.2 µm) using bicinchoninic acid assay and Rhodamine 6 G fluorescence intensity by 3.1 folds (22.4 ± 12.3 versus 7.1 ± 4.1) and coverage area by 2.6 folds (40.4 ± 9.1% versus 15.8 ± 2.9%). No morphological changes on the sonicated sclera samples were found using a surface electron microscope.Conclusions: In summary, pulsed-HIFU may be an effective modality in the transsclera drug delivery with a high transporting rate and depth. In vivo studies are necessary to further evaluate its performance, including the drug penetration and its possible side effects.

High intensity therapeutic ultrasound research in the former USSR in the 1950s–1970s

A historical overview of therapeutic ultrasound research performed in the former USSR in the 1950s–1970s is presented. In the 1950s, the team of A.K.Burov in Moscow proposed the use of non-thermal, non-cavitational mechanisms of high intensity unfocused ultrasound to induce specific immune responses in treating Brown Pearce tumors in an animal model and melanoma tumors in a number of patients. Later, in the early 1970s, new studies began at the Acoustics Institute in Moscow jointly with several medical institutions. Significant results included first measurements of cavitation thresholds in animal brain tissues in vivo and demonstration of the feasibility to apply high intensity focused ultrasound (HIFU) for local ablation of brain structures through the intact skull. Another direction was ultrasound stimulation of superficial and deep receptors in humans and animals using short HIFU pulses; these studies became the basis for ultrasound stimulation of different neural structures and have found useful clinical applications for diagnostics of skin, neurological, and hearing disorders. Initial studies on the synergism between ultrasound in therapeutic doses combined with consecutive application of ionizing radiation were carried out. Later, hyperthermia research was also performed for brain tissues and for ophthalmology. [Work supported by the grant RSF 14-12-00974.]

Quantitative Ultrasound Imaging for Monitoring In Situ High-Intensity Focused Ultrasound Exposure

Quantitative ultrasound (QUS) imaging is hypothesized to map temperature elevations induced in tissue with high spatial and temporal resolution. To test this hypothesis, QUS techniques were examined to monitor high-intensity focused ultrasound (HIFU) exposure of tissue. In situ experiments were conducted on mammary adenocarcinoma tumors grown in rats and lesions were formed using a HIFU system. A thermocouple was inserted into the tumor to provide estimates of temperature at one location. Backscattered time-domain waveforms from the tissue during exposure were recorded using a clinical ultrasonic imaging system. Backscatter coefficients were estimated using a reference phantom technique. Two parameters were estimated from the backscatter coefficient (effective scatterer diameter (ESD) and effective acoustic concentration (EAC). The changes in the average parameters in the regions corresponding to the HIFU focus over time were correlated to the temperature readings from the thermocouple. The changes in the EAC parameter were consistently correlated to temperature during both heating and cooling of the tumors. The changes in the ESD did not have a consistent trend with temperature. The mean ESD and EAC before exposure were 120 ± 16 μm and 32 ± 3 dB/cm3, respectively, and changed to 144 ± 9 μm and 51 ± 7 dB/cm3, respectively, just before the last HIFU pulse was delivered to the tissue. After the tissue cooled down to 37 °C, the mean ESD and EAC were 126 ± 8 μm and 35 ± 4 dB/cm3, respectively. Peak temperature in the range of 50-60 °C was recorded by a thermocouple placed just behind the tumor. These results suggest that QUS techniques have the potential to be used for non-invasive monitoring of HIFU exposure.

Cavitation-enhanced MR-guided focused ultrasound ablation of rabbit tumors in vivo using phase shift nanoemulsions

Advanced tumors are often inoperable due to their size and proximity to critical vascular structures. High intensity focused ultrasound (HIFU) has been developed to non-invasively thermally ablate inoperable solid tumors. However, the clinical feasibility of HIFU ablation therapy has been limited by the long treatment times (on the order of hours) and high acoustic intensities required. Studies have shown that inertial cavitation can enhance HIFU-mediated heating by generating broadband acoustic emissions that increase tissue absorption and accelerate HIFU-induced heating. Unfortunately, initiating inertial cavitation in tumors requires high intensities and can be unpredictable. To address this need, phase-shift nanoemulsions (PSNE) have been developed. PSNE consist of lipid-coated liquid perfluorocarbon droplets that are less than 200 nm in diameter, thereby allowing passive accumulation in tumors through leaky tumor vasculature. PSNE can be vaporized into microbubbles in tumors in order to nucleate cavitation activity and enhance HIFU-mediated heating. In this study, MR-guided HIFU treatments were performed on intramuscular rabbit VX2 tumors in vivo to assess the effect of vaporized PSNE on acoustic cavitation and HIFU-mediated heating. HIFU pulses were delivered for 30 s using a 1.5 MHz, MR-compatible transducer, and cavitation emissions were recorded with a 650 kHz ring hydrophone while temperature was monitored using MR thermometry. Cavitation emissions were significantly higher (P < 0.05) after PSNE injection and this was well correlated with enhanced HIFU-mediated heating in tumors. The peak temperature rise induced by sonication was significantly higher (P < 0.05) after PSNE injection. For example, the mean per cent change in temperature achieved at 5.2 W of acoustic power was 46 ± 22% with PSNE injection. The results indicate that PSNE nucleates cavitation which correlates with enhanced HIFU-mediated heating in tumors. This suggests that PSNE could potentially be used to reduce the time and/or acoustic intensity required for HIFU-mediated heating, thereby increasing the feasibility and clinical efficacy of HIFU thermal ablation therapy.

Real-Time Monitoring and Quantitative Evaluation of Cavitation Bubbles Induced by High Intensity Focused Ultrasound Using B-Mode Imaging

A software-based method is proposed to eliminate the flooding interference strips in B-mode images, and to evaluate the cavitation bubbles generated during high intensity focused ultrasound (HIFU) exposures. In vitro tissue phantoms are exposed to 1.12 MHz HIFU pulses with a fixed 100 Hz pulse repetition frequency. HIFU-induced cavitation bubbles are detected as hyperechoic regions in B-mode images. The temporal evolution of cavitation bubbles, generated by HIFU pulses with varying driving amplitude and pulse length, is analyzed by measuring the time-varying area of the hyperechoic region. The results show that: first, it is feasible to monitor HIFU-induced cavitation bubble activity in real-time using B-mode imaging; second, more cavitation bubbles can be generated with higher acoustic energy delivered; third, the hyperechoic region is observed to shrink gradually after ceasing the HIFU pulses, which indicates the dissolution of cavitation bubbles. This work will be helpful for developing an effective tool to realize real-time monitoring and quantitative evaluation of HIFU-induced cavitation bubble activity using a current commercialized B-mode machine.

Application of High-Intensity Focused Ultrasound to the Study of Mild Traumatic Brain Injury

Though intrinsically of much higher frequency than open-field blast overpressures, high-intensity focused ultrasound (HIFU) pulse trains can be frequency modulated to produce a radiation pressure having a similar form. In this study, 1.5-MHz HIFU pulse trains of 1-ms duration were applied to intact skulls of mice in vivo and resulted in blood-brain barrier disruption and immune responses (astrocyte reactivity and microglial activation). Analyses of variance indicated that 24 h after HIFU exposure, staining density for glial fibrillary acidic protein was elevated in the parietal and temporal regions of the cerebral cortex, corpus callosum and hippocampus, and staining density for the microglial marker, ionized calcium binding adaptor molecule, was elevated 2 and 24 h after exposure in the corpus callosum and hippocampus (all statistical test results, p < 0.05). HIFU shows promise for the study of some bio-effect aspects of blast-related, non-impact mild traumatic brain injuries in animals.