Guillaume Bouchoux

Validation of an acoustic cavitation dose with hydroxyl radical production generated by inertial cavitation in pulsed mode: application to in vitro drug release from liposomes.

The purpose of this study was to define and validate an inertial cavitation dose (CD) based on the detection of broadband noise, designed to monitor ultrasound-mediated drug release from liposomes. The validation consists of using the terephthalate dosimeter to quantify by fluorescence measurements the extent of hydroxyl radical (()OH) production during inertial cavitation. Sonication of samples was performed using tone bursts (pulse repetition frequency (PRF): 10 Hz(-1) kHz, duty cycle (dc): 5-25%, Isppa: 4100-12,200 W/cm(2)) generated by a 1 MHz focused transducer. Three sets of ultrasound parameters with different PRF and dc were selected to be more precisely compared. Results demonstrated an excellent correlation between *OH radical production and CD for each set of parameters, but significant differences in hydroxyl radical levels were observed among the sets of parameters. The results were compared with other studies, and the same tendency of variation with pulse duration was demonstrated. Results also showed that the CD was not distorted by peak intensity variations and was a much more reliable indicator than sonication time. Consequently, one validated parameter was selected to monitor drug release from two liposome formulations, and compare their ultrasound sensitivity.

Dual-mode transducers for ultrasound imaging and thermal therapy

Medical imaging is a vital component of high intensity focused ultrasound (HIFU) therapy, which is gaining clinical acceptance for tissue ablation and cancer therapy. Imaging is necessary to plan and guide the application of therapeutic ultrasound, and to monitor the effects it induces in tissue. Because they can transmit high intensity continuous wave ultrasound for treatment and pulsed ultrasound for imaging, dual-mode transducers aim to improve the guidance and monitoring stages. Their primary advantage is implicit registration between the imaging and treatment axes, and so they can help ensure before treatment that the therapeutic beam is correctly aligned with the planned treatment volume. During treatment, imaging signals can be processed in real-time to assess acoustic properties of the tissue that are related to thermal ablation. Piezocomposite materials are favorable for dual-mode transducers because of their improved bandwidth, which in turn improves imaging performance while maintaining high efficiency for treatment. Here we present our experiences with three dual-mode transducers for interstitial applications. The first was an 11-MHz monoelement designed for use in the bile duct. It had a 25x7.5 mm(2) aperture that was cylindrically focused to 10mm. The applicator motion was step-wise rotational for imaging and therapy over a 360 degrees, or smaller, sector. The second transducer had 5-elements, each measuring 3.0x3.8 mm(2) for a total aperture of 3.0x20 mm(2). It operated at 5.6 MHz, was cylindrically focused to 14 mm, and was integrated with a servo-controlled oscillating probe designed for sector imaging and directive therapy in the liver. The last transducer was a 5-MHz, 64-element linear array designed for beam-formed imaging and therapy. The aperture was 3.0x18 mm(2) with a pitch of 0.280 mm. Characterization results included conversion efficiencies above 50%, pulse-echo bandwidths above 50%, surface intensities up to 30 W/cm(2), and axial imaging resolutions to 0.2 mm. The second transducer was evaluated in vivo using porcine liver, where coagulation necrosis was induced up to a depth of 20 mm in 120 s. B-mode and M-mode images displayed a hypoechoic region that agreed well with lesion depth observed by gross histology. These feasibility studies demonstrate that the dual-mode transducers had imaging performance that was sufficient to aid the guidance and monitoring of treatment, and could sustain high intensities to induce coagulation necrosis in vivo.

In Vivo Evaluation of a Mechanically Oscillating Dual-Mode Applicator for Ultrasound Imaging and Thermal Ablation

Unresectable liver tumors are often treated with interstitial probes that modify tissue temperature, and efficacious treatment relies on image guidance for tissue targeting and assessment. Here, we report the in vivo evaluation of an interstitial applicator with a mechanically oscillating five-element dual-mode transducer. After thoroughly characterizing the transducer, tissue response to high-intensity ultrasound was numerically calculated to select parameters for experimentation in vivo. Using perfused porcine liver, B-mode sector images were formed before and after a 120-s therapy period, and M-mode imaging monitored the therapy axis during therapy. The time-averaged transducer surface intensity was 21 or 27 W/cm2. Electroacoustic conversion efficiency was maximally 72 ± 3% and impulse response length was 295 ± 1.0 ns at -6 dB. The depth of thermal damage measured by gross histology ranged from 10 to 25 mm for 13 insertion sites. For six sites, M-mode data exhibited a reduction in gray-scale intensity that was interpreted as the temporal variation of coagulation necrosis. Contrast ratio analysis indicated that the gray-scale intensity dropped by 7.8 ±3.3 dB, and estimated the final lesion depth to an accuracy of 2.3 ± 2.4 mm. This paper verified that the applicator could induce coagulation necrosis in perfused liver and demonstrated the feasibility of real-time monitoring.

Interstitial thermal ablation with a fast rotating dual-mode transducer

Interstitial ultrasound applicators can be a minimally invasive alternative for treating targets that are unresectable or are inaccessible by extracorporeal methods. Dualmode transducers for ultrasound imaging and therapy were developed to address the constraints of a miniaturized applicator and real-time treatment monitoring. We propose an original treatment strategy that combines ultrasound imaging and therapy using a dual-mode transducer rotating at 8 revolutions per second. Real-time B-mode imaging was interrupted to emit high-intensity ultrasound over a selected therapy aperture. A full 360° image was taken every 8th rotation to image the therapy aperture. Numerical simulations were performed to study the effect of rotation on tissue heating, and to study the effect of the treatment sequence on transducer temperature. With the time-averaged transducer surface intensity held at 12 W/ cm2 to maintain transducer temperature below 66°C, higher field intensities and deeper lesions were produced by narrower therapy apertures. A prototype system was built and tested using in vitro samples of porcine liver. Lesions up to 8 mm were produced using a time-averaged transducer surface intensity of 12 W/cm2 applied for a period of 240 s over a therapy aperture of 40°. Apparent strain imaging of the therapy aperture improved the contrast between treated and spared tissues, which could not be differentiated on B-mode images. With appropriate limits on the transducer output, real-time imaging and deep thermal ablation are feasible and sustainable using a rotating dual-mode transducer.

MONITORING AND FOLLOW UP OF HIFU LESIONS BY ULTRASOUND

Although it is possible to both measure temperature and monitor the damage caused by HIFU treatment sessions with magnetic resonance imaging, a number of studies have been carried out proposing an ultrasound solution. Conventional B-mode ultrasound seems to be valid, but cannot be applied to all organs, and the hyperechogenic areas often observed during HIFU treatments do not necessarily and exactly correspond to the thermal damage. The aim of this paper is to summarize recent work in this field. The various techniques have been divided into three main groups, characterizing the lesions by measuring the acoustic properties, mechanical properties or vascularization.

In vitro evaluation of an oscillating dual-mode ultrasound probe for sector imaging and directive therapy

Interstitial probes have been shown as effective devices to deliver high-intensity ultrasound therapy. Here, cylindrically-focused dual-mode transducers with either one or 5-elements were characterized, and a monoelement probe was evaluated in vitro. In therapy mode, the transducers were maximally efficient (≥70%) at 5.6 MHz with surface intensities up to 20 W/cm2. In imaging mode, fractional bandwidths were 46% and 50±4% (ave±std) for the monoelement and 5-element transducers respectively. Axial and lateral resolutions were 0.5 mm and 1.0 mm, respectively, for both transducers as measured with a point scatterer in the focal plane. After characterization, the oscillating probe was used to image and apply therapy to porcine liver. B-mode images over a 140° sector were formed before and after therapy, which was applied for 90 s at each of 5 angles separated by 20° (e.g. −40°, −20°, 0°, 20°, 40°) to form a composite lesion. Transducer surface intensity was 18 W/cm2. Therapy was interrupted at 125 ms intervals to collect pulse/echo data along the therapy axes. Data were displayed in real-time as an M-mode image to monitor therapy. B-mode images adequately represented the liver tissue. M-mode image data agreed well with the formation of lesions in the liver.

Two Treatment Strategies Using a Therapy / Imaging Rotating Transducer

Deep‐seated tumours can be treated by high intensity interstitial ultrasound using a miniature transducer brought in contact with the target. A dual mode transducer was designed for performing simultaneous imaging. Two therapeutic strategies are envisaged in this study. First, the transducer can be rotated step‐by‐step and therapy interrupted periodically for acquiring echo lines. In a second approach, fast rotation of the transducer allows 2D‐imaging and therapy is applied transiently over a small angular sector. Simultaneous imaging and therapy were performed in vitro with the designed transducer (2.5×7.5mm2, cylindrically focused at 10mm, 11MHz) following these two approaches. Up to 10mm deep lesions were obtained with the immobile transducer emitting an intensity of 17W/cm2 for 120s. M‐mode images were constructed on‐line during treatment. For the second strategy, the transducer rotated at a 7 rotations per second pace. Each turn, imaging was interrupted for ≈0.02s in order to perform therapy at insta...

Ultrasound interstitial applicators for thermal ablation in liver

Aggressive treatment of localized hepatic metastases, by surgery or other means, was proven to be a viable strategy for improving the prognoses of many patients. In that context, thermal ablation by high intensity ultrasound was proposed and used in clinics. However, for treating deep‐seated tumors and in most cases, radiofrequency and cryotherapy probes are applied interstitially. Interstitial ultrasound applicators were proposed as an intermediate solution. The treatment can be focused, deeper than with other physical agents, and the transducer can eventually both treat and image tissues. In our experience, two approaches were investigated: percutaneous and intratissular, or endo vascular. The active element was a miniature flat transducer operating at a frequency of 5 MHz, for a satisfactory tradeoff between beam penetration and energy absorption. In vivo trials on a porcine model demonstrated that both procedures are minimally invasive and that large thermal lesions, up to 20 mm deep, can be obtained....

Thrombolytic efficacy and cavitation activity of rt-PA echogenic liposomes versus Definity exposed to 120-kHz ultrasound

Echogenic liposomes can be used as a vector for co-encapsulation of the thrombolytic drug rt-PA and microbubbles. These agents can be acoustically activated for localized cavitation-enhanced drug delivery. The objective of our study was to characterize thrombolytic efficacy and sustained cavitation nucleation and activity from rt-PA-loaded echogenic liposomes (t-ELIP). A spectrophotometric method was used to determine the enzymatic activity of rt-PA released from t-ELIP and compared to unencapsulated rt-PA. The thrombolytic efficacy of t-ELIP, rt-PA alone, or rt-PA and the commercial contrast agent Definity® exposed to sub-megahertz ultrasound was determined in an in vitro flow model. Ultraharmonic (UH) emissions from stable cavitation were recorded during insonation. Both UH emissions and thrombolytic efficacy were significantly greater for rt-PA and Definity® over either rt-PA alone or t-ELIP with equivalent rt-PA loading. Furthermore, the enzymatic activity of t-ELIP was significantly lower than free r...

Combined effect of ultrasound and liposomal doxorubicin on AT2 Dunning tumor growth in rats: Preliminary results.

Previous in vitro studies conducted in our group have shown the feasibility of monitoring drug release from liposomes by an inertial acoustic cavitation index. We currently report in vivo experiments utilizing the cavitation index in combined treatment of AT2 Dunning tumor grafted rats with focused ultrasound and liposomal doxorubicin. Sixty‐three rats were allocated into seven groups: control, low level ultrasound treatment, high level ultrasound treatment, free doxorubicin+high level ultrasound treatment, and liposomal doxorubicin, liposomal doxorubicin+low level ultrasound treatment, and liposomal doxorubicin+high level ultrasound treatment. Based on pharmacokinetic studies, it was decided to apply ultrasound to the tumor 48 h after drug injection. An experimental setup was built to perform repeatable and rapid sonications of tumors monitored by the cavitation index. Tumor growth was assessed for a period of 35 days after tumor inoculation. Results showed that liposomal doxorubicin significantly slowed...