Morphological analysis of the interstitial ultrasonic ablation in porcine liver in vivo.

BACKGROUND: The shape of the induced thermal ablation area is as important as its dimension. The aim of this study was to analyze the size reproducibility and the aspect of the interstitial ultrasonic ablation obtained by a planar transducer in porcine liver in vivo. METHODS: Five pigs were used. Two complete ultrasonic lesions were made in each animal under pedicle clamping. All the lesions underwent MR examination on day 7 and then a histological analysis. RESULTS: The tested probe has the advantage of providing a step-by-step and highly directional treatment in the target zone. The ultrasonic lesions presented as well-defined and homogenous areas of tissue coagulation. The lesion volumes ranged from 8.1 to 92.3 cm3 with an averaged lesion length of 56 mm at gross examination. Three-dimensional reconstruction of the lesions from the MR images showed cylindrical and conical shapes. Large intrahepatic vessels distorted the lesion shape, and the vicinity of the application to the liver surface increased significantly the volume of the ultrasonic necrosis. Histological examination showed complete necrosis in the area of damage. CONCLUSION: The ultrasonic ablation has a regular shape, always with sharply defined borders. However, it showed some variability in the size of the induced lesions.

64-element intraluminal ultrasound cylindrical phased array for transesophageal thermal ablation under fast MR temperature mapping: an ex vivo study.

This work was undertaken to investigate the feasibility of using a cylindrical phased array for transoesophaeal thermal ablation under magnetic resonance (MR) imaging guidance. Sixty-four transducers (0.45 mm wide by 15 mm tall), operating at 4.6 MHz, were spread around the periphery of a 10.6-mm-diam cylinder. The head of the applicator was covered with a 65-microm thick latex balloon attached using watertight seals. This envelope was inflated with degassed water to provide acoustic coupling between the transducer and the tissues. The underlying operating principle of this applicator is to rotate a plane ultrasound beam electronically. For this purpose, eight adjacent transducers were excited with appropriate delay times so as to generate a plane wave. The exposure direction was changed by exciting a different set of eight elements. Ex vivo experiments conducted on 47 samples of pig liver under MR temperature monitoring demonstrated the ability of this applicator to generate cylindrical or sector-based coagulation necroses at depths up to 19 mm with excellent angular precision by applying 20 W/cm2. MR thermometry was performed in "real-time" with segmented echo-planar imaging gradient echo sequences. The temporal resolution was approximately 3 s/ image. The average value for the temperature baseline in liver tissue close to the applicator was 0.3 degrees C (+/- 0.6 degrees C). The thermal dose delivered in tissues was computed on-line during temperature imaging. Excellent MR compatibility was demonstrated, all MR acquisitions were performed without susceptibility artifacts or radio-frequency interferences with the ultrasound device. Thermal lesions identified on post-treatment follow up showed good correlation with online MR thermometry data. The individual differences between measurements performed visually and using MRI thermal dose maps were about 11% of volume. This study demonstrated the feasibility of thermal ablation using a phased array intraluminal ultrasound applicator and on-line MR monitoring.

Cytotoxic effects of acoustic cavitation on HT-29 cells and a rat peritoneal carcinomatosis in vitro.

Damage to cells and tissues exposed to shock waves (SWs) is thought to be secondary to cavitation phenomena involving the collapse of gas bubbles in a fluid. Using HT-29 cells and DHDK12PROb tumors, we tried to enhance SW-related damage by the simultaneous administration of gas microbubbles. Bubbles resulted from a mixture of air and gelatin (HT-29 cells) or from a carbonated NaCl solution (tumors). HT-29 cells in suspension received either SW (50, 250, or 1000 SWs) alone or in association with bubbles. Trypan blue-negative cells decreased as the number of SWs increased. Exposure to SWs and bubbles resulted in not only an increased but also a delayed mortality as compared to SWs only. One thousand SWs with bubbles induced a complete inhibition of cell growth, with cytoplasmic vacuolae, ruptured membranes, and abnormal nuclear shape and chromatin. Exponential and confluent cells exhibited a similar mortality and growth. DHDK12PROb tumors received either SWs only (50, 100, 250, 500, or 1000 SWs) or SWs with bubbles in vitro. Thymidine incorporation was significantly lower after exposure to SWs with bubbles as compared with controls and SWs only; it was nil by 1000 SWs with bubbles. Histopathological features of tumors exposed to SWs with bubbles included erosion and hemorrhage, disorganized structure, pyknotic nuclei, and cytoplasmic vacuolae. We conclude that cavitation, as produced by a combination of SWs and gas microbubbles, can achieve bioeffects which are relevant to cancer therapy.

Thromboresistance of bulk heparinized catheters in human.

Bulk heparinized catheters (1 mm internal diameter) containing 10% heparin ionically bound, were tested in four human volunteers. Catheters containing 0% and 10% heparin were compared in each individual using ultrasound microflow velocimetry, permeability test, sequential determinations of activated partial thromboplastin time, heparin levels and generation of Fibrinopeptide A, beta thromboglobulin and Platelet factor 4. Although the release of heparin expressed by its anti-IIa activity is of similar range in the four individuals the release of anti-Xa activity is variable and generally of greater magnitude, suggesting a privileged migration of low molecular weight components of heparin. These antiproteasic activities of heparin are sufficient to inhibit fibrin formation and blood coagulation despite their relative inability to prevent platelet activation.

Intraluminal ultrasound applicator compatible with magnetic resonance imaging "real-time" temperature mapping for the treatment of oesophageal tumours: an ex vivo study.

High intensity ultrasound has shown considerable ability to produce precise and deep thermal coagulation necrosis. Focused, cylindrical, spherical or plane transducers have been used to induce high temperatures in tissues to coagulate proteins and kill cells. Recently magnetic resonance imaging (MRI) has been used, with extracorporeal or intracavitary focused transducers and cylindrical interstitial applicators, to monitor temperature distribution and provide feedback during heating procedures. If intraluminal applicators are used, the active part is in contact with the region of interest and it is essential to provide an accurate view of heat deposition and the extent of coagulation necrosis close to the transducer. The purpose of this study was to develop a 10 mm diameter intraluminal ultrasound applicator, designed to treat oesophageal cancers and compatible with MRI "real-time" temperature mapping. The active part of the ultrasound applicator, covered by a latex balloon, is a 15 X 8 mm2 plane transducer, which is in contact with the tumours during treatment. Each ultrasound exposure generates coagulation necrosis, in an area with the approximate shape of a rectangular parallelepiped up to 10 mm deep. When the exposures were repeated by rotating the applicator on its axis, sector-based or cylindrical volumes of necrosis could be produced, matching the shape of oesophageal cancers. Ex vivo trials were performed to demonstrate the applicator's compatibility with a clinical MRI scanner (1.5 T). MRI signals were acquired without any magnetic susceptibility distortion, even close to the applicator. Fast (0.72 images per second) 2D temperature mapping was performed during ultrasound exposure, using temperature-related proton resonance frequency shift at a resolution of 0.5 degrees C. Coagulation necrosis viewed with inversion recovery sequences, were in good agreement with the qualitative macroscopic observations made for the few cases tested in this study.

Influence of water conductivity on the efficiency and the reproducibility of electrohydraulic shock wave generation.

In an electrohydraulic generator, two underwater metal electrodes are connected with a capacitor charged to a high voltage. When the circuit is switched on, a plasma is generated reaching temperatures of thousands of K, resulting in a compressive pressure pulse. The formation of the plasma is a nonreproducible phenomenon inducing great variations of the pressure pulse. When the electrodes are immersed in an electrolyte instead of degassed water, the conditions of electrical discharge are dramatically modified. The latency time and the amplitude of the oscillations of the discharge current decrease as the conductivity of the electrolyte increases. For a conductivity of 7 omega.cm, there is no latency, and the critically damped discharge is achieved. The expanding pressure wave is increased by 10%, and the mean peak pressure value over 120 shocks at the second focus after focalization is increased by 50%. The relative standard deviation of the pressure value at the second focus is only 5%, while it is about 30% in ordinary water. The fragmentation efficiency is considerably increased because total fragmentation is obtained in 220 shocks instead of 450 shocks in ordinary water when standard stones are used, and in 131 shocks instead of 304 shocks when gallstones are used. Last, we show that the wear of the electrodes is reduced by a factor 8 when electrolyte is used. The improvement is supposed to have two causes: First, the energy is delivered into the medium in a shorter time, and, second, the center of the shock wave is always located at the same place. The decreased wear should make it possible to treat a much greater number of patients without changing electrodes, and the enhancement of the pressure should increase the efficiency of the fragmentation of the gallstones without aggravating the patient's pain.

Noninvasive aortic blood flow measurement using an intraesophageal probe.

The continuous measurement of cardiac output by the thermodilution technique is invasive, impractical and unpleasant for the patient. This paper describes the measurement of aortic blood flow with a specially designed intraesophageal echo Doppler probe. An A-scan unit allows the measurement of the diameter of the thoracic aorta and a continuous wave Doppler velocimeter is used for measurement of instantaneous blood flow velocity. In vitro experimental results as well as clinical studies are presented.

Volume measurement by ultrasonic transverse or sagittal cross-sectional scanning.

A technique is described that provides an accurate estimation of the volume of an organ from its ultrasonic cross-sectional images. The technique is applied to two types of ultrasonic investigation, one providing transverse and the other sagittal images. The organ outline has to be traced on each scan. The computer first calculates the area and then the volume from the vector areas and the centroids of a series of sections. The technique has been tested with phantoms of various shapes and volumes made with agar gel. These experiments show that the error in the volume estimation is less than 10% and the variability of measurements is less than 2%.

Ultrasound-induced tissue ablation: studies on isolated, perfused porcine liver.

Minimally invasive methods for the treatment of cancers, such as high-intensity focused ultrasound (HIFU) and high-energy shock waves (SW), have been proposed recently. Their feasibility for treatment of human cancer needs to be confirmed. A simplified model of isolated perfused pig liver that is close to the human liver in vivo has been proposed. The objective was to study the feasibility of deep focused tissue ablation with HIFU and SW in large organs approaching the size of the human liver. The model was demonstrated to be physiologically valid during the first 2 h of anoxic perfusion with a composite saline solution; arterial and portal pressure, enzymes, urea levels and bile secretion remained stable. It can simulate the major effects of perfusion and physical phenomena that occur in vivo during treatment. Histological analysis revealed no major changes. Previous results obtained in vivo in animal models at a depth of 2-3 cm were successfully reproduced and deeper lesion arrays at 4, 6, 8 and 9 cm from the surface were produced using the same principles. The depth of 9 cm from the liver surface is consistent with an extracorporeal treatment of most of the liver segments in man. Other applications of the model are proposed, particularly for the study of the role of interferences such as ribs and intestinal gas, blood perfusion and respiratory movements.

Electronic beam steering of shock waves.

Shock-wave generators are now currently used for the treatment of renal stones. In all these generators the focal zone is determined by their geometrical parameters. We propose, for the first time, a piezocomposite shock-wave generator with electronic focusing. The system is composed of a two-dimensional array and its electronic hardware. The array is composed of 121 independent piezocomposite transducers arranged in a spherical shell 20 cm in diameter and focused at 190 mm. The electronic hardware includes 121 x 6 kV-impulse generators. The interdelay of each channel can be adjusted between 10 ns to 100 microseconds by steps of 10 ns. The results show: the use of composite material is possible for the generation of high amplitude pressure waves; the pressure-voltage relationship is linear up to a pressure of about 28 x 10(5) Pa at the transducer front face; the material can be used for a long period of time; i.e., after one million shocks, no decrease in sensitivity, no alteration in its electrical behaviour and no time wave form distortion were observed. Electronic focusing is efficient in an ellipsoidal region of about 4 cm in diameter and 6 cm in length. The pressure in the focal zone is about 600 x 10(5) Pa.

A novel method to control P+/P- ratio of the shock wave pulses used in the extracorporeal piezoelectric lithotripsy (EPL).

There is growing evidence that acoustic cavitation plays an important role in stone fragmentation during extracorporeal shock wave lithotripsy (ESL) treatment. In addition, side effects of the treatment, such as the hemorrhage and destruction of the tissue in the vicinity of the stone are also ascribed to cavitation phenomenon. Since cavitation is associated with the maximum negative pressure in the shock pulse, it would thus appear that possibility of controlling this pressure would be desirable in ESL applications. This paper describes a novel technique developed to control the ratio of compressional peak (P+) to rarefactional peak pressure (P-) of the shock wave for use in lithotripsy treatment. The procedure is based on the finite amplitude wave generation by focused piezoelectric transducers and subsequent interaction of the shocked waves in the common focal region. The highly asymmetrical shock wave is produced in the focal region by providing an appropriate time delay to each of the high voltage electrical excitation signals which drive the transducers. The degree of relative reduction of negative halfcycles and the corresponding positive halfcycles amplification increases with the number of the acoustic sources used. The practical implementation of the shock wave generator was obtained by using 5 cm diameter, focused 1 MHz transmitter, and additional transducers of identical construction having frequencies corresponding to the harmonics and subharmonics of the 1 MHz frequency. The importance of the results for the future development of lithotripters, and stone treatment efficiency is pointed out.

Assessment of a potentially noninvasive method for monitoring aortic blood flow in children.

Ultrasonic methods have rendered possible noninvasive quantitative blood flow measurement. In this work, a method is proposed to measure aortic blood flow in children by means of a specially designed miniaturized esophageal probe and an autonomous apparatus combining an M-mode imaging system and a pulsed Doppler. In vivo experimental results in animals are presented and demonstrate the interest of simultaneous and continuous measurement of aortic diameter and blood flow velocity giving accurate measurements. A 0.94 correlation coefficient is found when comparing blood flow in the descending aorta measured using this method and using an electromagnetic flowmeter.

On the spectral properties of Doppler thread phantoms.

It is shown that some of the threads used in Doppler phantoms have a repetitive structure which leads to peaks in the angular distribution of the backscattered power at beam axis-to-flow angles of theta = 90 degrees and approximately theta = 70 degrees. This nonuniform scattering does not significantly interfere with modelling the Doppler spectrum peak as a function of velocity and beam-to-thread angle, but makes it impossible to model the spectral width as a function of these parameters. A new plaited structure is described which has a periodicity too small to lead to subsidiary reflection peaks, and which has a more uniform backscattering profile than the other threads studied.

A piezocomposite shock wave generator with electronic focusing capability: application for producing cavitation-induced lesions in rabbit liver.

In this work, a piezocomposite shock wave generator with electronic focusing capability is presented. The system is composed of a bidimensional array and its electronic hardware. The array is composed of 274 independent piezocomposite transducers arranged in a spherical shell of 280 mm in diameter and focused at 190 mm from its surface. The electronic hardware includes 274 x 6.6 kV distinct impulse generators. For the purpose of performing the electronic steering of shock waves, the delay time of each channel can be adjusted from 100 ns to 100 microseconds in steps of 100 ns. In order to enhance the effect of cavitation at the focus for the purpose of tissue destruction, the pressure-time waveform starts with a half cycle of negative pressure with a peak amplitude of about -150 x 10(5) Pa, followed by a very steep shock front with a positive peak pressure > 1000 x 10(5) Pa and a rise time of about 10 ns. Using this generator, the cavitation-induced lesions in rabbit liver were studied. To obtain a predefined lesion volume, two methods of scanning were used: mechanical and electronic. Comparison of the lesions obtained by these two methods shows that they have identical macroscopic and histological characteristics, which justify the feasibility of electronic beam steering of shock waves in tissue destruction applications.

Development of an interstitial ultrasound applicator for endoscopic procedures: animal experimentation.

Biliary cancer is very difficult to treat, mainly because of the advanced stage at which such tumours are detected and the low efficacy of systemic therapeutic modalities like radiotherapy. Palliative measures designed to clear the duct (either by means of surgery or an endoscopic procedure) are presently performed. A relatively noninvasive alternative could be developed to fill this gap in the therapeutic arsenal. To this end, we have designed an interstitial ultrasound (US) applicator suitable for use with a digestive endoscope. This applicator is based on a water-cooled plane transducer that operates at 10 MHz. Although, because the target zone is cylindrical in shape, it might have seemed more logical to use a cylindrical transducer. Nevertheless, a plane transducer was chosen because the pressure field from this kind of emitter decreases less quickly, which means faster and deeper heating. However, to generate coagulation necrosis all around the duct, the applicator has to be rotated around its axis; this is achieved by means of a flexible metallic shaft (2 m in length and 3. 8 mm in diameter) that joins the device's active head (which contains the transducer) to the casing with all the connectors. A holder is fixed at the endoscope channel inlet; it controls the rotation of the applicator. Trials were conducted on pigs. The duodenoscope was introduced via the oesophagus down through the duodenum as far as the hepatopancreatic ampulla. Using a guide wire, the applicator was navigated into the duct via the endoscope instrument channel. Well defined, reproducible volumes of coagulation necrosis with a diameter of 20 mm were generated in the biliary tissue and the liver. These promising results indicate that this kind of endoscopic US delivery system may represent an effective tool for the treatment of biliary tumours in humans. An Independent Ethics Committee recently approved preliminary clinical trials of this applicator.

Venous thrombosis generation by means of high-intensity focused ultrasound.

Sclerotherapy of superficial varicose veins is now performed with chemical agents since physical agents have given only poor clinical results. We investigated the possibility of using high intensity focused ultrasound energy to achieve this goal in an animal model, the rat femoral vein. A specially designed probe delivering ultrasonic energy at a central frequency of 7.31 MHz was constructed and evaluated. Femoral veins of six rats were surgically exposed to a set of between four and seven 3-s exposures at 1-mm increments at a power level of 167 W/cm2. At 2 days following the irradiation, control veins were patent while occlusive thrombus was documented by Doppler flow and histological studies in all six of the irradiated veins. No damage to the surrounding soft tissues was noted. We concluded that high-intensity focused ultrasound can be used to induce thrombosis in this animal model.

Design and preliminary results of an ultrasound applicator for interstitial thermal coagulation.

The extracorporeal high-intensity focused ultrasound (HIFU) techniques are not still transposable for tumors of the digestive tract because of their locations. This study was designed to evaluate the feasibility of interstitial applicators (3.8 mm O.D.) to comply with this therapeutic lack and to demonstrate the possibility of producing coagulation necrosis by a specially designed probe and with a short exposure time (20 s). The active surface of the applicators consists of plane water-cooled PZT transducers working at 10 or 5 MHz. They were evaluated in terms of acoustic power emitted as a function of the frequency, and applied electrical input (electroacoustic efficiency of 75% at their working frequency) and in vitro and in vivo pig liver tissue destruction. The in vitro and in vivo necroses depth from the applicator surface ranged from 8 to 20 mm. This showed the advantage of a nondivergent source: the pressure decay is only due to the tissue absorption in the Fresnel zone. The lesions dimensions are slightly dependent on perfusion: 8 +/- 2 mm deep in vitro for a 10.7-MHz transducer working at 14 W/cm2 against 10 mm in vivo. Operating at 5 MHz makes it possible to increase the therapeutic heating depth. For example, at a similar close-to-transducer temperature, the 5-MHz applicator induced, at a depth of 10 mm, a temperature elevation of 27 degrees C against 15 degrees C for that working at 10 MHz.

Characterization of extracorporeal ablation of normal and tumor-bearing liver tissue by high intensity focused ultrasound.

Treatment parameters of extracorporeal high intensity focused ultrasound (HIFU) were analysed in normal and tumor-bearing rabbit liver. HIFU was generated with a 1 MHz transducer and energy was provided by a 7.5 kW power amplifier. In vivo experiments were conducted on 74 New Zealand rabbits. Normal rabbits and rabbits bearing an intrahepatic VX2 tumor were used. In group 1, spatial peak temporal peak (SPTP) intensities ranging from 1470 to 5500 W cm-2 and exposure times from 0.5 to 5 s were tested at a constant depth in the liver; in group 2, the output power was adjusted as a function of the target depth in order to keep constant the focal in situ intensity in the liver; in group 3 (liver tumors), the focal in situ intensity was 1365 W cm-2 in eight rabbits and 500 W cm-2 in nine. In groups 1, 2 and 3, rabbits were sacrificed 48 h after the treatment. Groups 4 and 5 were designated for analysis of the lesion in the normal liver 4 weeks after treatment at 1000 W cm-2 and 3000 W cm-2 SPTP intensities, respectively. In normal rabbits, the lesion volume increased with exposure time at constant intensity; there was a negative correlation between intensity and exposure time (group 1). When the output power was adjusted as a function of the path length, the lesion size was nearly constant (group 2). In VX2 rabbits, tumor destruction rates were significantly higher in rabbits treated at 500 W cm-2 than in rabbits treated at 1365 W cm-2 (p < 0.05; group 3). As in the normal liver, the lesion volume increased with the exposure time at constant intensity. HIFU lesions treated at 1000 w cm-2 (SPTP) healed as thin fibrous scars, and no severe complication occurred (group 4); at 3000 W cm-2 (SPTP), scars were larger and perforation of a neighbouring organ was seen in 7 of 11 rabbits (group 5).

New piezoelectric transducers for therapeutic ultrasound.

Therapeutic ultrasound (US) has been of increasing interest during the past few years. However, the development of this technique depends on the availability of high-performance transducers. These transducers have to be optimised for focusing and steering high-power ultrasonic energy within the target volume. Recently developed high-power 1-3 piezocomposite materials bring to therapeutic US the exceptional electroacoustical properties of piezocomposite technology: these are high efficiency, large bandwidth, predictable beam pattern, more flexibility in terms of shaping and definition of sampling in annular arrays, linear arrays or matrix arrays. The construction and evaluation of several prototypes illustrates the benefit of this new approach that opens the way to further progress in therapeutic US.

Prostatic tissue destruction by high-intensity focused ultrasound: experimentation on canine prostate.

High-intensity focused ultrasound (HIFU) has been used transrectally to induce intraprostatic coagulation necrosis lesion in the canine prostate. The device combines a firing system (power amplifier and therapy transducer) and a localization system (ultrasound scanner). Thirty-seven dogs have been treated with ultrasound intensity ranging from 720 W/cm2 to 2300 W/cm2 and shot durations ranging from 1 to 4 seconds. The threshold for focal ultrasonic lesions was determined to be 1000 W/cm2 with a 1-second shot duration. Intraprostatic lesions were obtained without any damage to the rectal wall. These lesions were homogeneous coagulation necroses and progressed first to an inflammatory fibrosis and then to sclerosis with cavity formation. Intraprostatic lesions also occurred with a combination of moderate acoustic intensity (720 W/cm2) and longer shot duration (4 seconds). The temperature reached at the focal point of the transducer was 85 degrees C. The study confirms the possibility of creating irreversible lesions in the prostatic tissue through the rectal wall. The destruction of localized prostatic cancer seems to be possible in the near future using HIFU delivered by the transrectal route.