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.

Bloodless partial nephrectomy with a new high-intensity collimated ultrasonic coagulating applicator in the porcine model.

OBJECTIVES: To evaluate the long-term hemostatic efficacy of a new high-intensity collimated ultrasonic (HICU) applicator for open subhilar partial nephrectomy (PN) in the porcine model. METHODS: An applicator was designed with a planar 3.78-MHz HICU transducer and a reflector to optimize the delivery of acoustic energy to coagulate renal tissue. Six female pigs underwent right PN, followed at day 7 by left PN. The 6 pigs were killed on day 14. The treatment consisted of delivering HICU to a lower pole subhilar location, under a vascular clamp, then releasing the clamp, and cutting the kidney lower pole. The immediate and delayed hemostatic efficacy, treatment parameters, blood loss, complications, and renal function were evaluated at each surgical event and at necropsy. RESULTS: Perfect hemostasis was achieved with all 12 kidneys, with a mean treatment time of 7.2 minutes (range 5 to 9.2). The mean proportion of resected parenchyma was 21% (range 14% to 32%). No renal function impairment and no major complications were recorded. At necropsy, no secondary hematoma was observed, and three urinomas (25%) were found. CONCLUSIONS: Our HICU applicator has shown promising results during PN in the pig model with no other method of hemostasis. More studies are needed to refine our probe for laparoscopic surgery, improve its ergonomics, and extend our experiments to human laparoscopic nephron-sparing surgery.

Development of a compact self-focusing piezoelectric generator using electrical pre-strain piezocomposite material.

New clinical concepts in lithotripsy demand small shock heads. Reducing the size of piezoelectric shock heads will only be possible if the pressure generated at the surface of each transducer can be increased so that, the total pressure at the focus remains very high. So, we propose a new method allowing the generation of large surface pressures. It is well known that the piezoelectric rods in piezocomposite material are more fragile in the extension mode than in the compression mode. For this reason, actuators are mechanically pre-stressed between two flasks. This method cannot be used for transducers working at high frequencies, about 0.5 MHz. For this reason, we proposed to electrically pre-strain the piezoelectric material by applying high electric field in the opposite direction of the polarisation. In a first mode we proposed to pre-strain in continuous mode the transducer. Unfortunately we noticed a rapid de-poling and re-poling in the inverse direction. In a second mode to reduce depolarisation, this field was applied only during a short time just before the generation of the pulse which generate the compressive wave and in a third mode, the transducer was re-poled between two successive electrical pulses. Using this last method, it was possible to increase the maximum pressure at the surface of a 20 mm diameter plane piston to 20% and reach 4 MPa. According to this idea a very compact shock wave generator was designed. The generator made of a 1-3 piezocomposite material has a diameter of 120 mm and focused at 120 mm. The maximum pressure and the width of the compressive wave at the focus were, respectively, 60 MPa and 1.5 micros. The focal zone measured at -3 dB is an ellipsoid 6 mm high in the propagating axis and 3 mm width in the perpendicular direction. The efficacy of this generator was measured as the number of shocks necessary to totally disintegrate plaster balls 15 mm in diameter mimicking the kidney stones. At full power the number of shocks was only 150 which is rather the same number as the one obtained using electrohydraulic machine generally considered as the gold standard. This results show that piezoelectric material may be advantageously used for the manufacturing of shock wave generators.

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.

Electric current generated by ultrasonically induced Lorentz force in biological media.

The ions of solutions exposed to the propagation of ultrasound in the presence of a magnetic field experience Lorentz force. Their movement gives rise to a local electric current density, which is proportional to the electric conductivity of the medium. In vitro assessment of this current is performed using simple models of biological media. A constant magnetic field of 0.35 T and 500 kHz pulsed ultrasound are used. The sensing electrodes are exposed to neither the pressure wave nor the magnetic field, thus ensuring that the signal is not due to any undesirable electrode effect. The experimental results confirm that the current is proportional to the electrical conductivity of the medium. The changes in the measured current against the width of the measurement chamber show that the electrodes only collect a fraction of the current created within the medium. The magnitude of the measured current is 50nA in a saline solution of 0.5 S/m conductivity. The technique enabled the determination of the conductivity of a porcine blood sample against haematocrit. It is concluded that this type of measurement has the potential to allow the electrical conductivity of a medium to be determined using ultrasound.

Cylindrical thermal coagulation necrosis using an interstitial applicator with a plane ultrasonic transducer: in vitro and in vivo experiments versus computer simulations.

Extracorporeal HIFU techniques still cannot be used to treat tumours of the digestive tract, therefore an interstitial applicator has been developed to fill this gap. The object of the study was to validate the use of a plane ultrasonic transducer in an interstitial applicator to obtain large sector based or cylindrical coagulation necrosis. Two very different shot sequences were performed in vitro and in vivo and compared with numerical calculations. Each sequence consisted of 20 shots. After each shot the applicator was rotated through an angle of 18 degrees. Each shot in sequence 1 lasted 20 s, with a 2-min interval between shots which can be considered as independent. The second sequence involved coupling the shots so that each benefits from the heat deposited by the preceding ones. The first shot lasted 20 s to establish the lesion, then the duration of the subsequent 19 shots was 10 s to take into account the temperature rise due to preceding shots. In both cases, it was shown that cylindrical necrosis resulted in vivo and in vitro: 20 mm diameter and 8mm in height. The dimensions and the shapes of the necrosed volumes agreed with numerical predictions: the necrosed area induced by sequence 1 had a serrated border, whereas that of the second sequence was much more uniform. It was also shown that, for the two sequences, less than 20 s were necessary to coagulate the tissues in each direction. The results with sequence 2 showed that coupling the shots could be used to reduce treatment time without modifying the necrosed volume.

Generation of very high pressure pulses at the surface of a sandwiched piezoelectric material.

New clinical concepts in lithotripsy demand small shock heads. Reducing the size of piezoelectric shock heads will only be possible if the pressure generated at the surface of each transducer can be increased so that the total pressure at the focus remains very high. We propose for the first time to increase the pressure without increasing the transducer voltage by using sandwiched transducers, which are a combination of several stacked transducers. When excited at appropriate time intervals, the pressure waves generated by each one reinforce when they reach the load. This new technique has been successfully tested. A pressure of 2.5 MPa was generated with two stacked, 5 mm-thick 1-3 piezocomposite transducers operating at an excitation voltage of 8 kV. No transducer damage was detected after 10(6) shocks, which corresponds approximately to the treatment of 500 patients.

Experimental measurement of the acousto-electric interaction signal in saline solution.

Acoustic pressure alters local electrical conductivity in tissues and solutions. This work concerns the measurement of electrical conductivity in a liquid which is subjected to an acoustic pressure field created by a focused transducer. Measurements were made with four electrodes positioned in the ultrasonic focal zone, and the signal concerned is referred to as the acousto-electric interaction signal. A solution of sodium chloride in a measurement cell was subjected to ultrasound pressures of upto 1 MPa. It was shown that it is possible to quantitate the acousto-electric interaction signal once the ultrasonic vibration potential due to the Debye effect has been subtracted. The acousto-electric interaction signal was shown to be directly proportional to both the applied acoustic pressure and current. For the measurement cell used in this work, the interaction factor was found to be 5.3 microVmA(-1) MPa(-1).

Modeling of high-intensity focused ultrasound-induced lesions in the presence of cavitation bubbles

The classical "Bio Heat Transfer Equation (BHTE)" model is adapted to take into account the effects of oscillating microbubbles that occur naturally in the tissue during high-intensity focused ultrasound (HIFU) treatment. First, the Gilmore-Akulichev model is used to quantify the acoustic pressure scattered by microbubbles submitted to HIFU. Because this scattered pressure is not monochromatic, the concept of harmonic attenuation is introduced and a global attenuation coefficient is estimated for bubble-filled tissues. The first results show that this global attenuation coefficient varies significantly with respect to several parameters such as the frequency and the density of microbubbles in the medium, but also with respect to the incident acoustic pressure which thus becomes a transcendental function. Under these conditions, a layer-by-layer modeling, in the direction of propagation, is proposed to calculate the ultrasonic beam. Finally, the BHTE is solved and the HIFU-induced lesions are estimated by the calculation of the thermal dose. Using this model, it can be observed first that, when the firing power increases, the lesion develops clearly in the direction of the transducer, with a shape agreeing with in vivo experimentation. Next, it is observed that the lesion can be significantly modified in size and position, if an interface (skin or inner wall) is simulated as a zone with multiple cavitation nuclei. With a firing power increase, it is also shown how a secondary lesion can appear at the interface and how, beyond a certain threshold, this lesion develops at the main lesion expense. Finally, a better in-depth homogeneity of lesions is observed when the acoustic frequency of HIFU is increased.

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.

The feasibility of constructing a cylindrical array with a plane rotating beam for interstitial thermal surgery.

Thermal surgery has been shown to be a useful therapeutic option when external ultrasound applicators cannot be used as their beam will not reach the target site. If plane transducers are used, the ultrasound beam has to be rotated in order to generate a sufficiently large volume of necrosis. However, rotating deep-seated interstitial applicators and controlling their shooting direction presents major technical problems. The purpose of this study is to evaluate the feasibility of constructing a cylindrical array with a plane rotating beam for ablating esophageal tumors by interstitial hyperthermia. The feasibility of such an array has been initially evaluated using a plane array (which is easier to make from a technical point of view). This array was made with a new piezoelectric material because its mechanical properties make it ideal for the construction of a cylindrical array in the future. We showed that the beam of each array element is sufficiently divergent and that cross-coupling is small enough to generate a plane wave from a cylindrical array. In addition, power tests and electro-acoustic efficiency measurements demonstrated that the output was sufficient to induce tissue necrosis in the relevant conditions.

Quantitative assessment of ultrasound-induced resistance change in saline solution.

The purpose of the study was the experimental assessment of the interaction coefficient characterising the influence of pressure on the conductivity of electrolyte solutions. Pressure pulses were applied to samples of 9 gl-1 sodium chloride contained in cuboid measurement cells of identical cross-sectional dimensions but different thickness along the acoustic beam axis. The magnitude of the changes induced in cell resistance was recorded for three values of applied pressure increment (delta P = 0.94, 1.39 and 1.78 MPa) and three values of cell thickness (e = 0.58, 1.13 and 1.62 mm). A thick, focused transducer generated short (0.1 microsecond), unipolar pressure pulses. A model accounting for the characteristics of the pressure pulse and the geometry of the measurement cell was developed to predict the ultrasound-dependent changes in the measured electrical resistance. Despite some discrepancy between theoretical and experimental results, discussed in the paper, the results validated the order of magnitude of the interaction coefficient (10(-9) Pa-1). The predictions varied from about 50% (e = 1.62 mm, delta P = 0.94 MPa) to 77% (e = 0.58 mm, delta P = 1.78 MPa) of the experimental values.

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.

Theoretical comparison of two interstitial ultrasound applicators designed to induce cylindrical zones of tissue ablation.

Although interstitial techniques are invasive, they are still the first-line therapeutic modalities for certain types of tumour. They are mainly relevant to tumours that are either inoperable or located so deep that access is complicated. Of the various types of radiation that can be delivered by the interstitial route, ultrasound is the most suitable for deep heating. The study compares the efficacy of two types of applicator with respect to their ability to induce cylindrical zones of coagulation necrosis. The transducer of the first applicator is tubular, whereas the second is plane and can rotate around its axis. Both have an external diameter of 4 mm, are fitted with surface cooling systems and operate at 10.7 MHz and 14 W.cm-2. Comparison involves mathematical modelling of ablated tissue in the targeted area by resolving the bioheat transfer equation (BHTE) using an algorithm based on finite differences. The BHTE gives a temperature value from which the thermal dose can be determined. It is shown that tissue ablation by tubular transducers is slow, and, in consequence, perfusion disturbs the heating pattern: in vivo, irradiation with a tubular transducer lasting 1081 s would be required to ablate a tissue mass with a radius of 8 mm. The corresponding period using a rotating plane transducer with 20 firing angles is only 618 s. The mean exposure time of each shot lasts 31 +/- 7 s. Therefore perfusion would have much less impact in the case of therapy administered using a plane transducer than that using a tubular one.

A high-intensity US probe designed for intraductal tumor destruction: experimental results.

BACKGROUND: Many digestive tract tumors spread inside the lumen and are not amenable to curative surgical treatment. An intraluminal method of tumor destruction would be useful for palliative or even curative purposes. High-intensity ultrasound (US) is suitable for such purposes. Our objective was to perform experiments with animal models that would lead to development of a high-intensity US probe for intraductal tumor destruction suitable for insertion through a large-channel endoscope. METHODS: The active part of the high-intensity US applicator consisted of a water-cooled piezoceramic plane transducer (3 x 10 mm) operating at 5 MHz for deep or 10 MHz for shallow tissue penetration. A cylinder of tissue was destroyed by means of rotating the transducer on its axis through a flexible shaft. Experiments were conducted in vitro on livers of butchered pigs (10 lesions), in vivo on exteriorized pig livers (15 lesions), and on metastatic Dunning tumors (AT(2 ) subline) implanted subcutaneously in 28 rats (treated n = 16, controls n = 12). RESULTS: In experiments on pig livers, high-intensity US induced highly reproducible cylinders of coagulation necrosis (diameter 20 +/- 1 mm, height 8 +/- 1 mm) with sharply demarcated and serrated boundaries. The exposure duration to achieve such lesions was 5 minutes. Regions of coagulation necrosis obtained in vivo were similar in size and shape. All 12 control rats died or were killed because of diffuse cancer by day 15 after implantation; 64% of the treated rats were tumor free 30 days after treatment, and 36% had local recurrences. CONCLUSION: This high-intensity US probe induces highly reproducible cylinders of coagulation necrosis and is effective against tumors in animals.

New use of cyanosilane coupling agent for direct binding of antibodies to silica supports. Physicochemical characterization of molecularly bioengineered layers.

A simple protocol to fix biological species to silica-based surfaces (silica microbeads and glass slides), using a bifunctional silane reagent (3-cyanopropyl dimethyl chlorosilane), is presented. This silane reagent was used without further derivatization. This system led to strong, but not covalent, linkage of antibodies through their glycosylated regions (OH groups) to solid supports. The use of a microsized sample revealed that the coupling process depends not only on physicochemical interactions but also on steric phenomena, and in this case, it was shown that a molecule acting as a spacer was required for more efficient cell fixation. Here, monoclonal mouse antibodies against the CD45 molecule expressed on rat lymphocytes (MAR anti CD45 Ab) were linked to lymphocytes, and as spacers, sheep anti-mouse antibodies (SAM Ab) were immobilized on silica surfaces, allowing the cells to stick to the floating hollow silica microbeads by simple incubation. Under such conditions, a single microbead can fix several cells. The potential of this hollow, low-density support is in ultrasound applications, for the destruction by cavitation phenomena of cells selectively fixed onto such a support. Such a study can serve as a basic model for various microbiosystems involving cell manipulation.

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.

Design and in vitro results of a high intensity ultrasound interstitial applicator.

Interstitial technologies were proposed for the treatment of deep-seated and unresectable tumours. This study was designed to demonstrate the possibility of producing coagulation necrosis for a short exposure duration (20s) and a large volume with an interstitial ultrasonic applicator equipped with a plane transducer. The applicator was evaluated in terms of electroacoustic efficiency (58% at 10.7 MHz), temperature pattern and in vitro pig liver tissues destruction. The temperature elevation reached 52, 39, 22 and 15 degrees C at, respectively, 2.5, 7.5 and 10 mm from the applicator surface along the propagation axis. The evident cigar-shaped lesions spread on a depth of (8 +/- 2) mm from the surface applicator, (10 +/- 1) mm high and (3 +/- 1) mm high and (3 +/- 1) mm wide. The temperature measurements showed the limitations encountered with a 10 MHz transducer. The high increase in temperature of tissues close to the transducer can induce vaporisation and a gaseous barrier opaque to ultrasound. Owing to the shape and the operating frequency of the transducer, we hope to obtain the same satisfactory performances in vivo with weakly perfusion-dependent lesions. Axial and longitudinal applicator motions will enable us to treat more important volumes.