Delivering Focused Ultrasound to Intervertebral Discs Using Time-Reversal.

Chronic low back pain causes more disability worldwide than any other condition and is thought to arise in part through loss of biomechanical function of degenerate intervertebral discs (IVDs). Current treatments can involve replacing part or all of the degenerate IVDs by invasive surgery. Our vision is to develop a minimally invasive approach in which high intensity focused ultrasound (HIFU) is used to mechanically fractionate degenerate tissue in an IVD; a fine needle is then used to first remove the fractionated tissue and then inject a biomaterial able to restore normal physiologic function. The goal of this manuscript is to demonstrate the feasibility of trans-spinal HIFU delivery using simulations of 3-D ultrasound propagation in models derived from patient computed tomography (CT) scans. The CT data were segmented into bone, fat and other soft tissue for three patients. Ultrasound arrays were placed around the waist of each patient model, and time-reversal was used to determine the source signals necessary to create a focus in the center of the disc. The simulations showed that for 0.5 MHz ultrasound, a focus could be created in most of the lumbar IVDs, with the pressure focal gain ranging from 3.2-13.7. In conclusion, it is shown that with patient-specific planning, focusing ultrasound into an IVD is possible in the majority of patients despite the complex acoustic path introduced by the bony structures of the spine.

Nonlinear acoustic properties of ex vivo bovine liver and the effects of temperature and denaturation.

Thermal ablation by high intensity focused ultrasound (HIFU) has a great potential for the non-invasive treatment of solid tumours. Due to the high pressure amplitudes involved, nonlinear acoustic effects must be understood and the relevant medium property is the parameter of nonlinearity B/A. Here, B/A was measured in ex vivo bovine liver, over a heating/cooling cycle replicating temperatures reached during HIFU ablation, adapting a finite amplitude insertion technique, which also allowed for measurement of sound-speed and attenuation. The method measures the nonlinear progression of a plane wave through liver and B/A was chosen so that numerical simulations matched the measured waveforms. To create plane-wave conditions, sinusoidal bursts were transmitted by a 100 mm diameter 1.125 MHz unfocused transducer and measured using a 15 mm diameter 2.25 MHz broadband transducer in the near field. Attenuation and sound-speed were calculated using a reflected pulse from the smaller transducer using the larger transducer as the reflecting interface. Results showed that attenuation initially decreased with heating then increased after denaturation, the sound-speed initially increased with temperature and then decreased, and B/A showed an increase with temperature but no significant post-heating change. The B/A data disagree with other reports that show a significant change and we suggest that any nonlinear enhancement in the received ultrasound signal post-treatment is likely due to acoustic cavitation rather than changes in tissue nonlinearity.

Real-time temperature estimation and monitoring of HIFU ablation through a combined modeling and passive acoustic mapping approach.

Passive acoustic mapping (PAM) has been recently demonstrated as a method of monitoring focused ultrasound therapy by reconstructing the emissions created by inertially cavitating bubbles (Jensen et al 2012 Radiology 262 252-61). The published method sums energy emitted by cavitation from the focal region within the tissue and uses a threshold to determine when sufficient energy has been delivered for ablation. The present work builds on this approach to provide a high-intensity focused ultrasound (HIFU) treatment monitoring software that displays both real-time temperature maps and a prediction of the ablated tissue region. This is achieved by determining heat deposition from two sources: (i) acoustic absorption of the primary HIFU beam which is calculated via a nonlinear model, and (ii) absorption of energy from bubble acoustic emissions which is estimated from measurements. The two sources of heat are used as inputs to the bioheat equation that gives an estimate of the temperature of the tissue as well as estimates of tissue ablation. The method has been applied to ex vivo ox liver samples and the estimated temperature is compared to the measured temperature and shows good agreement, capturing the effect of cavitation-enhanced heating on temperature evolution. In conclusion, it is demonstrated that by using PAM and predictions of heating it is possible to produce an evolving estimate of cell death during exposure in order to guide treatment for monitoring ablative HIFU therapy.

In vivo quantification of lead in bone with a portable x-ray fluorescence system--methodology and feasibility.

This study was conducted to investigate the methodology and feasibility of developing a portable x-ray fluorescence (XRF) technology to quantify lead (Pb) in bone in vivo. A portable XRF device was set up and optimal settings of voltage, current, and filter combination for bone lead quantification were selected to achieve the lowest detection limit. The minimum radiation dose delivered to the subject was calculated by Monte Carlo simulations. An ultrasound device was used to measure soft tissue thickness to account for signal attenuation, and an alternative method to obtain soft tissue thickness from the XRF spectrum was developed and shown to be equivalent to the ultrasound measurements (intraclass correlation coefficient, ICC = 0.82). We tested the correlation of in vivo bone lead concentrations between the standard KXRF technology and the portable XRF technology. There was a significant correlation between the bone lead concentrations obtained from the standard KXRF technology and those obtained from the portable XRF technology (ICC = 0.65). The detection limit for the portable XRF device was about 8.4 ppm with 2 mm soft tissue thickness. The entrance skin dose delivered to the human subject was about 13 mSv and the total body effective dose was about 1.5 µSv and should pose minimal radiation risk. In conclusion, portable XRF technology can be used for in vivo bone lead measurement with sensitivity comparable to the KXRF technology and good correlation with KXRF measurements.

Lithotripsy.

Shock wave lithotripsy (SWL) is the process of fragmentation of renal or ureteric stones by the use of repetitive shock waves generated outside the body and focused onto the stone. Following its introduction in 1980, SWL revolutionized the treatment of kidney stones by offering patients a non-invasive procedure. It is now seen as a mature technology and its use is perceived to be routine. It is noteworthy that, at the time of its introduction, there was a great effort to discover the mechanism(s) by which it works, and the type of sound field that is optimal. Although nearly three decades of subsequent research have increased the knowledge base significantly, the mechanisms are still controversial. Furthermore there is a growing body of evidence that SWL results in injury to the kidney which may have long-term side effects, such as new onset hypertension, although again there is much controversy within the field. Currently, use of lithotripsy is waning, particularly with the advent of minimally invasive ureteroscopic approaches. The goal here is to review the state of the art in SWL and to present the barriers and challenges that need to be addressed for SWL to deliver on its initial promise of a safe, effective, non-invasive treatment for kidney stones.

Strategies for improved shock wave lithotripsy.

Research in lithotripsy that started with the effort to characterize acute shock wave damage to the kidney has led to advances on several fronts, including discovery of strategies that have improved clinical treatment. It is appreciated now that shock wave trauma is primarily a vascular lesion, that injury is dose dependent, and that hemorrhage can be severe and can lead to a permanent loss of functional renal mass. Studies of the renal functional response to lithotripsy have shown that shock wave treatment triggers vasoconstriction in the kidney. This finding has been turned to advantage, and it is now known that when treatment is begun using low amplitude pulses, subsequent high amplitude shock waves are far less damaging. Thus, when shock waves are delivered judiciously, treatment can have a protective effect. The finding that cavitation is a key mechanism in vessel rupture has led to the development of novel experimental methods of shock wave delivery that can suppress bubble expansion and minimize tissue damage. Progress has also been made in understanding the physical mechanisms involved in stone comminution, and it is seen that the forces generated by cavitation, shear stress and circumferential squeezing act synergistically to fragment stones. Recent work suggests that a broad focal zone may be an advantage, allowing stones to be broken with lower amplitude pulses. Cavitation has been shown to play a critical role in reducing stone fragments to a size that can be voided. Cavitation is also the factor that limits the rate at which treatment can be performed, as stones break significantly better at slow rate than at fast ratean observation from basic research that is now appreciated in clinical practice. The current environment in lithotripsy research is encouraging. There is great interest in developing new technology, and in finding ways to improve how lithotripsy is performed.

High strain rate testing of kidney stones.

Sections of struvite kidney stones were tested in compression at high strain rates ( approximately 3000s(-1)) using a Kolsky bar and at low strain rates ( < 0.001 s(-1)) using an Instron testing machine. The peak stress in both cases appeared to be similar. At high strain rates the values of flow stress measured were between 40 and 65 MPa and at low strain rates they were between 37 and 58 MPa. However, the morphology of the damage was dramatically different. Stones tested at low strain rates formed a small number of cracks but otherwise remained intact at the end of the test. In comparison, stones tested at high strain rates were reduced to a powder. Kidney stones are a two-phase material consisting of a crystalline ceramic phase and an organic binder. We speculate that in the high strain rate tests the large difference in the sound speed between the matrix and the crystalline grains leads to shear stresses that destroy the stone. These data indicate that shear stress induced by the internal structure may be a mechanism by which shock waves comminute kidney stones in lithotripsy.

Simulations of the thermo-acoustic lens effect during focused ultrasound surgery.

Laboratory measurements of soft tissue properties show a dependence of background propagation properties on temperature. For typical focused ultrasound surgery (FUS) applications, only the slow variations in tissue background parameters need to be accounted for when computing the outcome of a FUS sonication. The cumulative effect of slowly varying sound speed has been referred to in the literature as a thermal lens, or a thermo-acoustic lens because of its beam-distorting properties. An algorithm to solve the coupled acoustic-thermal problem is described, and numerical results are presented to illustrate the effects of dynamic sound-speed profiles in layered tissues undergoing FUS. The results of simulations in liver with and without a fat layer indicate that the thermal-acoustic interaction results in more complex dynamics in FUS than a simple model will predict. Both the size and the position of the lesions predicted from the simulations are affected by the thermo-acoustic lens effect. However, the overall effect from short sonications at high power from sharply focused single element sources (F-no. from 0.8 to 1.3) around 1 MHz similar to those used in clinical setups is found to be small.

Scattering of ultrasound in cancellous bone: predictions from a theoretical model.

An understanding of the interaction between acoustic waves and cancellous bone is needed in order to realize the full clinical potential of ultrasonic bone measurements. Scattering is likely to be of central importance but has received little attention to date. In this study, we adopted a theoretical model from the literature in which scattering was assumed to be proportional to the mean fluctuation in sound speed, and bone was considered to be a random continuum containing identical scatterers. The model required knowledge only of sound speeds in bone and marrow, porosity, and scatter size. Predicted attenuation, broadband ultrasonic attenuation (BUA) and backscatter coefficient were obtained for a range of porosities and scatterer sizes, and were found to be comparable to published values for cancellous bone. Trends in predicted BUA with porosity agreed with previous experimental observations. All three predicted acoustic parameters showed a non-linear dependence on scatterer size which was independent of porosity. These data confirm the value of the scattering approach and provide the first quantitative predictions of the independent influence of structure and porosity on bone acoustic properties.

A dual passive cavitation detector for localized detection of lithotripsy-induced cavitation in vitro.

A passive cavitation detector (PCD) identifies cavitation events by sensing acoustic emissions generated by the collapse of bubbles. In this work, a dual passive cavitation detector (dual PCD), consisting of a pair of orthogonal confocal receivers, is described for use in shock wave lithotripsy. Cavitation events are detected by both receivers and can be localized to within 5 mm by the nature of the small intersecting volume of the focal areas of the two receivers in association with a coincidence detection algorithm. A calibration technique, based on the impulse response of the transducer, was employed to estimate radiated pressures at collapse near the bubble. Results are presented for the in vitro cavitation fields of both a clinical and a research electrohydraulic lithotripter. The measured lifetime of the primary growth-and-collapse of the cavitation bubbles increased from 180 to 420 microseconds as the power setting was increased from 12 to 24 kV. The measured lifetime compared well with calculations based on the Gilmore-Akulichev formulation for bubble dynamics. The radiated acoustic pressure 10 mm from the collapsing cavitation bubble was measured to vary from 4 to 16 MPa with increasing power setting; although the trends agreed with calculations, the predicted values were four times larger than measured values. The axial length of the cavitation field correlated well with the 6-dB region of the acoustic field. However, the width of the cavitation field (10 mm) was significantly narrower than the acoustic field (25 mm) as bubbles appeared to be drawn to the acoustic axis during the collapse. The dual PCD also detected signals from "rebounds," secondary and tertiary growth-and-collapse cycles. The measured rebound time did not agree with calculations from the single-bubble model. The rebounds could be fitted to a Rayleigh collapse model by considering the entire bubble cloud as an effective single bubble. The results from the dual PCD agreed well with images from high-speed photography. The results indicate that single-bubble theory is sufficient to model lithotripsy cavitation dynamics up to time of the main collapse, but that upon collapse bubble cloud dynamics becomes important.

Numerical simulations of heating patterns and tissue temperature response due to high-intensity focused ultrasound.

The results of this paper show-for an existing high intensity, focused ultrasound (HIFU) transducer-the importance of nonlinear effects on the space/time properties of wave propagation and heat generation in perfused liver models when a blood vessel also might be present. These simulations are based on the nonlinear parabolic equation for sound propagation and the bio-heat equation for temperature generation. The use of high initial pressure in HIFU transducers in combination with the physical characteristics of biological tissue induces shock formation during the propagation of a therapeutic ultrasound wave. The induced shock directly affects the rate at which heat is absorbed by tissue at the focus without significant influence on the magnitude and spatial distribution of the energy being delivered. When shocks form close to the focus, nonlinear enhancement of heating is confined in a small region around the focus and generates a higher localized thermal impact on the tissue than that predicted by linear theory. The presence of a blood vessel changes the spatial distribution of both the heating rate and temperature.

Comparison of electrohydraulic lithotripters with rigid and pressure-release ellipsoidal reflectors. II. Cavitation fields.

Dramatically different cavitation was produced by two separate acoustic pulses that had different shapes but similar duration, frequency content, and peak positive and negative pressure. Both pulses were produced by a Dornier HM-3 style lithotripter: one pulse when the ellipsoidal reflector was rigid, the other when the reflector was pressure release. The cavitation, or bubble action, generated by the conventional rigid-reflector pulse was nearly 50 times longer lived and 3-13 times stronger than that produced by the pressure-release-reflector pulse. Cavitation durations measured by passive acoustic detection and high-speed video agreed with calculations based on the Gilmore equation. Cavitation intensity, or destructive potential, was judged (1) experimentally by the size of pits in aluminum foil detectors and (2) numerically by the calculated amplitude of the shock wave emitted by a collapsing bubble. The results indicate that the trailing positive spike in the pressure-release-reflector waveform stifles bubble growth and mitigates the collapse, whereas the trough after the positive spike in the rigid-reflector waveform triggers inertially driven growth and collapse. The two reflectors therefore provide a tool to compare effects in weakly and strongly cavitating fields and thereby help assess cavitation's role in lithotripsy.

Effect of high-intensity focused ultrasound on whole blood with and without microbubble contrast agent.

Using human whole blood samples with and without contrast agent (CA), we evaluated the effect of exposures to focused, continuous wave (CW) 1.1-MHz ultrasound for durations of 10 ms to 1 s at spatial average intensities of 560 to 2360 W/cm2. Cavitation was monitored with a passive cavitation detector and hemolysis was determined with spectroscopy. In whole blood alone, no significant cavitation, heating or hemolysis was detected at any exposure condition. Conversely, cavitation and hemolysis, but not heating, were detected in whole blood with CA. A CA concentration as low as 0.28 microL CA per mL whole blood at an intensity of 2360 W/cm2 for 1 s resulted in measurable cavitation and a 6-fold increase in hemolysis compared to shams. Cavitation and hemolysis increased proportional to the concentration of CA and duration of exposure. In samples containing 4.2 microL CA per mL whole blood exposed for 1 s, a threshold was seen at 1750 W/cm2 where cavitation and hemolysis increased 10-fold compared to exposures at lower intensities. HIFU exposure of whole blood containing CA leads to significant hemolysis in vitro and may lead to clinically significant hemolysis in vivo.

Modeling of an electrohydraulic lithotripter with the KZK equation.

The acoustic pressure field of an electrohydraulic extracorporeal shock wave lithotripter is modeled with a nonlinear parabolic wave equation (the KZK equation). The model accounts for diffraction, nonlinearity, and thermoviscous absorption. A numerical algorithm for solving the KZK equation in the time domain is used to model sound propagation from the mouth of the ellipsoidal reflector of the lithotripter. Propagation within the reflector is modeled with geometrical acoustics. It is shown that nonlinear distortion within the ellipsoidal reflector can play an important role for certain parameters. Calculated waveforms are compared with waveforms measured in a clinical lithotripter and good agreement is found. It is shown that the spatial location of the maximum negative pressure occurs pre-focally which suggests that the strongest cavitation activity will also be in front of the focus. Propagation of shock waves from a lithotripter with a pressure release reflector is considered and because of nonlinear propagation the focal waveform is not the inverse of the rigid reflector. Results from propagation through tissue are presented; waveforms are similar to those predicted in water except that the higher absorption in the tissue decreases the peak amplitude and lengthens the rise time of the shock.

Effect of macroscopic air bubbles on cell lysis by shock wave lithotripsy in vitro.

In studies of cells or stones in vitro, the material to be exposed to shock waves (SWs) is commonly contained in plastic vials. It is difficult to remove all air bubbles from such vials. Because SWs reflect at an air-fluid interface, and because existing gas bubbles can serve as nuclei for cavitation events, we sought to determine in our system whether the inclusion of small, visible bubbles in the specimen vial has an effect on SW-induced cell lysis. We found that even small bubbles led to increased lysis of red blood cells (1- to 3-mm diameter bubbles, 9.8+/-0.5% lysis, n = 7; no bubbles, 4.4+/-0.8%, n = 4), and that the degree of lysis increased with bubble size. Damage could not be reduced by centrifuging the cells to the opposite end of the vial, away from the bubble. B-scan ultrasound imaging of blood in polypropylene pipette bulbs showed that, with each SW, bubbles were recruited from the air interface, mixing throughout the fluid volume, and these appeared to serve as nuclei for increased echogenicity during impact by subsequent SWs; thus, bubble effects in vials could involve the proliferation of cavitation nuclei from existing bubbles. Whereas injury to red blood cells was greatly increased by the presence of bubbles in vials, lytic injury to cultured epithelial cells (LLC-PK1, which have a more complex cytoarchitecture than red blood cells) was not increased by the presence of small air bubbles. This suggests different susceptibility to SW damage for different types of cells. Thus, the presence of even a small air bubble can increase SW-induced cell damage, perhaps by increasing the number of cavitation nuclei throughout the vial, but this effect is variable with cell type.

FDTD simulation of finite-amplitude pressure and temperature fields for biomedical ultrasound.

Full wave simulations provide a valuable tool for studying the spatial and temporal nature of an acoustic field. One method for producing such simulations is the finite-difference time-domain (FDTD) method. This method uses discrete differences to approximate derivatives in the governing partial differential equations. We used the FDTD method to model the propagation of finite-amplitude sound in a homogeneous thermoviscous fluid. The calculated acoustic pressure field was then used to compute the transient temperature rise in the fluid; the heating results from absorption of acoustic energy by the fluid. As an example, the transient temperature field was calculated in biological tissue in response to a pulse of focused ultrasound. Enhanced heating of the tissue from finite-amplitude effects was observed. The excess heating was attributed to the nonlinear generation of higher-frequency harmonics which are absorbed more readily than the fundamental. The effect of nonlinear distortion on temperature rise in tissue was observed to range from negligible at 1 MPa source pressure to an 80% increase in temperature elevation at 10 MPa source pressure.

In vivo pressure measurements of lithotripsy shock waves in pigs.

Stone comminution and tissue damage in lithotripsy are sensitive to the acoustic field within the kidney, yet knowledge of shock waves in vivo is limited. We have made measurements of lithotripsy shock waves inside pigs with small hydrophones constructed of a 25-microm PVDF membrane stretched over a 21-mm diameter ring. A thin layer of silicone rubber was used to isolate the membrane electrically from pig fluid. A hydrophone was positioned around the pig kidney following a flank incision. Hydrophones were placed on either the anterior (shock wave entrance) or the posterior (shock wave exit) surface of the left kidney. Fluoroscopic imaging was used to orient the hydrophone perpendicular to the shock wave. For each pig, the voltage settings (12-24 kV) and the position of the shock wave focus within the kidney were varied. Waveforms measured within the pig had a shape very similar to those measured in water, but the peak pressure was about 70% of that in water. The focal region in vivo was 82 mm x 20 mm, larger than that measured in vitro (57 mm x 12 mm). It appeared that a combination of nonlinear effects and inhomogeneities in the tissue broadened the focus of the lithotripter. The shock rise time was on the order of 100 ns, substantially more than the rise time measured in water, and was attributed to higher absorption in tissue.

Comparison of electrohydraulic lithotripters with rigid and pressure-release ellipsoidal reflectors. I. Acoustic fields.

The most common lithotripter, a Dornier HM-3, utilizes an underwater spark to generate an acoustic pulse and a rigid ellipsoidal reflector to focus the pulse on the kidney stone to be comminuted. The pulse measured in water with a PVDF membrane hydrophone at the external focus of the ellipsoid was a 1-microsecond positive-pressure spike followed by a 3-microsecond negative-pressure trough. When we replaced the rigid reflector in our experimental lithotripter with a pressure-release reflector, the pulse was a 1.6-microsecond trough followed by a 0.6-microsecond positive spike. The waveforms are nearly time inverses (i.e., their spikes and troughs are reversed). The frequency spectra, the maximum peak positive pressures P+ (42 MPa, rigid and 43 MPa, pressure-release), and the maximum peak negative pressures P- (-12 MPa and -14 MPa) are comparable. The maximum P- occurred 20 mm closer to the reflector than did the maximum P+, for both reflectors. However, the spatial maxima of the peak pressures (P+ and P-) produced by the pressure-release reflector were located 20 mm nearer to the reflector than those produced by the rigid reflector. Qualitative explanation of the waveforms and the location of pressure maxima as well as comparison to previous theoretical and experimental results is given. The alternate waveform produced by the pressure-release reflector may be a tool in determining the role of cavitation in lithotripsy because cavitation is highly sensitive to waveform.

The effect of polypropylene vials on lithotripter shock waves.

In studies to understand the mechanisms responsible for shock wave lithotripsy (SWL) cell injury, we observed that shock waves (SWs) are influenced by the shape of the specimen vial. Lytic injury to kidney cells treated in a Dornier HM3 lithotripter was higher (p < 0.0001) when SWs entered the vial through the flat end (cap end) compared to the round end. Measurements of the acoustic field within polypropylene vials were carried out using both lithotripter SWs and pulsed ultrasound (US) in the megahertz frequency range. We compared pressure amplitudes inside the round and flat vials and found significant differences. When SWs entered through the round end, the average peak positive pressure was 40% of free-field pressure, due mostly to a dramatic reduction in pressure off axis. The average peak pressure inside the flat vial was twice that of the round vial. Experiments with US demonstrated that sound field focusing was induced by the curved interface of the round vial. Ray analysis for the round vial indicates the presence of "hot spots" on axis and "cold spots" off axis, in qualitative agreement with pressure profiles. We conclude that the shape of the specimen vial is an important factor that should be considered in model systems of SWL cell injury.