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During clinical procedures, the lithotripter shock wave (LSW) that is incident on the stone and resultant stress field is often asymmetric due to the respiratory motion of the patient. The variations of the LSW-stone interaction and associated fracture pattern were investigated by photoelastic imaging, phantom experiments, and three-dimensional fluid-solid interaction modeling at different lateral locations in a lithotripter field. In contrast to a T-shaped fracture pattern often observed in the posterior region of the disk-shaped stone under symmetric loading, the fracture pattern gradually transitioned to a tilted L-shape under asymmetric loading conditions. Moreover, the model simulations revealed the generation of surface acoustic waves (SAWs), i.e., a leaky Rayleigh wave on the anterior boundary and Scholte wave on the posterior boundary of the stone. The propagation of SAWs on the stone boundary is accompanied by a progressive transition of the LSW reflection pattern from regular to von Neumann and to weak von Neumann reflection near the glancing incidence and, concomitantly, the development and growth of a Mach stem, swirling around the stone boundary. The maximum tensile stress and stress integral were produced by SAWs on the stone boundary under asymmetric loading conditions, which drove the initiation and extension of surface cracks into the bulk of the stone that is confirmed by micro-computed tomography analysis.

Passive cavitation mapping, which generates images using bubble acoustic emission signals, has been increasingly used for monitoring and guiding focused ultrasound surgery. Passive cavitation mapping can be used as an adjunct to magnetic resonance imaging to provide crucial information on the safety and efficacy of focused ultrasound surgery. The most widely used algorithm for passive cavitation mapping is delay-and-sum. One of the major limitations of delay-and-sum is its suboptimal computational efficiency. Although frequency-domain delay-and-sum can partially resolve this issue, such an algorithm is not suitable for imaging the evolution of bubble activity in real time and for cases in which cavitation events occur asynchronously. This study investigates a transient angular spectrum approach for passive cavitation mapping. The working principle of this approach is to back propagate the received signal to the domain of interest and reconstruct the spatial-temporal wave field encoded with the bubble location and collapse time. The transient angular spectrum approach is validated using an in silico model and water bath experiments. It is found that the transient angular spectrum approach yields similar results to delay-and-sum, but it is one order of magnitude faster. The results obtained by this study suggest that the transient angular spectrum approach is promising for fast and accurate passive cavitation mapping.

OBJECTIVE: To investigate the mechanism of stone dusting in Holmium (Ho): YAG laser lithotripsy (LL). MATERIALS AND METHODS: Cylindrical BegoStone samples (6 × 6 mm, H × D) were treated in water using a clinical Ho:YAG laser lithotripter in dusting mode (0.2–0.4 J with 70–78 μs in pulse duration, 20 Hz) at various fiber tip to stone standoff distances (SD = 0, 0.5, and 1 mm). Stone damage craters were quantified by optical coherence tomography and bubble dynamics were captured by high-speed video imaging. To differentiate the contribution of cavitation vs thermal ablation to stone damage, three additional experiments were performed. First, presoaked wet stones were treated in air to assess stone damage without cavitation. Second, the laser fiber was advanced at various offset distances (OSD = 0.25, 1, 2, 3, and 10 mm) from the tip of a flexible ureteroscope to alter the dynamics of bubble collapse. Third, stones were treated with parallel fiber to minimize photothermal damage while isolating the contribution of cavitation to stone damage. RESULTS: Treatment in water resulted in 2.5- to 90-fold increase in stone damage compared with those produced in air where thermal ablation dominates. With the fiber tip placed at OSD = 0.25 mm, the collapse of the bubble was distracted away from the stone surface by the ureteroscope tip, leading to significantly reduced stone damage compared with treatment without the scope or with scope at large OSD of 3–10 mm. The average crater volume produced by parallel fiber orientation at 0.2 J after 100 pulses, where cavitation is the dominant mechanism of stone damage, was comparable with those produced by using perpendicular fiber orientation within SD = 0.25–1 mm. CONCLUSION: Cavitation plays a dominant role over photothermal ablation in stone dusting during short pulse Ho:YAG LL when 10 or more pulses are delivered to the same location.

The penetration depth of photoacoustic imaging in biological tissues has been fundamentally limited by the strong optical attenuation when light is delivered externally through the tissue surface. To address this issue, we previously reported internal-illumination photoacoustic imaging using a customized radial-emission optical fiber diffuser, which, however, has complex fabrication, high cost, and non-uniform light emission. To overcome these shortcomings, we have developed a new type of low-cost fiber diffusers based on a graded-scattering method in which the optical scattering of the fiber diffuser is gradually increased as the light travels. The graded scattering can compensate for the optical attenuation and provide relatively uniform light emission along the diffuser. We performed Monte Carlo numerical simulations to optimize several key design parameters, including the number of scattering segments, scattering anisotropy factor, divergence angle of the optical fiber, and reflective index of the surrounding medium. These optimized parameters collectively result in uniform light emission along the fiber diffuser and can be flexibly adjusted to accommodate different applications. We fabricated and characterized the prototype fiber diffuser made of agarose gel and intralipid. Equipped with the new fiber diffuser, we performed thorough proof-of-concept studies on ex vivo tissue phantoms and an in vivo swine model to demonstrate the deep-imaging capability (~10 cm achieved ex vivo) of photoacoustic tomography. We believe that the internal light delivery via the optimized fiber diffuser is an effective strategy to image deep targets (e.g., kidney) in large animals or humans.

Purpose: Although cavitation during laser lithotripsy (LL) contributes to the Moses effect, the impact of cavitation on stone damage is less clear. Using different laser settings, we investigate the role of cavitation bubbles in energy delivery and stone damage. Materials and Methods: The role of cavitation in laser energy delivery was characterized by using photodetector measurements synced with high-speed imaging for laser pulses of varying durations. BegoStone samples were treated with the laser fiber oriented perpendicularly in contact with the stone in water or in air to assess the impact of cavitation on crater formation. Crater volume and geometry were quantified by using optical coherence tomography. Further, the role of cavitation in stone damage was elucidated by treatment in water with the fiber oriented parallel to the stone surface and by photoelastic imaging. Results: Longer pulse durations resulted in higher energy delivery but smaller craters. Stones treated in water resulted in greater volume, wider yet shallower craters compared with those treated in air. Stones treated with the parallel fiber showed crater formation after 15 pulses, confirmed by high-speed imaging of the bubble collapse with the resultant stress field captured by photoelastic imaging. Conclusions: Despite improved energy delivery, the longer pulse mode produced smaller crater volume, suggesting additional processes secondary to photothermal ablation are involved in stone damage. Our critical observations of the difference in stone damage treated in water vs in air, combined with the crater formation by parallel fiber, suggest that cavitation is a contributor to stone damage during LL.

Shock wave lithotripsy (SWL) has been widely used for non-invasive treatment of kidney stones. Cavitation plays an important role in stone fragmentation, yet it may also contribute to renal injury during SWL. It is therefore crucial to determine the spatiotemporal distributions of cavitation activities to maximize stone fragmentation while minimizing tissue injury. Traditional cavitation detection methods include high-speed optical imaging, active cavitation mapping (ACM), and passive cavitation mapping (PCM). While each of the three methods provides unique information about the dynamics of the bubbles, PCM has most practical applications in biological tissues. To image the dynamics of cavitation bubble collapse, we previously developed a sliding-window PCM (SW-PCM) method to identify each bubble collapse with high temporal and spatial resolution. In this work, to further validate and optimize the SW-PCM method, we have developed tri-modality cavitation imaging that includes three-dimensional high-speed optical imaging, ACM, and PCM seamlessly integrated in a single system. Using the tri-modality system, we imaged and analyzed laser-induced single cavitation bubbles in both free field and constricted space and shock wave-induced cavitation clusters. Collectively, our results have demonstrated the high reliability and spatial-temporal accuracy of the SW-PCM approach, which paves the way for the future in vivo applications on large animals and humans in SWL.

A damage model suggested by the Tuler–Butcher concept of dynamic accumulation of microscopic defects is obtained from experimental data on microcrack formation in synthetic kidney stones. Experimental data on appearance of microcracks is extracted from micro-computed tomography images of BegoStone simulants obtained after subjecting the stone to successive pulses produced by an electromagnetic shock-wave lithotripter source. Image processing of the data is used to infer statistical distributions of crack length and width in representative transversal cross-sections of a cylindrical stone. A high-resolution finite volume computational model, capable of accurately modeling internal reflections due to local changes in material properties produced by material damage, is used to simulate the accumulation of damage due to successive shocks. Comparison of statistical distributions of microcrack formation in computation and experiment allows calibration of the damage model. The model is subsequently used to compute fracture of a different aspect-ratio cylindrical stone predicting concurrent formation of two main fracture areas as observed experimentally.

Temperature mapping is essential in many biomedical studies and interventions to precisely control the tissue’s thermal conditions for optimal treatment efficiency and minimal side effects. Based on the Grüneisen parameter’s temperature dependence, photoacoustic (PA) imaging can provide relative temperature measurement, but it has been traditionally challenging to measure absolute temperatures without knowing the baseline temperature, especially in deep tissues with unknown optical and acoustic properties. Here, we report a new thermal-energy-memory-based photoacoustic thermometry (TEMPT). By illuminating the tissue with a burst of nanosecond laser pulses, TEMPT exploits the temperature dependence of the thermal energy lingering, which is probed by the corresponding PA signals acquired within the thermal confinement. A self-normalized ratiometric measurement cancels out temperature-irrelevant quantities and estimates the Grüneisen parameter. The temperature can then be evaluated, given the tissue’s temperature-dependent Grüneisen parameter, mass density, and specific heat capacity. Unlike the conventional PA thermometry, TEMPT does not require the knowledge of tissue’s baseline temperature, nor the optical properties. We have developed a mathematical model to describe the temperature dependence in TEMPT. We have demonstrated the feasibility of the temperature evaluation on tissue phantoms at 1.5 cm depth within a clinically relevant temperature range. Finally, as proof-of-concept, we applied TEMPT for temperature mapping during focused ultrasound treatment in mice in vivo at 2 mm depth. As a generic temperature mapping method, TEMPT is expected to find applications in thermotherapy of cancers on small animal models.

A multiphysics computational model of the focusing of an acoustic pulse and subsequent shock wave formation that occurs during extracorporeal shock wave lithotripsy is presented. In the electromagnetic lithotripter modeled in this work the focusing is achieved via a polystyrene acoustic lens. The transition of the acoustic pulse through the solid lens is modeled by the linear elasticity equations and the subsequent shock wave formation in water is modeled by the Euler equations with a Tait equation of state. Both sets of equations are solved simultaneously in subsets of a single computational domain within the BEARCLAW framework which uses a finite-volume Riemann solver approach. This model is first validated against experimental measurements with a standard (or original) lens design. The model is then used to successfully predict the effects of a lens modification in the form of an annular ring cut. A second model which includes a kidney stone simulant in the domain is also presented. Within the stone the linear elasticity equations incorporate a simple damage model.

In this manuscript, we first describe the fabrication protocol of a microfluidic chip, with gold dots and fibronectin-coated regions on the same glass substrate, that precisely controls the generation of tandem bubbles and individual cells patterned nearby with well-defined locations and shapes. We then demonstrate the generation of tandem bubbles by using two pulsed lasers illuminating a pair of gold dots with a few-microsecond time delay. We visualize the bubble-bubble interaction and jet formation by high-speed imaging and characterize the resultant flow field using particle image velocimetry (PIV). Finally, we present some applications of this technique for single cell analysis, including cell membrane poration with macromolecule uptake, localized membrane deformation determined by the displacements of attached integrin-binding beads, and intracellular calcium response from ratiometric imaging. Our results show that a fast and directional jetting flow is produced by the tandem bubble interaction, which can impose a highly localized shear stress on the surface of a cell grown in close proximity. Furthermore, different bioeffects can be induced by altering the strength of the jetting flow by adjusting the standoff distance from the cell to the tandem bubbles.

In shock wave lithotripsy (SWL), acoustic pulses with a leading compression wave followed by a tensile wave are delivered into the patient’s body using a water-filled coupling cushion. Cavitation-related acoustic energy loss in the coupling unit depends critically on water conditions, e.g. dissolved gas concentration and exchange flow rate. We have systematically investigated the attenuation mechanism in the coupling water via pressure measurements and cavitation characterization. In non-degassed water the bubble cluster became progressively dense (i.e., proliferated because of gas diffusion into bubbles and splitting of bubbles into many daughter bubbles) in shock waves delivered at 1 Hz leading to reduction in the tensile wave duration from a nominal value of 4.6 to 1.8 µs. To reduce cavitation in the coupling water along the beam path, we have used a continuous jet flow to remove residual daughter bubbles between consecutive shocks. As a result, stone fragmentation efficiency was increased from 16±4% t...

Carefully timed tandem microbubbles have been shown to produce directional and targeted membrane poration of individual cells in microfluidic systems, which could be of use in ultrasound-mediated drug and gene delivery. This study aims at contributing to the understanding of the mechanisms at play in such an interaction. The dynamics of single and tandem microbubbles between two parallel plates is studied numerically and analytically. Comparisons are then made between the numerical results and the available experimental results. Numerically, assuming a potential flow, a three-dimensional boundary element method (BEM) is used to describe complex bubble deformations, jet formation, and bubble splitting. Analytically, compressibility and viscous boundary layer effects along the channel walls, neglected in the BEM model, are considered while shape of the bubble is not considered. Comparisons show that energy losses modify the bubble dynamics when the two approaches use identical initial conditions. The initial conditions in the boundary element method can be adjusted to recover the bubble period and maximum bubble volume when in an infinite medium. Using the same conditions enables the method to recover the full dynamics of single and tandem bubbles, including large deformations and fast re-entering jet formation. This method can be used as a design tool for future tandem-bubble sonoporation experiments.

Previous studies have demonstrated that stone comminution decreases with increased pulse repetition frequency as a result of bubble proliferation in the cavitation field of a shock wave lithotripter (Pishchalnikov et al 2011 J. Acoust. Soc. Am. 130 EL87-93). If cavitation nuclei remain in the propagation path of successive lithotripter pulses, especially in the acoustic coupling cushion of the shock wave source, they will consume part of the incident wave energy, leading to reduced tensile pressure in the focal region and thus lower stone comminution efficiency. We introduce a method to remove cavitation nuclei from the coupling cushion between successive shock exposures using a jet of degassed water. As a result, pre-focal bubble nuclei lifetime quantified by B-mode ultrasound imaging was reduced from 7 to 0.3 s by a jet with an exit velocity of 62 cm s(-1). Stone fragmentation (percent mass2 mm) after 250 shocks delivered at 1 Hz was enhanced from 22 ± 6% to 33 ± 5% (p = 0.007) in water without interposing tissue mimicking materials. Stone fragmentation after 500 shocks delivered at 2 Hz was increased from 18 ± 6% to 28 ± 8% (p = 0.04) with an interposing tissue phantom of 8 cm thick. These results demonstrate the critical influence of cavitation bubbles in the coupling cushion on stone comminution and suggest a potential strategy to improve the efficacy of contemporary shock wave lithotripters.

INTRODUCTION AND OBJECTIVES: A new intracorporeal lithotriptor uses a nanosecond duration electrical discharge through a flexible coaxial probe to endoscopically fragment urinary stones. This device was compared to a holmium laser with regards to stone fragmentation efficiency and their impact on flexible ureteroscope deflection and flow of irrigation. METHODS: Using a custom bench model, stone fragmentation efficiency of the Nano-electric Pulse Lithotriptor (NPL, Lithotech Group, Israel) was evaluated with a begostone (mixture 5:2) confined under 0.9% normal saline atop sequential mesh sieves. Two NPL probe sizes (2.0 and 3.6F) and two holmium laser fibers (200 mm and 365mm) were evaluated using 6mm begostones. Time to first break, time to complete break (all fragments

Kidney stones are a common and painful affliction, but fortunately physics offers some relief: Sound can be used to break up the stones, without invasive surgery. Efficacy of this ``lithotripsy'' treatment, however, depends strongly on cavitation, which can both attenuate the sound waves and provoke significant tissue damage. In this collaboration between a physicist, engineers, and materials scientists, our understanding of this process is advanced through measurements and modeling, providing insight into the relations between bubble dynamics and lithotripsy effectiveness.

The efficiency of shock wave lithotripsy (SWL), a noninvasive first-line therapy for millions of nephrolithiasis patients, has not improved substantially in the past two decades, especially in regard to stone clearance. Here, we report a new acoustic lens design for a contemporary electromagnetic (EM) shock wave lithotripter, based on recently acquired knowledge of the key lithotripter field characteristics that correlate with efficient and safe SWL. The new lens design addresses concomitantly three fundamental drawbacks in EM lithotripters, namely, narrow focal width, nonidealized pulse profile, and significant misalignment in acoustic focus and cavitation activities with the target stone at high output settings. Key design features and performance of the new lens were evaluated using model calculations and experimental measurements against the original lens under comparable acoustic pulse energy (E+) of 40 mJ. The −6-dB focal width of the new lens was enhanced from 7.4 to 11 mm at this energy level, and peak pressure (41 MPa) and maximum cavitation activity were both realigned to be within 5 mm of the lithotripter focus. Stone comminution produced by the new lens was either statistically improved or similar to that of the original lens under various in vitro test conditions and was significantly improved in vivo in a swine model (89% vs. 54%, P = 0.01), and tissue injury was minimal using a clinical treatment protocol. The general principle and associated techniques described in this work can be applied to design improvement of all EM lithotripters.

The dynamics of luminescence generation and cavitation in the field of spherically focused and plane shock-acoustic waves in water, glycerin, and their mixtures is studied. It is shown that in the spherical focusing of shock-acoustic waves, the first pulse of luminescence correlates with cavitational rupture of the liquid. It is assumed that the registered luminescence is caused by electrokinetic processes upon formation and growth of cavitational bubbles.

The acoustic lens of the Modularis electromagnetic shock wave lithotripter (Siemens, Malvern, Pennsylvania) was modified to produce a pressure waveform and focal zone more closely resembling that of the original HM3 device (Dornier Medtech, Wessling, Germany). We assessed the newly designed acoustic lens in vivo in an animal model.Stone fragmentation and tissue injury produced by the original and modified lenses of the Modularis lithotripter were evaluated in a swine model under equivalent acoustic pulse energy (about 45 mJ) at 1 Hz pulse repetition frequency. Stone fragmentation was determined by the weight percent of stone fragments less than 2 mm. To assess tissue injury, shock wave treated kidneys were perfused, dehydrated, cast in paraffin wax and sectioned. Digital images were captured every 120 μm and processed to determine functional renal volume damage.After 500 shocks, the mean ± SD stone fragmentation efficiency produced by the original and modified lenses was 48% ± 12% and 52% ± 17%, respectively (p = 0.60). However, after 2,000 shocks, the modified lens showed significantly improved stone fragmentation compared to the original lens (mean 86% ± 10% vs 72% ± 12%, p = 0.02). Tissue injury caused by the original and modified lenses was minimal at a mean of 0.57% ± 0.44% and 0.25% ± 0.25%, respectively (p = 0.27).With lens modification the Modularis lithotripter demonstrates significantly improved stone fragmentation with minimal tissue injury at a clinically relevant acoustic pulse energy. This new lens design could potentially be retrofitted to existing lithotripters, improving the effectiveness of electromagnetic lithotripters.

An experimental system for digital stereoscopic imaging produced by using a high-speed color camera is described. Two bright-field image projections of a three-dimensional object are captured utilizing additive-color backlighting (blue and red). The two images are simultaneously combined on a two-dimensional image sensor using a set of dichromatic mirrors, and stored for off-line separation of each projection. This method has been demonstrated in analyzing cavitation bubble dynamics near boundaries. This technique may be useful for flow visualization and in machine vision applications.

The performance of a newly developed light spot hydrophone (LSHD) in lithotripter field characterization was compared to that of the fiber optic probe hydrophone (FOPH). Pressure waveforms produced by a stable electromagnetic shock wave source were measured by the LSHD and FOPH under identical experimental conditions. In the low energy regime, focus and field acoustic parameters matched well between the two hydrophones. At clinically relevant high energy settings for shock wave lithotripsy, the measured leading compressive pressure waveforms matched closely with each other. However, the LSHD recorded slightly larger |P–| (p < 0.05) and secondary peak compressive pressures (p < 0.01) than the FOPH, leading to about 20% increase in total acoustic pulse energy calculated in a 6 mm radius around the focus (p = 0.06). Tensile pulse durations deviated ∼5% (p < 0.01) due to tensile wave shortening from cavitation activity using the LSHD. Intermittent compression spikes and laser light reflection artifacts have been correlated to bubble activity based on simultaneous high-speed imaging analysis. Altogether, both hydrophones are adequate for lithotripter field characterization as specified by the international standard IEC 61846.

Previous studies have demonstrated that treatment strategy plays a critical role in ensuring maximum stone fragmentation during shockwave lithotripsy (SWL). We aimed to develop an optimal treatment strategy in SWL to produce maximum stone fragmentation.Four treatment strategies were evaluated using an in-vitro experimental setup that mimics stone fragmentation in the renal pelvis. Spherical stone phantoms were exposed to 2100 shocks using the Siemens Modularis (electromagnetic) lithotripter. The treatment strategies included increasing output voltage with 100 shocks at 12.3 kV, 400 shocks at 14.8 kV, and 1600 shocks at 15.8 kV, and decreasing output voltage with 1600 shocks at 15.8 kV, 400 shocks at 14.8 kV, and 100 shocks at 12.3 kV. Both increasing and decreasing voltages models were run at a pulse repetition frequency (PRF) of 1 and 2 Hz. Fragmentation efficiency was determined using a sequential sieving method to isolate fragments less than 2 mm. A fiberoptic probe hydrophone was used to characterize the pressure waveforms at different output voltage and frequency settings. In addition, a high-speed camera was used to assess cavitation activity in the lithotripter field that was produced by different treatment strategies.The increasing output voltage strategy at 1 Hz PRF produced the best stone fragmentation efficiency. This result was significantly better than the decreasing voltage strategy at 1 Hz PFR (85.8% vs 80.8%, P=0.017) and over the same strategy at 2 Hz PRF (85.8% vs 79.59%, P=0.0078).A pretreatment dose of 100 low-voltage output shockwaves (SWs) at 60 SWs/min before increasing to a higher voltage output produces the best overall stone fragmentation in vitro. These findings could lead to increased fragmentation efficiency in vivo and higher success rates clinically.

The dynamic interaction between laser-generated tandem bubble and individual polystyrene particles of 2 and 10 μm in diameter is studied in a microfluidic channel (25 μm height) by high-speed imaging and particle image velocimetry. The asymmetric collapse of the tandem bubble produces a pair of microjets and associated long-lasting vortices that can propel a single particle to a maximum velocity of 1.4 m/s in 30 μs after the bubble collapse with a resultant directional displacement up to 60 μm in 150 μs. This method may be useful for high-throughput cell sorting in microfluidic devices.

A simple method for preparing artificial kidney stones with varying physical properties is described. BegoStone was prepared with a powder to water ratio (by weight) ranging from 15:3 to 15:6. The acoustic properties of the phantoms were characterized by using an ultrasound transmission technique, from which the corresponding mechanical properties were calculated based on elastic wave theory. The measured parameters for BegoStone phantoms of different water contents are: longitudinal wave speed (3148 – 4159 m/s), transverse wave speed (1813 – 2319 m/s), density (1563 – 1995 kg/m3), longitudinal acoustic impedance (4.92 – 8.30 Kg/m2*s), transverse acoustic impedance (2.83 – 4.63 Kg/m2*s), Young’s modulus (12.9 – 27.4 GPa), bulk modulus (8.6 – 20.2 GPa), and shear modulus (5.1 – 10.7 GPa), which cover the range of corresponding properties reported in natural kidney stones. In addition, diametral compression tests were carried out to determine tensile failure strength of the stone phantoms. BegoStone phantoms with varying water content at preparation have tensile failure strength from 6.9 – 16.3 MPa when tested dry and 3.2 – 7.1 MPa when tested in water-soaked condition. Overall, it is demonstrated that this new BegoStone preparation method can be used to fabricate artificial stones with physical properties matched with those of natural kidney stones of various chemical compositions.

The interaction of laser-generated tandem microbubble (maximum diameter of about $50\text{ }\text{ }\ensuremath{\mu}\mathrm{m}$) with single (rat mammary carcinoma) cells is investigated in a $25\mathrm{\text{\ensuremath{-}}}\ensuremath{\mu}\mathrm{m}$ liquid layer. Antiphase and coupled oscillation of the tandem microbubble leads to the formation of alternating, directional microjets (with max microstreaming velocity of $10\text{ }\text{ }\mathrm{m}/\mathrm{s}$) and vortices (max vorticity of $350\text{ }000\text{ }\text{ }{\mathrm{s}}^{\ensuremath{-}1}$) in opposite directions. Localized and directional membrane poration (200 nm to $2\text{ }\text{ }\ensuremath{\mu}\mathrm{m}$ in pore size) can be produced by the tandem microbubble in an orientation and proximity-dependent manner, which is absent from a single oscillating microbubble of comparable size and at the same stand-off distance.

Using a reflector insert, the original HM-3 lithotripter field at 20 kV was altered significantly with the peak positive pressure (p(+)) in the focal plane increased from 49 to 87 MPa while the -6 dB focal width decreased concomitantly from 11 to 4 mm. Using the original reflector, p(+) of 33 MPa with a -6 dB focal width of 18 mm were measured in a pre-focal plane 15-mm proximal to the lithotripter focus. However, the acoustic pulse energy delivered to a 28-mm diameter area around the lithotripter axis was comparable ( approximately 120 mJ). For all three exposure conditions, similar stone comminution ( approximately 70%) was produced in a mesh holder of 15 mm after 250 shocks. In contrast, stone comminution produced by the modified reflector either in a 15-mm finger cot (45%) or in a 30-mm membrane holder (14%) was significantly reduced from the corresponding values (56% and 26%) produced by the original reflector (no statistically significant differences were observed between the focal and pre-focal planes). These observations suggest that a low-pressure/broad focal width lithotripter field will produce better stone comminution than its counterpart with high-pressure/narrow focal width under clinically relevant in vitro comminution conditions.

To correlate thermal dose from focused ultrasound (FUS) with gene expression and tissue injury, a temperature plateau strategy was employed. Plasmids encoding luciferase gene under the control of hsp70B promoter were transfected into the right gastrocnemius muscle in a rat via electroporation. One day after transfection, hind limbs were treated with 3.3-MHz focused ultrasound, using one of four different temperature plateaus with spatial-peak time-average focal temperatures (T(SPTA)) of 46 degrees C, 48 degrees C, 51 degrees C and 62 degrees C. The treatment duration at the plateau temperature was varied from 0 to 30s. Gene expression was analyzed in vivo one day following FUS treatment, and HE staining was employed to assess tissue injury. Gene activation and tissue damage correlated closely with thermal dose. The highest level of gene activation was induced by FUS at T(SPTA)=51 degrees C for 20s, which was found to be statistically equivalent to that produced by water-bath hyperthermia.

The dynamic interaction of a shockwave (modelled as a pressure pulse) with an initially spherically oscillating bubble is investigated. Upon the shockwave impact, the bubble deforms non-spherically and the flow field surrounding the bubble is determined with potential flow theory using the boundary-element method (BEM). The primary advantage of this method is its computational efficiency. The simulation process is repeated until the two opposite sides of the bubble surface collide with each other (i.e. the formation of a jet along the shockwave propagation direction). The collapse time of the bubble, its shape and the velocity of the jet are calculated. Moreover, the impact pressure is estimated based on water-hammer pressure theory. The Kelvin impulse, kinetic energy and bubble displacement (all at the moment of jet impact) are also determined. Overall, the simulated results compare favourably with experimental observations of lithotripter shockwave interaction with single bubbles (using laser-induced bubbles at various oscillation stages). The simulations confirm the experimental observation that the most intense collapse, with the highest jet velocity and impact pressure, occurs for bubbles with intermediate size during the contraction phase when the collapse time of the bubble is approximately equal to the compressive pulse duration of the shock wave. Under this condition, the maximum amount of energy of the incident shockwave is transferred to the collapsing bubble. Further, the effect of the bubble contents (ideal gas with different initial pressures) and the initial conditions of the bubble (initially oscillating vs. non-oscillating) on the dynamics of the shockwave-bubble interaction are discussed.

The focusing of laser-generated shock waves by a truncated ellipsoidal reflector was experimentally and numerically investigated. Pressure waveform and distribution around the first (F(1)) and second foci (F(2)) of the ellipsoidal reflector were measured. A neodymium doped yttrium aluminum garnet laser of 1046 nm wavelength and 5 ns pulse duration was used to create an optical breakdown at F(1), which generates a spherically diverging shock wave with a peak pressure of 2.1-5.9 MPa at 1.1 mm stand-off distance and a pulse width at half maximum of 36-65 ns. Upon reflection, a converging shock wave is produced which, upon arriving at F(2), has a leading compressive wave with a peak pressure of 26 MPa and a zero-crossing pulse duration of 0.1 mus, followed by a trailing tensile wave of -3.3 MPa peak pressure and 0.2 mus pulse duration. The -6 dB beam size of the focused shock wave field is 1.6 x 0.2 mm(2) along and transverse to the shock wave propagation direction. Formation of elongated plasmas at high laser energy levels limits the increase in the peak pressure at F(2). General features in the waveform profile of the converging shock wave are in qualitative agreement with numerical simulations based on the Hamilton model.

The interaction of laser-generated single inertial bubbles (collapse $\text{time}=121\phantom{\rule{0.3em}{0ex}}\ensuremath{\mu}\mathrm{s}$) near a silicon rubber membrane with a shock wave ($55\phantom{\rule{0.3em}{0ex}}\mathrm{MPa}$ in peak pressure and $1.7\phantom{\rule{0.3em}{0ex}}\ensuremath{\mu}\mathrm{s}$ in compressive pulse duration) is investigated. The interaction leads to directional, forced asymmetric collapse of the bubble with microjet formation toward the surface. Maximum jet penetration into the membrane is produced during the bubble collapse phase with optimal shock wave arrival time and stand-off distance. Such interaction may provide a unique acoustic means for in vivo microinjection, applicable to targeted delivery of macromolecules and gene vectors to biological tissues.

The interaction of a lithotripter shock wave (LSW) with laser-generated single vapor bubbles in water is investigated using high-speed photography and pressure measurement via a fiber-optic probe hydrophone. The interaction leads to nonspherical collapse of the bubble with secondary shock wave emission and microjet formation along the LSW propagation direction. The maximum pressure amplification is produced during the collapse phase of the bubble oscillation when the compressive pulse duration of the LSW matches with the forced collapse time of the bubble.

A previously introduced model for stone comminution in shock wave lithotripsy is extended to include damage produced by cavitation. At the macroscopic, continuum level a 3D elasticity model with time-varying material constants capturing localized damage provides the overall stress field within kidney stone simulants. Regions of high stress are identified and a mesoscopic crack propagation is used to dynamically update localized damage. The crack propagation model in turn is linked with a microscopic grain dynamics model. Continuum stresses and surface pitting is provided by a multiscale cavitation model (see related talk). The overall procedure is capable of tracking stone fragments and surface cavitation of the fragments through several levels of breakdown. Computed stone fragment distributions are compared to experimental results. [Work supported by NIH through 5R37DK052985-18.]

Cavitation damage is responsible for initial pitting of kidney stone surfaces, damage that is thought to play an important role in shock wave lithotripsy. We introduce a multiscale model of the formation of cavitation bubbles in water, and subsequent breakdown. At a macroscopic, continuum scale cavitation is modeled by the 3D Euler equations with a Tait equation of state. Adaptive mesh refinement is used to provide increased resolution at the liquid/vapor boundary. Cells with both liquid and vapor phases are flagged by the continuum solver for mesoscale, kinetic modeling by a lattice Boltzmann description capable of capturing non-equilibrium behavior (e.g., phase change, energetic jet impingement). Isolated and interacting two-bubble configurations are studied. Computational simulation results are compared with high-speed experimental imaging of individual bubble dynamics and bubble–bubble interaction. The model is used to build a statistical description of multiple-bubble interaction, with input from cavitation cloud imaging. [Work supported by NIH through 5R37DK052985-18.]

A challenge in clinical shock wave lithotripsy (SWL) is stone translation due to a patient’s respiratory motion, in a direction perpendicular to shockwave propagation, which may negatively affect stone comminution while increasing the risk of tissue injury. We have developed a method using external masks and a modified lens geometry to transform the axisymmetric pressure distribution in the focal plane of an electromagnetic lithotripter into a non-axisymmetric elliptical distribution. At equivalent acoustic pulse energy (46 mJ), the peak pressure was reduced from 44 MPa to 38 MPa while the −6 dB focal width was increased from 7.4 mm for the original to 11.7 mm (major axis) and 7.9 mm (minor axis) of the modified field. In vitro stone comminution was performed in a tube holder (d = 14 mm) using a translation pattern with 12 breaths per minute and 15 mm in excursion distance. Stone comminution after 1000 shocks are 71.2 ± 4.4% and 65.2 ±8.3% (p

Cavitation induced bioeffects has not been resolved satisfactorily due to the randomness in the inception and bubble dynamics produced by ultrasound. We have developed a microfluidic system to observe consistently the interaction of laser-generated tandem bubbles (50 μm in diameter) with resultant jet formation, cell deformation, and localized membrane rupture with progressive diffusion of propodium iodide (PI) into individual HeLa cells placed nearby. We observe a clear stand-off distance (SD) dependence in the bioeffects produced by the tandem bubbles. At SD of 10 μm, all cells underwent necrosis with high, unsaturated level of PI uptake. At SD of 20~30 μm, 58 to 80% of the cells showed repairable membrane poration with low to medium but saturated level of PI uptake. Within this range, the sub-population of cells that survived without apoptosis increased from ~9% at SD of 20 μm to ~70% at SD of 30 μm. The maximum PI uptake, pore size, and estimated membrane strain, however, could vary by more than an order of magnitude at each SD. At SD of 40 μm, no detectable PI uptake was observed. This experimental system provides a unique tool to probe the bioeffects of cavitation at the single cell level.

Previous research shows that a shockwave’s tensile phase can be strongly attenuated as a function of gas concentration in the coupling medium. Here, we seek to elucidate the relationship between tensile attenuation and gas concentration via pressure measurements at the focus and highspeed imaging. By performing in vitro experiments with water of varying gas concentrations (2.05 mg/L, 4.30 mg/L, and 6.50 mg/L), the negative impulsive pressure is correlated to the density of the bubble cloud that occurs in the beampath. It is found that for gas contents below 4 mg/L the bubble cloud remains sparse and the shockwave’s tensile phase is successfully transmitted with no loss in impulsive pressure. For gas contents 4 mg/L and above the bubble cloud becomes highly dense and prevents transmission with up to a 75% loss in impulsive pressure. Corresponding stone comminution experiments show that the treatment efficiency sharply decreases with increasing gas concentration. These results underlie the importance of degassing the water used in the coupling medium before treatment.

Recent experiments, motivated by ultrasound-mediated drug and gene delivery, have utilized laser-generated tandem microbubbles to produce directional and targeted membrane poration of individual cells in microfluidic systems [Sankin et al., Phys. Rev. Lett. 105, 078101 (2010)]. Two models describing the dynamics of coupled bubbles between parallel plates have been applied to understand these observations. The first approach is based on the Boundary Element Method in both 2D and 3D coordinate systems for bubbles bounded by finite rigid plates. Deformation of the bubble surfaces is taken into account, capturing phenomena such as bubble jetting and fragmentation [Hsiao et al., Ultrasound Med. Biol. 36, 2065-2079 (2010)]. The second approach is semi-analytic, accounts for fluid compressibility and elasticity of the plates, but is limited to spherical bubble pulsation [Hay et al., J. Acoust. Soc. Am. 129, 2477(A) (2011)]. Observations of tandem bubble interaction with adjacent biological cells and their potent...

To assess the role of stress waves and cavitation in comminuting residual fragments during shock wave lithotripsy (SWL), cylindrical 4 × 4 mm BegoStone phantoms were treated in an electromagnetic lithotripter either at the focus (z = 0, p+ = ∼45 MPa) or pre-focally (z = −30 mm, p+ = ∼24 MPa). The treatment was performed with the stone immersed either in degassed water or in Butanediol, which has similar acoustic impedance to water but much higher viscosity to suppress cavitation. At the focus, the first fracture was observed after 26 ± 9 shocks, both in water and Butanediol (p = 0.7). However, when stones were moved pre-focally where comparable cavitation is produced (based on high speed imaging), the average shock number required for the initial fracture was increased to 66 ± 10 in water and 122 ± 20 in Butanediol (p = 0.002). Below −40 mm prefocally (p+

The dynamics of tandem bubble interaction in a microfluidic channel (800 × 21 μm, W × H) have been investigated using high-speed photography, with resultant fluid motion characterized by particle imaging velocimetry. A single or tandem bubble is produced reliably via laser absorption by micron-sized gold dots (6 μm in diameter with 40 μm in separation distance) coated on a glass surface of the microfluidic channel. Using two pulsed Nd:YAG lasers at λ = 1064 nm and ∼10 μJ/pulse, the dynamics of tandem bubble interaction (individual maximum bubble diameter of 50 μm with a corresponding collapse time of 5.7 μs) are examined at different phase delays. In close proximity (i.e., interbubble distance = 40 μm or γ = 0.8), the tandem bubbles interact strongly with each other, leading to asymmetric deformation of the bubble walls and jet formation, as well as the production of two pairs of vortices in the surrounding fluid rotating in opposite directions. The direction and speed of the jet (up to 95 m/s), as well as the orientation and strength of the vortices can be varied by adjusting the phase delay.

We will present a computational model of the focusing of an electromagnetically induced pressure pulse by an acoustic lens and subsequent shock wave formation. Linear elasticity equations for the lens are solved simultaneously with Euler hydrodynamic equations for water considered to be a compressible medium with a Tait equation of state. The adaptive mesh refinement model allows both three‐dimensional and two‐dimensional axisymmetric computations. A number of coupling approaches at the lens‐water interface are investigated by comparison to experimental results: transfer only of pressure boundary condition, coupling of displacement velocities, and a buffer linear elasticity region in the water immediately adjacent to lens. The model is validated against single‐medium measurements (water or lens material), and the complete experimental shock wave formation process. Initial results from a crack propagation model in stone simulants placed at the lithotripter focus will also be presented.

The third‐generation electromagnetic (EM) shock wave lithotripters often have narrow focal width and high‐peak pressure compared to the original HM‐3. In addition, the pressure waveform produced by a typical EM lithotripter has a secondary compressive wave that suppresses lithotripter pulse induced cavitation, which is an important mechanism for stone comminution. These features have been contributed to the reduced effectiveness of the modern EM lithotripters. To overcome these drawbacks, we have designed a new acoustic lens for the Siemens Modularis EM lithotripter that produces an idealized pressure waveform similar to the HM‐3 with broad focal width and low‐peak pressure. At acoustic pulse energy of 53 mJ, the new lens design enlarges the −6 dB focal width of the Modularis by 47% while significantly reducing the second compressive wave throughout its focal plane. After 2000 shocks, in vitro comminution produced by the original and new lens designs are 100% and 99% at the lithotripter focus, and (49.7±15.0)% and (75.3±8.74)% (p < 0.001) at 10 mm off axis, respectively. Corresponding values in vivo are (63.4±17.4)% and (83.3±8.5)% (p < 0.01), demonstrating the significant performance improvement provided by the new lens design. [Work supported by NIH Grant Nos. R01DK052985 and S10RR016802.]

Understanding the dynamic interaction of cavitation bubbles with biological tissue is central to the effective and safe application of therapeutic ultrasound in clinical medicine. Coupled oscillation of two laser generated microbubbles (maximum radius = 28 μm) in constrained media and associated shear stresses are investigated experimentally. Bubble‐bubble interaction in a microchannel of 25‐μm height is observed using high‐speed video cameras and μPIV technique. Two liquid micro‐jets moving in opposite directions can be generated when the second bubble is produced at the maximum size of the first one. The interaction of these tandem microbubbles with single cell leads to controllable poration of adjacent cell membrane and dye uptake. Micro‐PIV data are compared with cell viability at various bubble‐cell distances and azimuthal orientations. This method provides a new approach for highly selective cell treatment in situ applicable to targeted microinjection of macromolecules and gene vectors in microfluid...

Coupled oscillations of two adjacent laser‐induced microbubbles have been shown to produce unique asymmetric bubble deformation and microjet formation. The resultant microstreaming and shear stress can cause localized cell membrane poration with potential application in targeted drug and gene delivery. In this study, we investigate the bubble dynamics and flow field produced by laser‐generated tandem microbubble in a microfluidic device. Flow field around the tandem microbubble is analyzed with respect to phase delay, inter‐bubble distance, and size ratio between the two microbubbles. In addition, micropatterning technique is used to control the adhesion site and growth pattern of HeLa cells in relation to the tandem microbubble. Flow vorticity is observed to be a key parameter that correlates with the strength of tandem microbubble oscillation and resultant macromolecule uptake efficiency. [Work supported by NIH Grant Nos. R01DK052985, R21CA135221, and S10RR016802].

Coupled oscillation of two laser generated microbubbles (maximum radius = 28 μm) and associated shear stresses are investigated experimentally. Bubble‐bubble interaction in a microchannel of 25 μm height is observed using high‐speed video cameras and μPIV technique. Two liquid microjets moving in opposite directions can be generated when the second bubble is produced at the maximum size of the first one. The interaction of these tandem microbubbles with single cell leads to controllable poration of adjacent cell membrane and dye uptake. μPIV data are compared with cell viability at various bubble‐cell distances and azimuthal orientations. This method provides a new approach for highly selective cell treatment in situ, applicable to targeted microinjection of macromolecules and gene vectors in microfluidics devices. [Work supported in part by NIH.]

Recent studies have highlighted the potential for using laser‐induced micro‐cavitation in lab‐on‐a‐chip devices. Shear stress in a liquid can be controlled and significantly enhanced by bubble‐bubble interaction, providing new options for in situ cell treatment. Two micro‐bubbles (10 μs life time) are generated in a 25‐μm liquid layer using 5 ns tandem laser pulses delivered through the objective of a microscope. Bubble‐bubble interaction in nearly two‐dimensional flow is observed using high‐speed video cameras. Two liquid micro‐jets moving in opposite directions can be generated when the second bubble is produced at the maximum size of the first one. The jet velocity is estimated about 35 m/s. Particle imaging velocimetry reveals vortex flow motion around the oscillating bubble lasting for about 200 μs. Cell lyses produced by jetting from asymmetric oscillation of tandem microbubbles are investigated at various bubble‐cell distances and compared with the results from single symmetric bubble oscillation. ...

A method to characterize shock wave lithotripters by examining the potential for cavitation associated with the lithotripter shock wave (LSW) has been developed. The method uses the maximum radius achieved by a bubble subjected to a LSW as a representation of the cavitation potential for that region in the lithotripter. It is found that the maximum radius is determined by the work done on a bubble by the LSW. The method is used to characterize two reflectors: an ellipsoidal reflector and an ellipsoidal reflector with an insert. The results show that the use of an insert reduced the -6 dB volume (with respect to peak positive pressure) from 1.6 to 0.4 cm(3), the -6 dB volume (with respect to peak negative pressure) from 14.5 to 8.3 cm(3), and reduced the volume characterized by high cavitation potential (i.e., regions characterized by bubbles with radii larger than 429 µm) from 103 to 26 cm(3). Thus, the insert is an effective way to localize the potentially damaging effects of shock wave lithotripsy, and suggests an approach to optimize the shape of the reflector.