Experimental observations and numerical modeling of lipid-shell microbubbles with calcium-adhering moieties for minimally-invasive treatment of urinary stones

Experimental observations and numerical modeling of lipid-shell

microbubbles with calcium-adhering moieties for minimally-

invasive treatment of urinary stones

Yuri A. Pishchalnikov

R&D, Applaud Medical, Inc., San Francisco, CA, 94107;

William Behnke-Parks

Applaud Medical, Inc., San Francisco, CA, 94107;

Kazuki Maeda

Department of Mechanical Engineering, University of Washington, Seattle, WA, 98105;

Tim Colonius

Division of Engineering and Applied Science, California Institute of Technology, Pasadena, CA,

91125;

Matthew Mellema

Applaud Medical, Inc., San Francisco,CA, 94107;

Matthew Hopcroft

Applaud Medical, Inc., San Francisco,CA, 94107;

Alice Luong

Applaud Medical, Inc., San Francisco,CA, 94107;

Scott Wiener

Department of Urology, University of California, San Francisco, CA, 94143;

Marshall L. Stoller

Department of Urology, University of California, San Francisco, CA, 94143;

Thomas Kenny

Department of Mechanical Engineering, Stanford University, Stanford, CA, 94305;

Daniel J. Laser

Applaud Medical, Inc., San Francisco, CA 94107;

Abstract

A novel treatment modality incorporating calcium-adhering microbubbles has recently entered

human clinical trials as a new minimally-invasive approach to treat urinary stones. In this

treatment method, lipid-shell gas-core microbubbles can be introduced into the urinary tract

through a catheter. Lipid moities with calcium-adherance properties incorporated into the lipid

shell facilitate binding to stones. The microbubbles can be excited by an extracorporeal source of

yurapish@gmail.com.

HHS Public Access

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Published in final edited form as:

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quasi-collimated ultrasound. Alternatively, the microbubbles can be excited by an intraluminal

source, such as a fiber-optic laser. With either excitation technique, calcium-adhering

microbubbles can significantly increase rates of erosion, pitting, and fragmentation of stones. We

report here on new experiments using high-speed photography to characterize microbubble

expansion and collapse. The bubble geometry observed in the experiments was used as one of the

initial shapes for the numerical modeling. The modeling showed that the bubble dynamics strongly

depends on bubble shape and stand-off distance. For the experimentally observed shape of

microbubbles, the numerical modeling showed that the collapse of the microbubbles was

associated with pressure increases of some two-to-three orders of magnitude compared to the

excitation source pressures. This in-vitro study provides key insights into the use of microbubbles

with calcium-adhering moieties in treatment of urinary stones.

1. INTRODUCTION

Stone-adhering microbubbles

have recently entered human clinical trials as a medical

device for minimally invasive approach to treat urinary stones. Gas-filled microbubbles are

introduced through a catheter and adhere to urinary stones with calcium-adhering moieties

incorporated into encapsulating lipid shells.

–

The microbubbles can be excited either

minimally invasively (e.g., with a laser coupled to an optical fiber delivered through the

ureter via a ureteroscope) or non-invasively with an extracorporeal source of ultrasound(Fig.

1).

With either excitation technique, recent studies suggest that the stone-adhering

microbubbles can significantly increase the breakage of urinary stones.

To better

understanding the mechanisms of action of microbubbles in treatment of urinary stones, here

we studied the dynamics of microbubbles at the surface of urinary stones

in vitro

. This study

is a continuation of the work presented at the previous 175

meeting of the Acoustical

Society of America.

The microbubbles were driven with quasi-collimated ultrasound at low

intensities and studied using a high-speed video microscopy. The observed bubble geometry

and the stand-off distance were used as input parameters for the numerical modeling of the

collapsing bubbles. The modeling showed that the collapse of stone-adhering microbubbles

can produce pressure spikes with amplitudes significantly greater than the amplitude of the

driving acoustic waves.

2. MATERIALS AND METHODS

A. LIPID-SHELL MICROBUBBLES AND URINARY STONES

Stone-adhering microbubbles (Applaud Medical, Inc.) were made of perfluoroalkane gas

encapsulated into lipid shells with calcium-adhering moieties.

–

The chemical

composition of the moieties was based on a synthetic pyrophosphate analog structure

conferring adhering affinity for calcium constituents urinary stones.

These experiments were conducted with surgically retrieved calcium-oxalate-monohydrate

urinary stones. The stones were hydrated in deionized water and positioned in the test tank

to study the dynamics of microbubbles with a high-speed video microscopy (Fig. 2).

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B. HIGH-SPEED VIDEO MICROSCOPY

Bubble dynamics was captured using a high-speed (HS) camera Shimadzu Hyper Vision

HPV-X2 (Shimadzu, Kyoto, Japan). The camera had a burst image sensor FTCMOS2 with

ISO sensitivity of 16,000 and a monochrome 10-bit resolution. The camera recorded 400- by

250-pixel frames either in FP or HP mode. The FP mode captured every pixel recording 128

frames at a rate up to five million frames per second (Mfps). The HP mode captured every

other pixel interpolating the images to 400- by 250-pixel frames and recording 256 frames at

a rate up to 10 Mfps. The physical size of sensor pixels was 32 by 32

The high-speed camera was used with a Nikon Eclipse TS100 microscope with a 4

objective (4

/0.13 PhL DL, WD 16.4, Nikon Plan Fluor), a 2.5× projection lens (Nikon CF

PL2.5

), and a 34-cm extension tube (Thorlabs Inc., Newton, NJ, USA). The optical

magnification was determined using a metallized hemacytometer (Hausser Bright-Line,

Hausser Scientific, Horsham, PA, USA) and was 1

m per pixel.

Nikon Eclipse TS100 microscope had inverted configuration in which the objective was

positioned at the bottom. To use this configuration, a test tank had a transparent glass

window at the bottom of the tank (Fig. 2). The window was made of a microscope slide

(75

1 mm, VistaVision, VWR International, LLC, Radnor, PA) glued along its edges to

the bottom of the tank. The tank was 3-D printed from a thermoplastic material—

acrylonitrile butadiene styrene—and covered with a waterproof coating (Marine Grade

Epoxy 109 Medium, Tap Plastics, CA, USA). The test tank was filled with six liters of water

(PURELAB Chorus 1 for Life Science Applications, ELGA, Veolia Water Solutions and

Technologies, UK) with an electrical resistivity of 18.2 MOhm-cm and the ultrafiltration to

particle size less than 0.05

m. The water remained in the tank for several days and was in

equilibrium with atmospheric gases.

We used both continuous and flashlight illumination. The continuous lighting was provided

by a fluorescence illumination system EXFO X-cite 120 (XE120, Photonic Solutions Inc.,

Mississauga, Ontario, CA). This light source used a 120-W Metal Halide lamp coupled to a

liquid lightguide. The end of the lightguide was positioned at about 1 cm above the stone to

backlit the stone (Fig. 2). The side lighting was provided by a flashlamp WRF300 (Hadland

Imaging LLC, Santa Cruz, CA). This spark-discharge lamp produced a light pulse with the

duration of about 10

s. The spark light was delivered through a liquid lightguide

illuminating the side of the stone proximal to the incoming acoustic waves (Fig. 2).

C. DRIVING ACOUSTIC WAVES

Driving acoustic waves were generated with a custom-made piezo-electric transducer

(manufactured for Applaud Medical by Sonic Concepts, Inc., Bothell, WA). The active

element of the transducer was made of a piezo-electric plate (72.3

30.3

3.18 mm) divided

into eight elements and connected in pairs. Each pair was driven by one of the four

controllable power amplifiers (AP-400B, ENI, USA). The frequency and duration of the

acoustic bursts were computer controlled by a specially designed signal generator, allowing

us to not only reproduce the frequency modulation used in the clinic but also to study other

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driving regimes. In this work, the acoustic bursts were generated with a frequency set of 400,

400, 433, and 433 kHz.

Acoustic waves were measured using a needle hydrophone with a frequency range of 50

kHz–1.9 MHz (Y-104, Sonic Concepts, Inc., Bothell, WA). The sensitive element of the

hydrophone was a ceramic crystal with a diameter of 1.5 mm. The sensitive element was

embedded at the rounded tip of the hydrophone enclosed in a metal tube with a diameter of 3

mm. As the diameter of the tip was comparable with the wavelength of acoustic waves (

3.4

–

3.8 mm), the hydrophone sensitivity depended on hydrophone’s orientations and was

about 6 V/MPa for the normal angle of incidence of acoustic waves. The angular response of

the hydrophone was measured and taken into account in these measurements. The

uncertainty of pressure measurements was estimated to be on the order of 30%. Another

uncertainty was related to the scattering of acoustic waves by the irregular surface of the

urinary stone. As the characterization of wave scattering was beyond the scope of this report,

the driving acoustic pressure was measured without the stone by positioning the sensitive tip

of the hydrophone at the focus of the microscope. The pressure at the stone, however, could

be greater due to reflection of pressure waves from the nearly rigid surface of the stone.

A typical trace of the hydrophone is shown in Fig. 3. The central frequency of the driving

acoustic bursts was 416.5 kHz with the duration of the beat envelope of

s. During the

first four acoustic cycles (

90 – 100

s), the driving pressure increased reaching a pressure

amplitude of ~1.5 ± 0.5 MPa. The increase of the driving acoustic pressure was associated

with the growth of bubbles toa larger size from cycle to cycle. The collapse of the larger

bubbles could produce daughter microbubbles that became visible in the subsequent acoustic

cycles. In this study, we focus on the dynamics of a single microbubble during one acoustic

cycle marked by a red rectangle starting at

s and lasting for a period of 2.4

s (Fig. 3).

D. NUMERICAL MODELING

The collapse of the gas bubble in the liquid was simulated using a compressible multi-

component flow solver.

In the solver, an anti-diffusion based interface sharpening

technique

was used to suppress numerical diffusion of the gas-liquid interface. We neglect

viscosity, surface tension, and heat and mass transfer across the gas-liquid interface. The

bubble was assumed to remain axisymmetric. The stone was modeled as an acoustically-

rigid infinite plane wall. Both fluids were initially at rest, assuming that the bubble was fully

expanded before its collapse. The initial pressure of the liquid was set to

∞

= 1.55 MPa.

The initial pressure and density of the gas, the shape of the bubble, and its stand-off distance

from the wall were varied.

3. RESULTS

A. HIGH-SPEED VIDEO MICROSCOPY OF BUBBLE DYNAMICS

Figures 4 and 5 show typical growth-collapse cycles of representative microbubbles at the

surface of an urinary stone. These sequences of images were recorded with the high-speed

camera during one acoustic cycle of the driving wave marked by the red rectangle in Fig. 3.

Under these driving conditions, microbubbles grew to several tens of micrometers. The

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bubble in Fig. 5 was smaller and collapsed earlier than the bubble in Fig. 4. Among

hundreds of microbubbles observed in this system over the course of months of experiments,

the vast majority exhibit a slightly non-spherical shape at their maximum expansion similar

to that seen in the

~ 1

s frames in Figs. 4 and 5, with a cross-section well modeled as an

ellipse.

B. NUMERICAL MODELING

We modeled the collapse approximating the initial shape of the bubble as an oblate spheroid

(major semi-axis of 31

m, minor semi-axis of 20

m, and the stand-off distance of 12

with two initial gas pressures (

= 10 Pa and

= 7 kPa) representing low and high gas

content in the bubble (Fig. 6). The pressure

was chosen by approximating that the

bubble filled with ambient air was polytropically expanded from about 1.2 to 26

m radius;

the pressure

would occur in the expanded bubble filled with water vapor at

39°C.

Despite the three-orders-of-magnitude difference in the gas content of the bubbles (10 Pa vs

7 kPa), the bubbles show similar dynamics (Fig. 6) and produced similar pressures at the

stone surface (Fig. 7). The bubble dynamics, however, strongly depended on the initial shape

and stand-off distance (Fig. 8).

Figure 8 shows the collapse of the bubbles with three distinct initial geometries: a

hemisphere (a), an oblate spheroid (b), and a sphere with the stand-off distances of 1.25 (c)

and 1.75 (d). The hemispherical bubble and the bubble with the initial shape of an oblate

spheroid were collapsing mainly in the direction toward the axis of symmetry of the bubble

with a circumferential narrowing pinching the bubbles. The spherical bubble collapsed

without the pinching even though the flow of liquid toward the axis of symmetry deformed

the sphere into the egg shape at the beginning of the collapse. Later during the collapse the

axial jet dominated the dynamics of the collapse of the initially spherical bubbles.

4. DISCUSSION

Kornfeld and Suvorov were among the first showing that cavitation bubbles growing and

collapsing at a rigid surface are non-spherical.

More recently, lipid-shell microbubbles

adherent to a flexible cellulose boundary were observed to oscillate asymmetrically

acquiring an ellipsoidal shape,

similar to the bubble shape observed in the present study

with microbubbles at the surface of urinary stones.

The present high-speed video observations showed that stone-adhering microbubbles driven

by ultrasound at sub–MHz frequencies with pressure amplitude on the order of 1.5 MPa

(Fig. 3) can grow to tens of micrometer in size (Figs. 4 and 5) and violently collapse.

Although the direct measurements of pressure produced by the collapsing bubbles is

difficult,

–

the numerical modeling of the collapse suggests that the bubbles can produce

pressures on the order of 0.5 GPa (Fig. 7). Hence, these results suggest that the collapsing

microbubbles can produce local pressures two-to-three orders of magnitude greater than the

amplitude of the driving wave.

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For comparison, this pressure amplitude is greater than peak positive pressures generated in

the focus of shock wave lithotripters. In shock wave lithotripsy, to break urinary stones the

shock pulses have peak positive pressure of 15–120 MPa.

–

This positive-pressure phase

of the lithotripter pulse is followed by the negative-pressure phase with a tensile stress of 5–

20 MPa. The tensile stress causes an inertial growth of cavitation bubbles that collapse

usually hundreds of microseconds after the passage of the lithotripter pulse.

–

Therefore,

cavitation bubbles in shock wave lithotripsy collapse under a static pressure of 0.1 MPa. In

comparison, the collapse of the stone-adhering microbubbles considered here was intensified

by the positive-pressure phase of the driving acoustic wave with the amplitude of ~1.5 MPa.

Further, the lithotripter shock pulses have a total duration of

s and are typically

administered at pulse repetition frequencies (PRFs) of 0.5–2 Hz.

–

Moreover, it has been

shown that stone breakage at 2 Hz PRF was significantly reduced in comparison with stone

breakage at 0.5 Hz.

–

In comparison with shock wave lithotripsy, the stone-adhering

microbubbles driven with acoustic bursts can produce thousands of collapses per second.

One caveat to the present numerical results is that mass transfer was not modeled. To assess

the extent to which the gas content may influence bubble dynamics, we modeled the

collapse with two initial gas pressures:

= 10 Pa and

= 7000 Pa. The pressure

which is the vapor pressure at

39°C, was likely a representation of high gas content in the

bubble. The modeling showed, however, that both bubbles had similar dynamics during the

collapse (Fig. 6) and produced similar pressures at the rigid surface (Fig. 7). Specifically, the

peak pressure produced by the collapsing bubbles at the rigid wall was 445 MPa at

and

421 MPa at

(Fig. 7). Hence, this numerical modeling suggests that the gas content in this

range did not substantially affect the results.

In the present modeling, we did not assess the influence of the grid resolution. We plan on

refining the grid resolution by using an adaptive mesh refinement approach.

Here the stone was modeled as an acoustically rigid plane wall neglecting elasticity and

geometry of urinary stones. It has been shown, however, that both factors influence the

dynamics of bubbles.

Furthermore, in this work the driving acoustic field was measured

without the stone in place. It is reasonable to anticipate that the actual pressure field at the

stone would be influenced by the scattering of the acoustic waves from the stone. The

geometry of the hydrophone, however, did not allow us using the hydrophone for acoustic

measurements at the stone without affecting the acoustic field. Here, the driving pressure

was modeled as a pressure step with a constant pressure

∞

at large distances from the

bubble.

The driving transducer was submerged in the water tank providing almost ideal transmission

of the acoustic waves. It has been observed with dry-head lithotripters that the coupling gel

could trap air pockets diminishing the transmission of acoustic energy to the target.

–

The investigation of the extent to which the above effects may affect the acoustic field was

beyond the scope of this report.

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5. CONCLUSION

In summary, we used high-speed video microscopy to observe the dynamics of microbubbles

at the surface of urinary stones

in vitro

. Microbubbles, driven by acoustic bursts with sub-

MHz central frequencies and

1.5 MPa pressure amplitudes, expanded to tens of

micrometers in diameter and were non-spherical. The bubble geometry observed in the high-

speed camera observations was used as the initial shape for the numerical modeling. The

modeling showed that microbubbles collapsing at the rigid surface produced pressure spikes

two-to-three orders of magnitude greater than the amplitude of the driving wave. This

focusing ability of stone-adhering microbubbles can enable stone-treatment modalities with

driving pressures significantly lower than those required without stone-adhering

microbubbles.

ACKNOWLEDGMENTS

We thank Dr. R. Shiraki for chemical analysis of stones’ composition. MS and TK are founding members of

Applaud Medical. YP, WBP, MM, MH and DL are employees/investigators for Applaud Medical, where the

experimental part of this work was done. Numerical modeling was performed in Caltech by TC and KM, who

acknowledge support from the National Institutes of Health (P01-DK043881) and the Office of Naval Research

(N00014-17-1-2676 and N0014-18-1-2625).

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Figure 1:

The concept of treating urinary stones using microbubbles with calcium-adhering moieties.

Gas-filled microbubbles are introduced into the urinary tract through a catheter and adhere

to an urinary stone (middle). The adhered microbubbles are excited with an extracorporeal

source of quasi-collimated ultrasound and erode the stone facilitating its passage through the

urinary tract.

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Figure 2:

Experimental setup. Left: general view with the HS-camera (top left), the spark-light source

(bottom left), and the water test tank positioned over the inverted microscope (center).

Middle: view in the test tank. Right: zoomed up view of an urinary stone positioned at the

focus of the microscope. Backand side-illumination was provided by two liquid lightguides

positioned at about 1 cm from the stone.

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Figure 3:

The driving acoustic pressure measured with a hydrophone positioned at the focus of the

microscope. The red rectangle marks the acoustic period shown in HS-camera movies (Figs.

4 and 5).

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Figure 4:

High-speed imaging of the growth (top row) and collapse (bottom row) of a bubble at the

surface of an urinary stone during one acoustic cycle recorded in FP mode at 5 Mfps and

100-ns exposure.

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Figure 5:

High-speed imaging of the growth and collapse of a bubble recorded in HP mode at 10 Mfps

and 50-ns exposure. The bubble growth (top row) is shown at 0.2-

s step skipping every

other frame.

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Figure 6:

Two simulations of bubbles collapsing with different initial gas pressure of

= 10 Pa (top)

and

= 7 kPa (bottom) representing low and high gas content in the bubble. The top

halves show the volume fraction of liquid

; the bottom halves show the pressure

. The

black contour lines are drawn at the volume fraction of

= 50% suggesting the position of

the liquid-gas interface. The stone was modeled as a rigid surface located along the left

boundary of the simulation domain, initially separated from the microbubbles by a thin layer

of liquid.

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Figure 7:

Pressure

vs time

at five lateral distances

along the stone surface for the two simulations

shown in Fig. 6. The radial distance

= 0 corresponds to the axis of symmetry of the bubble.

Regardless of the initial gas pressure in the bubble (

and

), the bubbles produced

pressure pulses with an amplitude about two-to-three orders of magnitude greater than the

driving pressure of

∞

= 1.55 MPa.

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. Author manuscript; available in PMC 2020 May 21.

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