Cav03-OS-2-1-006 Fifth International Symposium on Cavitation (CAV2003)

Osaka, Japan, November 1-4, 2003

CAVITATION IN SHOCK WAVE LITHOTRIPSY

Michael R. Bailey Lawrence A. Crum

Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, Seattle, Washington,

98105 USA bailey@apl.washington.edu

lac@apl.washington.edu

Andrew P. Evan James A. McAteer

James C. Williams, Jr. Department of Anatomy and Cell Biology, Indiana

University School of Anatomy, Indianapolis, Indiana, USA

evan@anatomy.iupui.edu mcateer@anatomy.iupui.edu williams@ anatomy.iupui.edu

Oleg A. Sapozhnikov Department of Acoustics,

Physics Faculty, M.V. Lomonosov Moscow State University, Moscow, Russia oleg@acs366.phys.msu.su

Robin O. Cleveland Department of Aerospace and Mechanical Engineering, Boston University, Boston,

Massachusetts, USA robinc@bu.edu

Tim Colonius Department of Mechanical Engineering, California

Institute of Technology, Pasadena, California, USA

colonius@caltech.edu ABSTRACT

A case is presented for the important role of cavitation in stone comminution and tissue injury in shock wave lithotripsy (SWL). Confocal hydrophones and a coincidence algorithm were used to detect cavitation in kidney parenchyma. Elevated hydrostatic pressure dissolved cavitation nuclei and suppressed cell injury and stone comminution in vitro. A low-insertion-loss, thin, mylar film nearly eliminated stone erosion and crack formation only when in direct contact with the stone. This result indicates not only that cavitation is important in both cracking and erosion but also that bubbles act at the surface. Time inversion of the shock wave by use of a pressure-release reflector reduced the calculated pressure at bubble collapse and the measured depth of bubble-induced pits in aluminum. Correspondingly tissue injury in vivo was nearly eliminated. Cavitation was localized and intensified by the use of synchronously triggered, facing lithotripters. This dual pulse lithotripter enhanced comminution at its focus and reduced lysis in surrounding blood samples. Enhancement of comminution was lost when stones were placed in glycerol, which retarded bubble implosion. Thus, cavitation is important in comminution and injury and can be controlled to optimize efficacy and safety.

INTRODUCTION

Shock wave lithotripsy (SWL) is a common and effective clinical method to comminute kidney stones [1]. With the

advent of percutaneous surgical techniques, SWL continues to be the favored method of treatment for uncomplicated, upper urinary tract calculi [1-3]. Further understanding of the mechanisms of action of SWL could help expand its application to complicated conditions, such as ureteral stones, for which SWL is currently rather ineffective.

However, the evidence is increasingly strong that SWL treatment also causes tissue injury [4]. Such injury includes vascular trauma in the kidney parenchyma [5], oxidative injury [6], and acute impairment of renal function [7-8]. Injury increases with shock wave number [9] and pressure amplitude [10]. There is a measurable risk of severe acute injury such as lacerations, hematoma [11], and acute renal failure [12]. The risk of acute and chronic injury, such as hypertension, may be higher in patient subsets, such as elderly or juvenile patients [13].

Clinicians and manufacturers have reacted positively to this research evidence of tissue injury. Clinicians commonly treat juvenile patients at lower energies [14]. Papers relating to lithotripsy-induced injury appear frequently in urology journals and now are featured prominently in nephrology journals as well (e.g., the Nephron featured the manuscript by Evan et al. [5] on its cover). Manufacturers have steadily increased the pressure amplitude at the focus of devices and reduced the focal size, perhaps, in an effort to reduce the required number of shocks and to avoid tissue damage by restricting high acoustic pressures to the stone. Figure 1 compares shock waves

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generated by two machines; approximately 2000 shock waves are applied at 1-2 Hz in a clinical treatment.

However, by many clinical measures, lithotripsy is becoming neither more efficacious nor safer. Comminution studies fail to show that newer tight-focal machines break stones more efficiently than the first lithotripter design (Dornier HM-3) to gain widespread clinical use in the 1980s [15]. Retreatment rates are higher with new machines [16-18]. Incidence of adverse effects is increasing [11,19-21]. We conclude from this current state of lithotripsy that there is a desire and a need for a fuller understanding of the mechanisms of tissue damage and stone comminution and for direction on how to use this understanding to improve clinical treatment.

BACKGROUND Mechanisms of Stone Comminution

Concurrent with the evolution of clinical lithotripsy, a great deal has been learned about the mechanisms of stone comminution and tissue injury. Primarily, five stone comminution mechanisms have been studied in lithotripsy. They are erosion [22], spallation [10,23], dynamic fatigue [24], shear [25], and circumferential compression [26]. These mechanisms may all be activated to differing degrees by either the lithotripter shock pulse or the subsequent collapse of cavitation bubbles excited by the pulse. Erosion results particularly when bubbles collapse against a surface. Individual bubbles and bubble clusters create jets as shown in Fig. 2. The shock wave transmitted into the stone when the jet impinges on the stone or the acoustic transmission into the stone of the lithotripter pulse can lead to spallation. Spallation in SWL is tensile failure of the stone near the back surface as the predominantly positive pulse reflects and inverts from the acoustically soft interface of stone to fluid (the specific acoustic impedance of stones is roughly three to five times higher than that of water or urine). The then-negative-pressure phase superimposes with the negative-pressure tail of the pulse creating a high tensile stress. Stones are often seen to spall.

Dynamic fatigue is a failure process whereby cracks grow under the repeated compressive and tensile cycles. Focusing the shock wave can create pressure gradients, and therefore, shear forces within the stone. Circumferential compression or “squeezing” is the result of the compressive shock pulse traveling faster in the stone than in the surrounding fluid. Hence, at some point the pulse has traveled through the stone, but ringing the stone is the high pressure of the shock pulse in water. The compressive ring at the equator of the stone produces tensile stress and cracks at its poles. Compression and spall contribute when the stone is large: stones are 2- 10 mm, bubble clusters reach ~10 mm, the lithotripter pulse is 1-10 mm, bubbles and jets are 1 µm-1 mm, and the shock front is 150 nm. Research indicates cavitation is an important factor [27-29], stones initially break by spall, and erosion grinds the fragments into a size suitable for the patient to pass [30]. Simply breaking the stone into pieces is a negative outcome: fragments must be 2 mm or smaller.

Figure 1. Comparison of waveforms measured by membrane hydrophone at the focus of an elecrtrohydraulic lithotripter (Dornier HM3) and an electromagnetic lithotripter (Storz SLX) at their highest energy settings. Comminution performance does not correlate with the peak pressure alone.

Mechanisms of Tissue Injury

50 SW’s50 SW’s

Figure 2. High speed images of a bubble cluster collapsing on the proximal face of the stone ~700 ms after shock wave passage and the ensuing damage after 50 shock waves [63].

Two main mechanisms have been suggested to explain the occurrence of tissue damage in SWL. These include 1) cavitation (defined here as SW-bubble interactions involving either the collapse or expansion of cavitation bubbles) and 2) non-cavitational forces such as a shear stress. Renal injury in SWL is primarily a vascular lesion [5] accompanied by a reduction in renal blood flow due to an SWL-induced vasoconstrictive response [4]. Cavitation within blood vessels may be directly responsible for SW-induced hemorrhage [7]; although it is also possible that non-cavitational injury initially tears the vessel creating a blood pool in which cavitation can take hold.

Objective of this report

This is a report of some of the evidence indicating a dominant role of cavitation in both stone comminution and tissue injury in SWL. In the process, methods of cavitation control in SWL are reported. It is suggested that these methods could form the basis for improved lithotripters.

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RESULTS Cavitation in vivo Our group and other groups have observed cavitation in

vivo with passive cavitation detection [33-5] and have seen bubbles in vivo on B-mode ultrasound [36-8], and our group detected and confirmed cavitation within the kidney parenchyma during SWL [38]. Pits attributed to cavitation have even been observed in gall stones treated with lithotripsy [39].

Cavitation in water The HM3 lithotripter generates a large cluster of bubbles

that last for hundreds of µs in water. Figure 3 shows the

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Cavitation sites were pinpointed with a system and a methodology that form the basis of our proposed monitoring system. The system, including micro-positioners, is mounted on the HM3 reflector. A real-time ultrasound-imaging probe (C15 cardiac probe for a Sonosite 180 imager (Bothell, WA)) is positioned in the middle. Other imaging systems have been used (e.g., BK, an ATL HDI-1000, HP Sonus). Two large, single-element focused source/receivers (10-cm diameter, 10-cm radius of curvature, 1.1 MHz resonance frequency) are angled so that their focal volumes intersect. These confocal transducers are used as dual passive cavitation detectors, such that the intersection of their sensitive areas together with coincidence detection make dual PCD sensitive to only a tiny region in the tissue (maximum dimension of 3 mm) [31].

222 µs after spark 519 µs

741 µs667 µs593 µs

7.25 cm

Figure 3. Bubble cluster growth and collapse in water.

ylindrical 1.5 cm x10 cm cavitation cloud created in the water ath of the lithotripter and recorded by the high speed camera. rame (a) shows the scale, and the pointer indicates the eometrical focus F2 of the lithotripter and the shock wave irection. The acoustic travel time from spark to F2 is 180 µs. cylindrical cloud grew and collapsed in ~540 µs. In frame (c)

he individual bubbles are the largest (0.5-1 mm in diameter) nd the cloud is the broadest. In frame (f) the cloud is 2-3 mm n diameter. Figure 3 was obtained by triggering 10 lithotripter hock waves at 1 Hz and recording the 11th.

Figure 5. Hyper-echo in kidney collecting system and parenchyma (bright spots) during SWL indicates bubbles produced by cavitation.

Collecting

Kidney

Figure 4 shows the simultaneous recording by a focused ingle element receiver or passive cavitation detector (PCD). he PCD had a radius of curvature of 200 mm, a diameter 100 m, and a resonance frequency 1.08 MHz. The output signal as high-pass filtered (300 kHz) to remove the noise created by

xcitation of a radial resonance of the sensing element. Signals ere demodulated to remove the 1-MHz ringing of the element,

nd the PCD was calibrated by Cleveland et al. [31] A strong pike is seen at 180 µs when the acoustic pulse arrives at the ocus and is a mix of scattering from ambient bubbles and coustic emission of the collapse of these bubbles. The second

We measured cavitation in porcine kidney parenchyma in

vivo. Figure 5 shows the hyper-echo, created after 338 shock waves (applied in bursts of 20 at 2 Hz with each burst alternating 18 kV and 24 kV), that corresponds to bubbles forming within the tissue. At the same location in the kidney parenchyma, our dual PCD transducers simultaneously detected the classic double acoustic emission signature of lithotripsy cavitation: one emission occurs when the shock first hits a bubble in the focal volume; a silent time ensues while the bubble grows, and then a second emission occurs when the bubble collapses. Figure 6 shows the demodulated transducer signals (the second signal is inverted for comparison). The initial emission on both occurred at 250 µs (the common

highspeed29jun98:pcd92 11-Aug-1998

0 100 200 300 400 500 600 700 800 900 10000

5

10

15

20

25

Pres

sure

(M

Pa)

Time (µs)

Figure 4. Passive Cavitation Detection signal.

pike 540 µs later corresponds with the final collapse of the line f bubbles. Simultaneous sonoluminescence spikes correspond emporally with the 2 acoustic emissions [32].

precursor is due to the direct wave) and has the appropriate travel-time from source to focus to the receiver. The second emission occurred at 680 µs and first appears with the shock wave that produces the hyper-echo. There are more spikes between 70 and 300 µs. Spikes in this region vary in time but

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region vary in time but are very rarely coincident. The silent/growth time is longer for higher amplitude shock waves, which is evidence that the emissions arise from cavitation.

( )R

RR

pRp g

&µσ 4 2 −−= , (3)

where pg is the pressure of the gas within the bubble, σ is the surface tension of the liquid, and µ is the coefficient of shear viscosity of the liquid. The gas pressure pg is proportional to the quantity of gas in the bubble and the gas temperature.

Figure 6. Coincident cavitation signatures (signal from one PCD receiver is inverted) record cavitation in kidney tissue.

0 300 600 Time

10 mV

Noncoincident signals

2nd Direct wave

1st

Pulse Repetition Frequency A means to regulate cavitation and one that is available to

the urologist at the time of treatment is to change the pulse-repetition frequency (PRF). Increasing the SW delivery rate generates more cavitation bubbles [40]. It has also been demonstrated that delivery of SW’s at very fast rate increases kidney injury in experimental animals [41]. We tested the hypothesis that increased overpressure and decreased PRF act to reduce cavitation activity by allowing bubbles to dissolve between shock pulses.

Our numerical model [46] is the synthesis of a bubble dynamics model created by Church [42] based on the Gilmore’s equation [43] and a bubble dissolution model described by Epstein and Plesset [44]. As shown in Fig. 7, our model traces the radius of a bubble as the lithotripter pulse sets the bubble into a dramatic growth and collapse (A) followed by a slow dissolution of the bubble (B). The bubble radius R is described by the Gilmore equation,

)(t

dtdH

CR

CRH

CRR

CRRR

CR

−+

+=

−+

−

&&&

&&&

&11

31

231 2 ,

(1) We use the approximation by Eller and Flynn [45] as

Church [42] did for the region A in Fig. 7 where the bubble radius is rapidly changing and the approximation by Epstein and Plesset for region B where the static bubble slowly dissolves.

1E-7 1E-6 1E-5 1E-4 1E-3 0.01 0.1 1 10 100 1 0001E-7

1E-6

1E-5

1E-4

1E-3

3 bars 2 bars

p0 = 1 barp+ = 100 bars

Bubb

le ra

dius

R (m

)

-500

0

500

1000

Acoustic pressure (bars)

1E-7 1E-6 1E-5 1E-4 1E-3 0.01 0.1 1 10 100 1 0001E-7

1E-6

1E-5

1E-4

1E-3

3 bars

2 bars

p0 = 1 barp+ = 500 bars

Bub

ble

radi

us R

(m)

-500

0

500

1000

Acoustic pressure (bars)

1E-7 1E-6 1E-5 1E-4 1E-3 0.01 0.1 1 10 100 1 0001E-7

1E-6

1E-5

1E-4

1E-3

Time (sec)

3 bars 2 bars

p0 = 1 barp+ = 1000 bars

Bub

ble

radi

us R

(m)

-500

0

500

1000

Acoustic pressure (bars)

A

B

A

B

A

B

Figure 7. Calculated R(t) curves (solid lines) for different amplitude shock waves p+ = 100, 500, and 1000 bar and varying static pressure p0 = 1, 2, and 3 bar. Initial bubble radius was R0 = 3 µm. The driving lithotripter waveforms are shown as dashed lines. Time intervals A and B, divided by dotted lines, distinguish different stages in bubble dynamics. The maximum bubble radius and the bubble lifetime increased with p+ and decreased with p0.

where a dot signifies a time derivative, C is the sound speed in the liquid at the bubble wall, H is the difference between the specific enthalpy in water at the bubble wall relative to the specific enthalpy in the water far from the bubble,

( )∫

∞

=Rp

p

dpHρ

.

(2)

The Eller and Flynn [45] model in their first order approximation, results in the following expression for the number of gas moles in the bubble:

( )∫ ′

′−

′−=

τ

ττττπ

00 4 dFDnn , (4)

Here p(R) and p∞ are the pressure in the liquid at the bubble interface and the pressure (static plus acoustic: p pp ′+=∞ 0 ) far from the bubble.

where and . ( ) tdtRt

′′= ∫0

4τ is ccF −=

The pressure in the liquid at the bubble wall is given by Then, after about tm=1 ms (region B in Fig. 7), the bubble has stopped pulsating. Its radius Rm = R(tm) is larger than the

4

initial bubble radius R0 because of gas diffusion into the bubble during bubble growth. Now, surface tension, static pressure and a gas concentration gradient drive gas diffusion from the bubble to the liquid, leading to the bubble dissolution (n=0). Eller and Flynn’s approximation is not valid during this process. On the other hand, the bubble radius during its dissolution varies relatively slowly, and the Epstien and Plesset model is appropriate. Then, for the number of gas moles in the bubble, one has

( )( )

−+⋅−⋅−=

mis ttDR

ccDRdtdn

ππ 114 2 .31

Parameter values chosen were for water at laboratory conditions: σ =0.071035 N/m, µ=0.0008019 Ns/m2, p0=0.1 MPa, ρ0=1000 kg/m3, C0=1480 m/s, T0=20 oC, γ=1.4, and kH= 116200 N ⋅ m/mole.

Calculated R(t) curves describing the bubble life for the fast increase in static pressure are shown in Fig. 7. The initial bubble radius is 3 µm and f0i=1. Three boxes correspond to different peak acoustic pressures p+ = 100, 500, and 1000 bar. The bubble radius curve is solid, and the acoustic pressure of the lithotripter pulse driving the bubble is represented by a dashed line. All axes except acoustic pressure are plotted in logarithmic scale. It is seen that the initial positive-pressure spike of the lithotripter pulse results in a rapid constriction of the bubble to a radius of about 1 µm (the first collapse). Then, the negative-pressure phase of the lithotripter pulse initiates the growth of the bubble. The inertia imparted to the liquid surrounding the bubble is sufficiently large that the bubble continues to grow after the lithotripter pulse has passed. Growth continues for a relatively long period (in excess of 100 µs). Eventually, the static pressure in the fluid forces the bubble to collapse again. Let us denote the time of this inertial collapse as tC*. After a series of rebounds (subsequent smaller growth and collapse cycles) at t=1 ms, the bubble reaches a more stable radius that Church [42] referred to as the “time-varying equilibrium radius.” The term equilibrium radius is used here too following Church’s convention, although the radius is changing slowly as the bubble dissolves. The equilibrium radius is larger than the initial radius. The gain in the bubble size is due to ingress of gas from the surrounding liquid during the expansion phase of the bubble life, when the pressure in the bubble is much lower than the static pressure in the liquid (i.e. liquid near the bubble wall is supersaturated with gas). However, the non-pulsating bubble slowly dissolves, and finally, the bubble radius tends to zero (i.e. the bubble disappears). This time tL* defines the bubble lifetime. Different curves in each box of Fig. 7 correspond to different static pressures p0. It is seen that during the first 10 µs the bubble radius behavior is not sensitive to p0. The strong negative acoustic pressure of the lithotripter pulse drives the bubble at this period. The peak positive (p+ = 100 - 1000 bar) and negative (p- = 16 - 160 bar) pressure amplitudes in the lithotripter pulse are much greater than p0 (1 - 3 bar). After the lithotripter pulse has passed, the static pressure becomes the main factor driving inertial behavior of the bubble. As a result,

the increase in p0 gives rise to a shortening of the collapse time tC*, a decrease in maximum bubble radius, and an increase in minimum radius. The equilibrium radius decreases and the lifetime tL* shortens for higher p0.

The lifetime tL* shows how fast cavitation seeds dissolve before the next pulse arrives. The lithotripter pulse repetition period (T=1/PRF) is of the order of T=1 s. If the lifetime exceeds this value, the cavitation bubbles do not have enough time to dissolve between successive pulses, i.e. the cavitation should be very pronounced. In contrary, if tL*< T, then the cavitation seeds dissolve, and the cavitation is suppressed. The lifetime is fairly insensitive to the initial bubble size, especially if R0 < 10 µm. This insensitivity is in agreement with the results of Church [42], who calculated that the R(t) curves for a bubble in a lithotripter are practically identical for different R0. As a result, the amount of the gas that diffuses into the bubble during the relatively long period of its inertial behavior is also insensitive to the value of R0. Note that the amount of diffused gas exceeds many times the initial amount of gas in the bubble. Diffusion makes the equilibrium bubble radius after the inertial

collapse and rebounds, Rm, fairly independent of R0.

0.8 1.0 1.2 1.4 1.6 1.8 2.0

10

20

30

40

50

60

70

300 bars

400 bars

Ambient pressure p0 (bars)

p+ = 500 barsD

isso

lutio

n tim

e t d

(sec

)Li

fetim

e t L*

(se

cond

s)

Figure 8. Comparison of calculations and measurements of the bubble lifetime versus p0. Measured lifetime tL (diamonds) was determined from the presence of hyperechogenicity in B-mode images of the pipette. Calculated lifetime tL* (solid line) is shown for shock wave amplitudes that cover the variation in the shock waves generated by this lithotripter.

Figure 8 shows a plot of bubble lifetime versus p0. The figure compares the calculated lifetime tL* for selected shock wave amplitudes (solid lines) with the measured lifetime tL of hyperecho in the pipette (diamonds). An initial radius of R0 = 3 µm was used in the calculations, but recall that the calculations were not very sensitive to initial bubble size. Peak pressures of the pulses were p+ = 384 ± 62 bar and p- = 100 ± 14 bar (mean ± standard error for N=10 measurements) but could not be recorded simultaneously with the measurement. Curves were calculated for three values of p+ to cover the range of p+ produced by inter-spark variation. Lifetime tL measured on B-mode ultrasound image was the time between the interference

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caused by spark discharge and hyper-echo dissipation and was quantified on digitized video frames as described in the Methods section. Both measured tL and calculated tL* decay quickly with increasing static pressure and are in excellent qualitative agreement with each other. The dissolution time in the experiment was slightly less than in the calculations for large overpressure. Passive cavitation signals are also suppressed and high speed camera images fail to capture bubbles at overpressures greater than 1 bar in the free field.

Overpressure Elevated hydrostatic pressure (overpressure) suppresses

stone comminution, pitting on aluminum foil, and tissue injury [47-8,65]. Figure 10 shows some results. The inset shows the chamber which has an acoustically matched window for efficient transmission of the shock wave. Area increase is the projected area of the stone fragments on a flat digital scanner relative to the projection of the intact stone. This method allows for rapid quantification of comminution without drying (i.e., introducing gas into) the stone. Comminution effectiveness is dramatically reduced at both 14 and 136 atm of static pressure although the negative pressure of the lithotripter shock wave is 100-120 atm.

High-speed camera images were collected for p0 = 1, 1.5, and 2 bar, and PRF = 0.5, 1, 2 and 3 Hz. Figure 11 shows the images recorded at one half of time for the second collapse tC/2. Charging potential was 18 kV. At zero overpressure (p0 = 1 bar), all four rates produced a dense cluster of bubbles in water. By visual inspection, cluster density appeared to increase with increased PRF. At 0.5 bar overpressure (p0 = 1.5 bar), bubbles were sparse at PRF = 0.5 and 1 Hz, but dense at 2 and 3 Hz. At overpressures of 1 bar and above, the field was sparse for all the tested PRFs. This result indicates that bubble lifetime was greater than 2 s at atmospheric pressure, was in the range of 0.5 - 1.0 s at 1.5 bar, and was less than 0.33 s at 2 bar. These values agree well with the measured values in Fig. 10 and are slightly lower than the calculated values. The similarity indicates that the ultrasound is able to detect bubbles that cause cavitation seen with the camera, and that p0 and PRF can be used together to suppress cavitation.

Pulse Repetition Rate (Hz)

0.5 1 2 3

Ove

rpre

ssur

e (a

tm)

0

0.5

1

Figure 9. High speed images of the peak bubble cloud as a function of overpressure and pulse repetition frequency (PRF). At p0 = 1 bar (top), bubbles did not dissolve between pulses and a dense bubble cluster is apparent for all the PRFs getting more dense with increasing PRF. At p0 = 2 bar (bottom), bubbles did dissolve between pulses and a sparse bubble cluster is apparent for all the clinical PRFs. At p0 = 1.5 bar (center), 2 and 3 Hz were fast enough rates to create a dense cluster, but 0.5 and 1 Hz were too slow. Hence, the lifetime tL at p0 = 1.5 bar was greater than (1 Hz)-1 = 1 s but lesser than (2 Hz)-1 = 0.5 s. These images show that increased static pressure and PRF can be used together to suppress cavitation.

Lysis of suspended cells drops from 10% to near control

levels (<1%) at only 1-2 atm of overpressure, although damage to aluminum foil or stones is not dramatically effected until over 5 atm [47-8]. The argument has been made that cavitation bubbles that injure the stone are stabilized by cracks and crevices in the stone surface [46]. Stabilization of bubbles by cracks was investigated with a glass microscope slide before and after it cracked. The PETE bottle pressure chamber was used, and the slide fit across the diameter of the bottle as shown in Fig. 11. The transparency of the glass enabled back lighting and visualization of the cluster of bubbles on both sides of the slide. Figure 11 shows camera images of the cluster produced at p0 = 1 bar (top) and at p0 = 4 bar (bottom) before (left) and after (right) a crack formed in the glass slide. Charging potential was 18 kV, and PRF was 1 Hz. At p0 = 1 bar, a dense cluster of bubbles was seen in both cases. The cluster was slightly bulbous at the interface with the glass. The crack can be seen in the center of the bulge. At p0 = 4 bar, no bubbles were seen on the crack-free glass (left) or in the free-field surrounding the cracked glass. But at the crack, bubbles can be seen. These data indicate that overpressure suppressed cavitation in the free field but not at the crack in this solid object. It is important to note that the crack shown in this image was caused by shock wave treatment while the slide was immersed in the water within the lithotripter tub. Thus, the crack could not have been filled a priori with gas. It appears, therefore, that the crack may have served to attract, then stabilize cavitation nuclei.

Figure 10. Stone comminution is dramatically reduced by elevating the static pressure. Overpressure’s effect is to dissolve cavitation nuclei.

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Stone Location The peak negative pressure in the Dornier HM3 lithotripter

occurs 2 cm proximal to the geometric focus of the ellipsoid where the stone is placed for treatment. The peak positive is ~1 cm distal. The difference in focusing is attributed to self-refraction and has been calculated and measured. Suitably the maximum cavitation activity (measured by a free-radical chemical reaction) in vitro is greatest at the -2 cm position [59]. Stone comminution and hemolysis in vitro are also greatest at the -2 cm position [59]. Figure 12 shows the stone results.

camera shock wave

overpressure glass plate

crack

p0 =

1 ba

r no crack crack

p0 =

4 ba

r

Figure 11. Images (3.8 cm per side) of the bubble cluster produced at p0 = 1 bar (top) and at p0 = 4 bar (bottom) before (left) and after (right) a crack formed in the glass slide. At 4 bar the cavitation was suppressed in the free-field but was persistent at the crack. Charging potential was 18 kV, and PRF was 1 Hz.

Cavitation Interference

Stones did not break when placed in a viscous liquid [39] and even a small membrane placed against the surface of the stone prevented cavitation collapse on the surface and reduced comminution [49]. Figure 12 shows the results of surrounding the stone in water-soaked gauze as a tissue phantom and placing a thin mylar disk either against or a few mm from the proximal surface of the stone [62]. The stones are cylindrical cement stones. The top are µCT images through the stones along the SW axis. The bottom show damage to the stone’s proximal face. This same cement stone implanted into a pig ureter also fails to fragment as well as stones implanted into the pig collecting system. Clinically, ureteral stones are very difficult to break. Our hypothesis is that the close contact with the ureter inhibits the formation of a cavitation cluster and violent collapse of the cluster on the stone surface. In contrast in a cavitation promoting medium, tissue injury is increased. Injection of microbubbles into the blood stream before lithotripsy significantly increased renal tissue injury [50].

W

sedu

7

Figure 12. Damage to stones without (left and with (right) a mylar film in contact with the proximal surface. Erosion and a fracture line (arrows) are apparent on the left but not i ht

aveform Manipulation

Position (cm from F2)

0

5

10

15

20

25

sham -4 -2 0 2 4

Perc

ent W

eigh

t Los

s

Figure 12. Stone comminution in vitro is significantly better at -2 cm where cavitation activity and peak negative pressure are greatest.

Dramatically different cavitation was produced by two parate acoustic pulses that had different shapes but similar ration, frequency content, and peak positive and negative

pressure [51-3]. 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. Our 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.

The pressure-release reflector nearly eliminated tissue injury in pigs. Pig kidneys treated with shock waves from a standard rigid reflector showed damage that was evident even on gross inspection as a subcapsular bleed consistently at the treated pole (lower pole) of the kidney but frequently extended to portions of the upper pole as well. Histologic analysis of the renal parenchyma showed a focal hemorrhagic lesion that involved both the cortex and medulla and commonly spanned the entire width of the kidney [5,7,54]. This zone of damage was focal, in that the parenchyma of the upper pole was never involved and there were broad areas of the treated, lower pole

that appeared undamaged. In comparison, very little damage occurred to kidneys treated with the PRel reflector [54]. These kidneys did not develop hematomas. On histological analysis the renal cortex was virtually undamaged and evidence of injury was limited to slight intraparenchymal bleeding in renal papillae that fell within the F2 focal zone of the lithotripter. Although such regions of bleeding were visible in histological sections these areas of hemorrhage were too slight to register by morphometric analysis. Based on our studies showing that the PRel reflector greatly suppresses cavitation in vitro [53], we believe the renal injury induced with the standard rigid reflector is caused by cavitation.

Rigid ReflectorRigid Reflector Pressure ReleasePressure Release

75 SW’s75 SW’s 150 SW’s150 SW’sFigure 14. The pressure-release reflector which creates shorter lived bubbles that collapse more weakly (i.e., bubbles radiate lower-amplitude calculated pressure waves and produce smaller shallower pits in aluminum foil) than cavitation produced by the rigid reflector, also fails to comminute stones.

P P ++ 43 +/43 +/-- 6 MPa6 MPaP P -- 14 +/14 +/-- 1 MPa1 MPa

P P ++ 42 +/42 +/-- 5 MPa5 MPaP P -- 12 +/12 +/-- 1 MPa1 MPa

Figure 13. The conventional lithotripter produced by the rigid reflector (left) and the essentially time-inverted waveform produced by the pressure-release reflector (right). The lower inset shows pitting at the focus and along the axis of the rigid reflector (left) and negligible pitting at the focus and along the axis of the pressure-release reflector (right).

Figure 13 shows sample waveforms and pits in foil from one pulse with each reflector. The sound source is an electrical spark which is highly variable. But he average peak positive and negative pressures are the same for he two pulses. The frequency content of the pulses is also nearly identical. Little has changed except that the pressure-release reflector creates a wave in which the negative tough precedes the positive spike not the other way around. It is not clear how this change would have a dramatic effect on SWL mechanism of action other than cavitation but it has a dramatic effect on cavitation. A line of pits is clear when the rigid reflector is used but cannot be seen when the pressure-release reflector is used. Pit depth is decreased by a factor of 3 and width by 7. The pressure generated in the bubbles as calculated using the Gilmore code is decreased by 13 with the pressure-release reflector waveform.

The PRel reflector also suppressed stone comminution. Figure 14 shows two typical stones. No measurable comminution was recorded with the PRel reflector whereas stone were well fragmented with the rigid reflector. Thus cavitation appears to be very important in stone comminution as well as tissue injury and the lithotripter waveform can have a stone influence on both bio-effects and cavitation.

Dual Pulse Sequences

A pair of pulses fired within hundreds of µs of each other usually from two sources can be used to mitigate or to intensify

8

τ = 300 µs τ = 190 µs τ = 25 µs

10 mm

(a) (b) (c)

Figure 15: Two pulse timing to increase or suppress cavitation pitting of aluminum foil. Second pulse has little effect: inter-pulse time τ is greater than collapse time of bubbles excited by one pulse tc (left). Second pulse intensifies collapse and pitting: τ ~tc (center). Second pulse mitigates bubble growth and reduces pitting: τ << tc (right).

10 m

m

depending upon the inter-pulse delay. As shown by the minimal bubble damage to the foil in Fig 15(right), [51,55] a second pulse that arrives as the bubble, excited by the first pulse begins to grow, is disrupted, and results in a weak bubble collapse. Thus, this spoiled collapse results in smaller and fewer pits

(right) than when the 2 pulses are far apart in time (left). However, a second pulse that arrives as the bubbles collapse intensifies the collapse and increases the number and depth of pits [as shown in the middle]. Cavitation intensification with two pulses is corroborated by the work of Zhong [57] and by numerical calculations as shown in Fig. 16. An increase in internal pressure in the bubbles rises and falls with the measured pit depth as a function of inter-pulse delay time normalized to the collapse cycle for a single pulse. The appropriate selection of a delay between the two pulses can be used to either suppress or to intensify cavitation; depending upon whether it is desirable to promote cavitation for stone comminution, or to suppress it to avoid tissue damage.

% W

eigh

t Los

s

0

10

20

30

40

50

60

-4 -2 0

sham

15 k

SP

DP

0

5

10

15

20

25

-4 -2 0 +215 kV

No.

frag

men

ts

SP

DP

Axia

Figure 18: By eifragments or maslithotripter broke stmore efficiently andsingle pulse lithothemolysis by the duathe single pulse at 18

A 180-degree, dual-pulse system was developed to localize and intensify cavitation on the stone while suppressing it within tissue. Two facing reflectors are used and the two

pulses are triggered simultaneously. Figure 17 compares the localized pitting of the dual reflectors to the long stripe of pits

produced by single pulses.following the pulse until the

centerline pulses superimposemore violent bubble growth athrough each other and supinitiated by the other pulse. for this dual-pulse system hcalculated. Initial investigati

1 cm

Figure 17. Two lithotriptersa stripe of pits when fired wthan tc1 and (b) a spot oregion when fired simultane

2e7

1e8

5e8

P

(M

Pa)

Interpulse Delay ∆t / t at F2 0 0.2 0.4 0.6 0.8 1 1.2

0

20

40

60 o

o oo o

o

o

Pit

Dep

th (

µm)

o

oo

oo

o

oo

oooo

o

c1

max

Figure 16. Cavitation intensity vs. inter-pulse delay relative to collapse time tc1 produced by one pulse: calculated pressure Pmax inside the bubble (top) and measured pit depth in foil (N=9).

9

(a)

(b)

facing each other produced (a) ith an inter-pulse delay greater f deep pits within a mitigated ously.

+2 +4 -4 -2 0 +2 +4

V 18 kV

b.

+4 -4 -2 0 +2 +418 kV

a.

l Position (cm from F2)

ther measure (number of s loss) the dual pulse ones exactly at the focus faster than conventional ripsy. Off the focus, l pulse at 15kV is less than kV.

Each pulse initiates cavitation pulses meet at the centerline. The

, creating strong pressures to drive nd collapse. Then the pulses pass press the growth of the bubbles The acoustic and cavitation fields ave been carefully measured and ons of other proposed mechanisms

for bubble suppression – such as bubble translation -- have been published [57, 58, 60].

REFERENCES 1. Lingeman JE. Extracorporeal shock wave lithotripsy.

Development, instrumentation, and current status. Urol Clin North Am;24:185-211 1997.

In vitro studies showed that stones at the focus of the 180-degree, dual pulse lithotripter broke more efficiently; in addition, hemolysis more than 1 cm off the focus is reduced when compared to that produced by a conventional, single-pulse lithotripter [61]. Figure 18 (top) shows the stone fragments remaining in the sieve and (bottom) shows mass loss through the sieve. 200 single pulses from the single-pulse lithotripter (white) were compared to 100 pulse pairs from the dual-pulse lithotripter (dark). Five axial stone locations are shown (0 is the focus F2) for two charging potentials 15 and 18 kV. The conclusion is that the dual-pulse lithotripter even at 15 kV increased the number of fragments by a factor of five and mass loss by a factor of three over the maximum levels achieved by single-pulses at 18kV, while decreasing or maintaining equivalent hemolysis levels off axis – all in half the time. Most importantly perhaps from the point of view of cavitation is that all improved comminution in the dual pulse lithotripter was lost when the stone was placed in glycerol to suppress cavitation during treatment.

2. Renner C, Rassweiler J. Treatment of renal stones by extracorporeal shock wave lithotripsy. Nephron 1999;81:77-81.

3. Gravenstein D. Extracorporeal shock wave lithotripsy and percutaneous nephrolithotomy. Anesthesiol Clin North America;18:953-971 2000.

4 Evan AP and J.A. McAteer, “Q-Effects of shock wave lithotripsy,” in Kidney Stones: Medical and Surgical Management, edited by F. Coe, C. Pak, and G.M. Preminger (Raven, New York), Vol. 1, pp. 549-570. 1996.

5. Evan AP, Willis, L. R., Lingeman, J. E. et al, “Renal trauma and the risk of long-term complications in shock wave lithotripsy,” Nephron 78: 1-10 1998.

6. Munver R, Delvecchio FC, Kuo RL, Brown SA, Zhong P, Preminger GM. In vivo assessment of free radical activity during shock wave lithotripsy using a microdialysis system: the renoprotective action of allopurinol. J Urol. Jan;167(1):327-34 2002.

CONCLUSIONS 7. Willis L. R., A. P. Evan, B. A. Connors, P. Blomgren, N. S. Fineberg, and J. E. Lingeman, “Relationship between kidney size, renal injury, and renal impairment induced by shock wave lithotripsy,” J Am Soc Nephrol 10 (8), 1753-62 (1999).

In conclusion, there is a wealth of data showing that cavitation plays a significant role in shock wave lithotripsy. Cavitation is clearly involved in stone breakage and there is solid evidence linking bubble activity with SWL-induced tissue damage. Pulse repetition rate, <1 atm of elevated static pressure, alteration of the fluid medium around the stone, waveform manipulation, and the timing between pulses were used to control cavitation and both ensuing bio-effects – stone comminution and tissue injury. The potential is there to use cavitation control techniques to engineer for improved lithotripsy and to improve lithotripsy technique.

8. Eterovic D., Juretic-Kuscuc L, Capkun V, and Dujic Z, “Pyrelithotomy improves while extracorporeal shock wave lithotripsy impairs kidney function,” J. Urol 161 39-44, 1999.

9. Willis, L.R.; Evan, A.P.; Lingeman, J.E. The impact of high-dose lithotripsy on renal function. Contemporary Urol., 11:45-50, 1999.

However, engineering development and clinical application would greatly benefit from further understanding of the precise mechanisms of bubble action in SWL. This is especially true because cavitation appears beneficial for stone comminution but deleterious in causing accompanying tissue injury. And there are simple steps toward improvements that are not understood and therefore clearly not optimized, e.g., a slower rate in addition to being safer also improves stone comminution [64]. Lastly, clinical challenges remain which lead to questions such as how might cavitation be enhanced around stones trapped in the ureter? Detailed models, such as the one described elsewhere in these proceedings [66], corroborated by further research and focusing on the collective effects of the bubble cloud on stone comminution and tissue injury have the potential to improve clinicians’ and manufacturers’ abilities to control cavitation for safer, more efficacious lithotripsy.

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ACKNOWLEDGMENTS This work was supported by NIH DK43381, DK55674, and

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