Pulsed high intensity focused ultrasound was shown to enhance chemotherapeutic drug uptake in tumor tissue through inertial cavitation, which is commonly assumed to require peak rarefactional pressures to exceed a certain threshold. However, recent studies have indicated that inertial cavitation activity also correlates with the presence of shocks at the focus. The shock front amplitude and corresponding peak negative pressure (p) in the focal waveform are primarily determined by the transducer F-number: less focused transducers produce shocks at lower p. Here, the dependence of inertial cavitation activity on the transducer F-number was investigated in agarose gel by monitoring broadband noise emissions with a coaxial passive cavitation detector (PCD) during pulsed exposures (pulse duration 1 ms, pulse repetition frequency 1 Hz) with p varying within 1–15 MPa. Three 1.5 MHz transducers with the same aperture, but different focal distances (F-numbers 0.77, 1.02, 1.52) were used. PCD signals were processed to extract cavitation probability, persistence, and mean noise level. At the same p, all metrics indicated enhanced cavitation activity at higher F-numbers; specifically, cavitation probability reached 100% when shocks formed at the focus. These results provide further evidence supporting the excitation of inertial cavitation at reduced p by waveforms with nonlinear distortion and shocks.

1.
Apfel
,
R. E.
, and
Holland
,
C. K.
(
1991
). “
Gauging the likelihood of cavitation from short-pulse, low-duty cycle diagnostic ultrasound
,”
Ultrasound Med. Biol.
17
,
179
185
.
2.
Bader
,
K. B.
, and
Holland
,
C. K.
(
2016
). “
Predicting the growth of nanoscale nuclei by histotripsy pulses
,”
Phys. Med. Biol.
61
(
7
),
2947
2966
.
3.
Bessonova
,
O. V.
, and
Wilkens
,
V.
(
2013
). “
Membrane hydrophone measurement and numerical simulation of HIFU fields up to developed shock regimes
,”
IEEE Trans. Ultrason. Ferroelectr. Freq. Control
60
(
2
),
290
300
.
4.
Canney
,
M.
,
Khokhlova
,
V.
,
Bessonova
,
O.
,
Bailey
,
M.
, and
Crum
,
L.
(
2010
). “
Shock-induced heating and millisecond boiling in gels and tissue due to high intensity focused ultrasound
,”
Ultrasound Med. Biol.
36
(
2
),
250
267
.
5.
Canney
,
M. S.
,
Bailey
,
M. R.
,
Crum
,
L. A.
,
Khokhlova
,
V. A.
, and
Sapozhnikov
,
O. A.
(
2008
). “
Acoustic characterization of high intensity focused ultrasound fields: A combined measurement and modeling approach
,”
J. Acoust. Soc. Am.
124
(
4
),
2406
2420
.
6.
Culjat
,
M. O.
,
Goldenberg
,
D.
,
Tewari
,
P.
, and
Singh
,
R. S.
(
2010
). “
A review of tissue substitutes for ultrasound imaging
,”
Ultrasound Med. Biol.
36
(
6
),
861
873
.
7.
Gateau
,
J.
,
Taccoen
,
N.
,
Tanter
,
M.
, and
Aubry
,
J. F.
(
2013
). “
Statistics of acoustically induced bubble-nucleation events in in vitro blood: A feasibility study
,”
Ultrasound Med. Biol.
39
(
10
),
1812
1825
.
8.
Haller
,
J.
, and
Wilkens
,
V.
(
2018
). “
Determination of acoustic cavitation probabilities and thresholds using a single focusing transducer to induce and detect acoustic cavitation events: II. Systematic investigation in an agar material
,”
Ultrasound Med. Biol.
44
(
2
),
397
415
.
9.
Johnsen
,
E.
, and
Colonius
,
T.
(
2009
). “
Numerical simulations of non-spherical bubble collapse
,”
J. Fluid. Mech.
629
,
231
262
.
10.
Kreider
,
W.
,
Crum
,
L. A.
,
Bailey
,
M. R.
, and
Sapozhnikov
,
O. A.
(
2011
). “
Observations of the collapses and rebounds of millimeter-sized lithotripsy bubbles
,”
J. Acoust. Soc. Am.
130
(
5
),
3531
3540
.
11.
Kreider
,
W.
,
Maxwell
,
A. D.
,
Khokhlova
,
T.
,
Simon
,
J. C.
,
Khokhlova
,
V. A.
,
Sapozhnikov
,
O.
, and
Bailey
,
M. R.
(
2013
). “
Rectified growth of histotripsy bubbles
,”
Proc. Mtgs. Acoust.
19
(
1
),
075035
.
12.
Lammers
,
T.
,
Kiessling
,
F.
,
Hennink
,
W. E.
, and
Storm
,
G.
(
2012
). “
Drug targeting to tumors: Principles, pitfalls and (pre-) clinical progress
,”
J. Control Release
161
(
2
),
175
187
.
13.
Li
,
T.
,
Chen
,
H.
,
Khokhlova
,
T.
,
Wang
,
Y. N.
,
Kreider
,
W.
,
He
,
X.
, and
Hwang
,
J. H.
(
2014
). “
Passive cavitation detection during pulsed HIFU exposures of ex vivo tissues and in vivo mouse pancreatic tumors
,”
Ultrasound Med. Biol.
40
(
7
),
1523
1534
.
14.
Li
,
T.
,
Wang
,
Y. N.
,
Khokhlova
,
T. D.
,
D'Andrea
,
S.
,
Starr
,
F.
,
Chen
,
H.
,
McCune
,
J. S.
,
Risler
,
L. J.
,
Mashadi-Hossein
,
A.
, and
Hwang
,
J. H.
(
2015
). “
Pulsed high-intensity focused ultrasound enhances delivery of doxorubicin in a preclinical model of pancreatic cancer
,”
Cancer Res.
75
(
18
),
3738
3746
.
15.
Maruvada
,
S.
,
Harris
,
G. R.
,
Herman
,
B. A.
, and
King
,
R. L.
(
2007
). “
Acoustic power calibration of high-intensity focused ultrasound transducers using a radiation force technique
,”
J. Acoust. Soc. Am.
121
(
3
),
1434
1439
.
16.
Maxwell
,
A. D.
,
Cain
,
C. A.
,
Hall
,
T. L.
,
Fowlkes
,
J. B.
, and
Xu
,
Z.
(
2013
). “
Probability of cavitation for single ultrasound pulses applied to tissues and tissue-mimicking materials
,”
Ultrasound Med. Biol.
39
(
3
),
449
465
.
17.
Maxwell
,
A. D.
,
Wang
,
T. Y.
,
Cain
,
C. A.
,
Fowlkes
,
J. B.
,
Sapozhnikov
,
O. A.
,
Bailey
,
M. R.
, and
Xu
,
Z.
(
2011
). “
Cavitation clouds created by shock scattering from bubbles during histotripsy
,”
J. Acoust. Soc. Am.
130
(
4
),
1888
1898
.
18.
Maxwell
,
A. D.
,
Wang
,
T. Y.
,
Yuan
,
L.
,
Duryea
,
A. P.
,
Xu
,
Z.
, and
Cain
,
C. A.
(
2010
). “
A tissue phantom for visualization and measurement of ultrasound-induced cavitation damage
,”
Ultrasound Med. Biol.
36
(
12
),
2132
2143
.
19.
Maxwell
,
A. D.
,
Yuldashev
,
P. V.
,
Kreider
,
W.
,
Khokhlova
,
T. D.
,
Schade
,
G. R.
,
Hall
,
T. L.
,
Sapozhnikov
,
O. A.
,
Bailey
,
M. R.
, and
Khokhlova
,
V. A.
(
2017
). “
A prototype therapy system for transcutaneous application of boiling histotripsy
,”
IEEE Trans. Ultrason. Ferroelectr. Freq. Control
64
(
10
),
1542
1557
.
20.
Nightingale
,
K. R.
,
Church
,
C. C.
,
Harris
,
G.
,
Wear
,
K. A.
,
Bailey
,
M. R.
,
Carson
,
P. L.
,
Jiang
,
H.
,
Sandstrom
,
K. L.
,
Szabo
,
T. L.
, and
Ziskin
,
M. C.
(
2015
). “
Conditionally increased acoustic pressures in nonfetal diagnostic ultrasound examinations without contrast agents: A preliminary assessment
,”
J. Ultrasound Med.
34
(
7
),
1
41
.
21.
Parker
K. J.
(
1983
). “
The thermal pulse decay technique for measuring ultrasonic absorption coefficients
,”
J. Acoust. Soc. Am.
74
,
1356
1361
.
22.
Rapoport
,
N.
,
Nam
,
K. H.
,
Gupta
,
R.
,
Gao
,
Z.
,
Mohan
,
P.
,
Payne
,
A.
,
Todd
,
N.
,
Liu
,
X.
,
Kim
,
T.
,
Shea
,
J.
,
Scaife
,
C.
,
Parker
,
D. L.
,
Jeong
,
E. K.
, and
Kennedy
,
A. M.
(
2011
). “
Ultrasound-mediated tumor imaging and nanotherapy using drug loaded, block copolymer stabilized perfluorocarbon nanoemulsions
,”
J. Controlled Release
153
(
1
),
4
15
.
23.
Rose
A.
(
1974
).
Vision: Human and Electronic
(
Plenum
,
New York
).
24.
Rosnitskiy
,
P. B.
,
Yuldashev
,
P. V.
,
Sapozhnikov
,
O. A.
,
Maxwell
,
A. D.
,
Kreider
,
W.
,
Bailey
,
M. R.
, and
Khokhlova
,
V. A.
(
2017
). “
Design of HIFU transducers for generating specified nonlinear ultrasound fields
,”
IEEE Trans. Ultrason. Ferroelectr. Freq. Control
64
(
2
),
374
390
.
25.
Rosnitskiy
,
P. B.
,
Yuldashev
,
P. V.
,
Vysokanov
,
B. A.
, and
Khokhlova
,
V. A.
(
2016
). “
Setting boundary conditions to the Khokhlov–Zabolotskaya equation for modeling ultrasound fields generated by strongly focused transducers
,”
Acoust. Phys.
62
(
2
),
151
159
.
26.
Sennoga
,
C. A.
,
Kanbar
,
E.
,
Auboire
,
L.
,
Dujardin
,
P. A.
,
Fouan
,
D.
,
Escoffre
,
J. M.
, and
Bouakaz
,
A.
(
2017
). “
Microbubble-mediated ultrasound drug-delivery and therapeutic monitoring
,”
Expert Opin. Drug Deliv.
14
(
9
),
1031
1043
.
27.
ter Haar
,
G.
,
Civale
,
J.
,
Rivens
,
I.
, and
Costa
,
M.
(
2014
). “
Cavitation threshold determination—Can we do it?
,”
J. Acoust. Soc. Am.
136
(
4
),
2301
.
28.
Vlaisavljevich
,
E.
,
Gerhardson
,
T.
,
Hall
,
T.
, and
Xu
,
Z.
(
2017
). “
Effects of F-number on the histotripsy intrinsic threshold and cavitation bubble cloud behavior
,”
Phys. Med. Biol.
62
(
4
),
1269
1290
.
29.
Vlaisavljevich
,
E.
,
Lin
,
K. W.
,
Maxwell
,
A.
,
Warnez
,
M. T.
,
Mancia
,
L.
,
Singh
,
R.
,
Putnam
,
A. J.
,
Fowlkes
,
B.
,
Johnsen
,
E.
,
Cain
,
C.
, and
Xu
,
Z.
(
2015
). “
Effects of ultrasound frequency and tissue stiffness on the histotripsy intrinsic threshold for cavitation
,”
Ultrasound Med. Biol.
41
(
6
),
1651
1667
.
30.
Wang
,
T. Y.
,
Xu
,
Z.
,
Hall
,
T.
,
Fowlkes
,
J.
,
Roberts
,
W.
, and
Cain
,
C.
(
2011
). “
Active focal zone sharpening for high-precision treatment using histotripsy
,”
IEEE Trans. Ultrason. Ferroelectr. Freq. Control
58
(
2
),
305
315
.
31.
Yount
,
D. E.
,
Yeung
,
C. M.
, and
Ingle
,
F. W.
(
1979
). “
Determination of the radii of gas cavitation nuclei by filtering gelatin
,”
J. Acoust. Soc. Am.
65
,
1440
1450
.
32.
Zeqiri
,
B.
,
Cook
,
A.
,
Rétat
,
L.
,
Civale
,
J.
, and
ter Haar
,
G.
(
2015
). “
On measurement of the acoustic nonlinearity parameter using the finite amplitude insertion substitution (FAIS) technique
,”
Metrologia
52
(
2
),
406
422
.
33.
Zhou
,
Y.
,
Wang
,
Y. N.
,
Farr
,
N.
,
Zia
,
J.
,
Chen
,
H.
,
Ko
,
B. M.
,
Khokhlova
,
T.
,
Li
,
T.
, and
Hwang
,
J. H.
(
2016
). “
Enhancement of small molecule delivery by pulsed high-intensity focused ultrasound: A parameter exploration
,”
Ultrasound Med. Biol.
42
(
4
),
956
963
.
You do not currently have access to this content.