The sensitivity and efficiency in contrast-enhanced ultrasound imaging and therapy can potentially be increased by the use of resonant monodisperse bubbles. However, bubbles of the same size may respond differently to ultrasound due to differences in their phospholipid shell. In an acoustic bubble sorting chip, resonant bubbles can be separated from the polydisperse agent. Here, a sample of acoustically sorted bubbles is characterized by measuring scattering and attenuation simultaneously using narrowband acoustic pulses at peak negative pressures of 10, 25, and 50 kPa over a 0.7–5.5 MHz frequency range. A second sample is characterized by attenuation measurements at acoustic pressures ranging from 5 to 75 kPa in steps of 2.5 kPa. Scattering and attenuation coefficients were modeled by integration over the pressure and frequency dependent response of all bubbles located within the non-uniform acoustic characterization beam. For all driving pressures and frequencies employed here, the coefficients could be modeled using a single and unique set of shell parameters confirming that acoustically sorted bubbles provide a uniform acoustic response. Moreover, it is shown that it is crucial to include the pressure distribution of the acoustic characterization beam in the modeling to accurately determine shell parameters of non-linearly oscillating bubbles.

1.
J. R.
Lindner
, “
Microbubbles in medical imaging: Current applications and future directions
,”
Nat. Rev. Drug Disc.
3
(
6
),
527
533
(
2004
).
2.
T. G.
Leighton
,
The Acoustic Bubble
(
Academic
,
London
,
1994
), Chap. 4.
3.
A. L.
Klibanov
, “
Microbubble contrast agents: Targeted ultrasound imaging and ultrasound-assisted drug-delivery applications
,”
Invest. Radiol.
41
(
3
),
354
362
(
2006
).
4.
E.
Talu
,
K.
Hettiarachchi
,
S.
Zhao
,
R. L.
Powell
,
A. P.
Lee
,
M. L.
Longo
, and
P. A.
Dayton
, “
Tailoring the size distribution of ultrasound contrast agents: Possible method for improving sensitivity in molecular imaging
,”
Mol. Imaging
6
(
6
),
384
392
(
2007
).
5.
M.
Overvelde
,
V.
Garbin
,
B.
Dollet
,
N.
de Jong
,
D.
Lohse
, and
M.
Versluis
, “
Dynamics of coated microbubbles adherent to a wall
,”
Ultrasound Med. Biol.
37
(
9
),
1500
1508
(
2011
).
6.
A.
Doinikov
,
L.
Aired
, and
A.
Bouakaz
, “
Acoustic response from a bubble pulsating near a fluid layer of finite density and thickness
,”
J. Acoust. Soc. Am.
129
(
2
),
616
621
(
2011
).
7.
J. M.
Tsutsui
,
F.
Xie
, and
R. T.
Porter
, “
The use of microbubbles to target drug delivery
,”
Cardiovasc. Ultrasound
2
,
23
(
2004
).
8.
S.
Hernot
and
A. L.
Klibanov
, “
Microbubbles in ultrasound-triggered drug and gene delivery
,”
Adv. Drug Deliv. Rev.
60
(
10
),
1153
1166
(
2008
).
9.
L. E.
Deelman
,
A. E.
Declèves
,
J. J.
Rychak
, and
K.
Sharma
, “
Targeted renal therapies through microbubbles and ultrasound
,”
Adv. Drug Deliv. Rev.
62
(
14
),
1369
1377
(
2010
).
10.
A. R.
Carson
,
C. F.
McTiernan
,
L.
Lavery
,
M.
Grata
,
X.
Leng
,
J.
Wang
,
X.
Chen
, and
F. S.
Villanueva
, “
Ultrasound-targeted microbubble destruction to deliver siRNA cancer therapy
,”
Cancer Res.
72
(
23
),
6191
6199
(
2012
).
11.
H.
Dewitte
,
K.
Vanderperren
,
H.
Haers
,
E.
Stock
,
L.
Duchateau
,
M.
Hesta
,
J. H.
Saunders
,
S. C.
De Smedt
, and
I.
Lentacker
, “
Theranostic mRNA-loaded microbubbles in the lymphatics of dogs: Implications for drug delivery
,”
Theranostics
5
(
1
),
97
109
(
2015
).
12.
A. M.
Gañán-Calvo
and
J. M.
Gordillo
, “
Perfectly monodisperse microbubbling by capillary flow focusing
,”
Phys. Rev. Lett.
87
,
274501
(
2001
).
13.
S. L.
Anna
,
N.
Bontoux
, and
H. A.
Stone
, “
Formation of dispersions using ‘flow focusing’ in microchannels
,”
Appl. Phys. Lett.
82
(
3
),
364
366
(
2003
).
14.
P.
Garstecki
,
H. A.
Stone
, and
G. M.
Whitesides
, “
Mechanism for flow-rate controlled breakup in confined geometries: A route to monodisperse emulsions
,”
Phys. Rev. Lett.
94
,
164501
(
2005
).
15.
E.
Talu
,
K.
Hettiarachchi
,
R. J.
Powell
,
A. P.
Lee
,
P. A.
Dayton
, and
M. L.
Longo
, “
Maintaining monodispersity in a microbubble population formed by flow-focusing
,”
Langmuir
24
,
1745
1749
(
2008
).
16.
R.
Shih
,
D.
Bardin
,
D. T.
Martz
,
P. S.
Sheeran
,
P. A.
Dayton
, and
A. P.
Lee
, “
Flow-focusing regimes for accelerated production of monodisperse drug-loadable microbubbles toward clinical-scale applications
,”
Lab. Chip
13
,
4816
4826
(
2013
).
17.
K.
Hettiarachchi
,
E.
Talu
,
M. L.
Longo
,
P. A.
Dayton
, and
A. P.
Lee
, “
On-chip generation of microbubbles as a practical technology for manufacturing contrast agents for ultrasonic imaging
,”
Lab. Chip
7
(
4
),
463
468
(
2007
).
18.
T.
Segers
,
L.
de Rond
,
N.
de Jong
,
M.
Borden
, and
M.
Versluis
, “
Stability of monodisperse phospholipid-coated microbubbles formed by flow-focusing at high production rates
,”
Langmuir
32
(
16
),
3937
3944
(
2016
).
19.
E.
Stride
and
M.
Edirisinghe
, “
Novel preparation techniques for controlling microbubble uniformity: A comparison
,”
Med. Biol. Eng. Comput.
47
,
883
892
(
2009
).
20.
M.
Emmer
,
H. J.
Vos
,
D. E.
Goertz
,
A.
van Wamel
,
M.
Versluis
, and
N.
de Jong
, “
Pressure-dependent attenuation and scattering of phospholipid-coated microbubbles at low acoustic pressures
,”
Ultrasound Med. Biol.
35
,
102
111
(
2009
).
21.
J. A.
Feshitan
,
C. C.
Chen
,
J. J.
Kwan
, and
M. A.
Borden
, “
Microbubble size isolation by differential centrifugation
,”
J. Coll. Interf. Sci.
329
(
2
),
316
324
(
2009
).
22.
D. E.
Goertz
,
N.
de Jong
, and
A. F. W.
van der Steen
, “
Attenuation and size distribution measurements of definity and manipulated definity populations
,”
Ultrasound Med. Biol.
33
(
9
),
1376
1388
(
2007
).
23.
M. P.
Kok
,
T.
Segers
, and
M.
Versluis
, “
Bubble sorting in pinched microchannels for ultrasound contrast agent enrichment
,”
Lab. Chip
15
(
18
),
3716
3722
(
2015
).
24.
J.
Sijl
,
B.
Dollet
,
M.
Overvelde
,
V.
Garbin
,
T.
Rozendal
,
N.
de Jong
,
D.
Lohse
, and
M.
Versluis
, “
Subharmonic behavior of phospholipid-coated ultrasound contrast agent microbubbles
,”
J. Acoust. Soc. Am.
128
(
5
),
3239
3252
(
2010
).
25.
J.
Sijl
,
M.
Overvelde
,
B.
Dollet
,
V.
Garbin
,
N.
de Jong
,
D.
Lohse
, and
M.
Versluis
, “ 
‘Compression-only’ behavior: A second-order nonlinear response of ultrasound contrast agent microbubbles
,”
J. Acoust. Soc. Am.
129
(
4
),
1729
1739
(
2011
).
26.
P.
Marmottant
,
S.
Van Der Meer
,
M.
Emmer
,
M.
Versluis
,
N.
de Jong
,
S.
Hilgenfeldt
, and
D.
Lohse
, “
A model for large amplitude oscillations of coated bubbles accounting for buckling and rupture
,”
J. Acoust. Soc. Am.
118
(
6
),
3499
3505
(
2005
).
27.
K.
Sarkar
,
W. T.
Shi
,
D.
Chatterjee
, and
F.
Forsberg
, “
Characterization of ultrasound contrast microbubbles using in vitro experiments and viscous and viscoelastic interface models for encapsulation
,”
J. Acoust. Soc. Am.
118
(
1
),
539
550
(
2005
).
28.
T.
Segers
and
M.
Versluis
, “
Acoustic bubble sorting for ultrasound contrast agent enrichment
,”
Lab. Chip
14
(
10
),
1705
1714
(
2014
).
29.
C. T.
Chin
,
C.
Lancee
,
J.
Borsboom
,
F.
Mastik
,
M. E.
Frijlink
,
N.
de Jong
,
M.
Versluis
, and
D.
Lohse
, “
Brandaris 128: A digital 25 million frames per second camera with 128 highly sensitive frames
,”
Rev. Sci. Instrum.
74
(
12
),
5026
5034
(
2003
).
30.
E. C.
Gelderblom
,
H. J.
Vos
,
F.
Mastik
,
T.
Faez
,
Y.
Luan
,
T. J. A.
Kokhuis
,
A. F. W.
van der Steen
,
D.
Lohse
,
N.
de Jong
, and
M.
Versluis
, “
Brandaris 128 ultra-high-speed imaging facility: 10 years of operation, updates, and enhanced features
,”
Rev. Sci. Instrum.
83
(
10
),
103706
(
2012
).
31.
S.
van der Meer
,
B.
Dollet
,
M.
Voormolen
,
C. T.
Chin
,
A.
Bouakaz
,
N.
de Jong
,
M.
Versluis
, and
D.
Lohse
, “
Microbubble spectroscopy of ultrasound contrast agents
,”
J. Acoust. Soc. Am.
121
(
1
),
648
656
(
2007
).
32.
N.
de Jong
,
M.
Emmer
,
C. T.
Chin
,
A.
Bouakaz
,
F.
Mastik
,
D.
Lohse
, and
M.
Versluis
, “ 
‘Compression-only’ behavior of phospholipid-coated contrast bubbles
,”
Ultrasound Med. Biol.
33
(
4
),
653
656
(
2007
).
33.
N.
de Jong
,
M.
Emmer
,
A.
van Wamel
, and
M.
Versluis
, “
Ultrasonic characterization of ultrasound contrast agents
,”
Med. Biol. Eng. Comput.
47
,
861
873
(
2009
).
34.
N.
de Jong
,
L.
Hoff
,
T.
Skotland
, and
N.
Bom
, “
Absorption and scatter of encapsulated gas filled microspheres: Theoretical considerations and some measurements
,”
Ultrasonics
30
(
2
),
95
103
(
1992
).
35.
L.
Hoff
, “
Acoustic characterization of contrast agents for medical ultrasound imaging
,” Ph.D. thesis, Norwegian University of Science and Technology, Norway,
2000
.
36.
H.
Medwin
, “
Counting bubbles acoustically: A review
,”
Ultrasonics
15
(
1
),
7
13
(
1977
).
37.
N.
de Jong
and
L.
Hoff
, “
Ultrasound scattering properties of Albunex microspheres
,”
Ultrasonics
31
(
3
),
175
181
(
1993
).
38.
M.
Overvelde
,
V.
Garbin
,
J.
Sijl
,
B.
Dollet
,
N.
de Jong
,
D.
Lohse
, and
M.
Versluis
, “
Nonlinear shell behavior of phospholipid-coated microbubbles
,”
Ultrasound Med. Biol.
36
(
12
),
2080
2092
(
2010
).
39.
K.
Vokurka
, “
On Rayleigh's model of a freely oscillating bubble. 1. Basic relations
,”
Czech. J. Phys.
35
(
1
),
28
40
(
1985
).
40.
A.
Prosperetti
, “
Thermal effects and damping mechanisms in the forced radial oscillations of gas bubbles in liquids
,”
J. Acoust. Soc. Am.
61
(
1
),
17
27
(
1976
).
41.
X.
Chen
,
D.
Philips
,
K. Q.
Schwarz
,
J. G.
Mottley
, and
K. J.
Parker
, “
The measurement of backscatter coefficient from a broadband pulse-echo system: A new formulation
,”
IEEE Trans. Ultrason. Ferroelec. Freq. Contr.
44
(
2
),
515
525
(
1997
).
42.
Y.
Luan
,
G.
Lajoinie
,
E.
Gelderblom
,
I.
Skachkov
,
A. F. W.
van der Steen
,
H. J.
Vos
,
M.
Versluis
, and
N.
de Jong
, “
Lipid shedding from single oscillating microbubbles
,”
Ultrasound Med. Biol.
40
(
8
),
1834
1846
(
2014
).
43.
B. E.
Treeby
and
B. T.
Cox
, “
Modeling power law absorption and dispersion for acoustic propagation using the fractional Laplacian
,”
J. Acoust. Soc. Am.
127
(
5
),
2741
2748
(
2010
).
44.
P. J. A.
Frinking
,
E.
Gaud
,
J.
Brochot
, and
M.
Arditi
, “
Subharmonic scattering of phopholipid-shell microbubbles at low acoustic pressure amplitudes
,”
IEEE Trans. Ultrason. Ferroelec. Freq. Contr.
57
(
8
),
1762
1771
(
2010
).
45.
M. M.
Lozano
and
M. L.
Longo
, “
Complex formation and other phase transformations mapped in saturated phosphatidylcholine/DSPE-PEG2000 monolayers
,”
Soft Matter
5
,
1822
1834
(
2009
).
46.
K. W.
Commander
and
A.
Prosperetti
, “
Linear pressure waves in bubbly liquids: A comparison between theory and experiment
,”
J. Acoust. Soc. Am.
85
,
732
746
(
1989
).
You do not currently have access to this content.