1962 ieee transactions on ultrasonics, ferroelectrics, and frequency control, vol. 52, no.
11, november 2005
Acoustic Detection of Controlled Laser-Induced
Microbubble Creation in Gelatin
Christine Tse, Student Member, IEEE, Marwa J. Zohdy, Student Member, IEEE,
Jing Yong Ye, Senior Member, IEEE, Theodore B. Norris, Member, IEEE, Lajos P. Balogh,
Kyle W. Hollman, Member, IEEE, and Matthew ODonnell, Fellow, IEEE
AbstractA high-frequency (85 MHz) acoustic tech-
nique is used to identify system parameters for controlled
laser-induced microbubble creation inside tissue-mimicking,
gelatin phantoms. Microbubbles are generated at the focus
of an ultrafast 793-nm laser source and simultaneously mon-
itored through ultrasonic pulse-echo recordings. Displayed
in waveeld form, these recordings illustrate microbubble
creation, and integrated backscatter plots provide specics
about microbubble characteristics and dissolution behav-
ior. By varying laser parameters, including pulse uence
(or pulse energy ux, J/cm2 ), total number of pulses deliv-
ered, and the period between pulses, the size, lifetime, and
dissolution dynamics of laser-induced microbubbles may be
independently controlled. Pulse uence is the main size-
controlling parameter, whereas both increases in pulse u-
ence and pulse number can lengthen microbubble lifetime
from tens to hundreds of milliseconds. In short, a microbub-
ble of particular lifetime does not necessarily have to be of a
particular size. Microbubble behavior, furthermore, is inde-
pendent of pulse periods below a uence-dependent thresh-
old value, but it exhibits stochastic behavior if pulse repeti-
tion is too slow. These results demonstrate that laser pulse
uence, number, and period may be varied to deposit en-
ergy in a specic temporal manner, creating and stabilizing
microbubbles with particular characteristics and, therefore,
potential uses in sensitive acoustic detection and manipu-
lation schemes.
I. Introduction
aser-induced optical breakdown (or LIOB) with fo-
L cused ultrafast laser beams can produce both pre-
cise subsurface biological eects and site-activated acoustic
contrast and, therefore, is an attractive tool for targeted
therapy and imaging applications combined with ultra-
sound. Above a material-specic irradiance threshold, fem-
tosecond laser pulses (which have high peak irradiance at
relatively small pulse energies) initiate a plasma-mediated
process that enables nonlinear energy deposition and local-
ized material vaporization in nominally transparent target
Manuscript received December 8, 2004; accepted May 25, 2005.
This work was supported in part by the National Institutes of Health
under Grants HL-47401 and HL-67647, N01-CO-27173, and by the
Whitaker Foundation.
C. Tse, M. J. Zohdy, K. W. Hollman, and M. ODonnell are with
the Department of Biomedical Engineering, University of Michigan,
Ann Arbor, Michigan 48109-2125 (e-mail: ctse@umich.edu).
J. Y. Ye and T. B. Norris are with the Center for Ultrafast Optical
Science, University of Michigan, Ann Arbor, Michigan 48109-2099.
L. Balogh is with the Center for Biologic Nanotechnology, the De-
partment of Internal Medicine, and the Department of Biomedical
Engineering, University of Michigan, Ann Arbor, Michigan 48109-
0533.
08853010/$20.00

materials, such as water and transparent biological tissues
[1], [2]. Because femtosecond breakdown occurs only when
the breakdown threshold is exceeded, the surface and other
untargeted areas can remain unaected as the laser beam
passes through. Furthermore, because light interacts with
the material on a femtosecond time scale, thermal eects
are conned to the plasma region and mechanical eects
are minimized, avoiding damage to surrounding material
and facilitating breakdown localization to micron and sub-
micron spatial scales [3][5]. The measurable eects of lo-
calized breakdown, namely shock wave emission and mi-
crobubble formation [3], [4], [6], [7], signal targeted areas
and generate a highly echogenic microbubble for sensitive
acoustic detection and potential manipulation.
The LIOB with focused femtosecond pulsed laser beams
already has been used in a number of medical and biolog-
ical systems to produce highly rened cell and tissue ef-
fects while minimizing thermal and mechanical damage to
surrounding material [8][12]. Furthermore, recent stud-
ies have demonstrated the potential for biochemically tar-
geted photodisruption using metal-dendrimer nanocom-
posites to locally manipulate LIOB threshold uences in
specic tissues and cells. Dendrimers have proven to be
excellent carrier vehicles for molecular targeting [13], [14].
By trapping metallic domains in dendrimers, enhanced
electric elds are established that signicantly reduce the
LIOB threshold of the organic host in water and biologic
tissue [15], [16]. Hence, these methods are very attractive
for molecular targeting, imaging, and therapy applications
in which the breakdown process site-activates the molecu-
lar delivery system.
We previously reported on a high-frequency ultrasonic
imaging technique developed to sensitively detect and
monitor localized LIOB in liquids at high resolution [17].
At each optical breakdown event, a transducer monitors
broadband pressure waves generated at the focus of an
ultrafast laser source, and simultaneously probes result-
ing microbubbles through pulse-echo recordings. These mi-
crobubbles not only act as site-activated, ultrasonic con-
trast agents, however, but also as targets for other po-
tential acoustical applications achieving desired biological
eects or performing elasticity measurements [18], [19]. To
be most useful, however, the LIOB process should operate
in controlled modes, creating bubbles with selectable char-
acteristics. Microbubble size and lifetime have been shown
to scale with the absorbed laser pulse energy [6]. However,
little previous research has investigated how bubble char-
c 2005 IEEE
tse et al.: microbubble creation and behavior 1963

acteristics vary with period and number of laser pulses

applied. The ability to control bubble size, dynamic be-
havior, and lifetime more independently should increase
their utility as site-activated agents.
In this study, we used a geometrically targeted LIOB
model to investigate the eect of tunable optical parame-
ters (pulse uence, number, and period) on LIOB bubble
characteristics. Our previously developed integrated, high-
frequency (85 MHz) acoustical and ultrafast optical setup
was used to study breakdown in a water-based collagen
gelatin phantom, which provided both tissue-like break-
down thresholds and mechanical properties.

II. Methods

The ultrafast optical source was a regeneratively am- Fig. 1. Schematic of integrated optical and acoustic experimental
setup.
plied Ti:sapphire laser ( = 793 nm) producing ap-
proximately 100 femtosecond pulses at a repetition rate
of 3.8 kHz. Laser exposure time was shutter-controlled,
and laser power was adjusted with a neutral-density l-
ter wheel. Using a 20 objective lens (N.A. = 0.4), the
laser source was focused to a 5 m diameter spot ap-
proximately 1 mm into a 5 w/w% water-based collagen
(Type-A, Sigma-Aldrich, St. Louis, MO) gelatin phan-
tom. Low strain rate (5E-3 Hz) mechanical measurements
on similar gels suggest an elastic modulus in the range
of 1.7 kPa for this medium. Phantoms were warmed to
room temperature before experiments. A spherically fo-
cused, single-element PVDF-TrFE ultrasonic transducer
(center frequency 85 MHz, 3.4 mm focal length, 1.6 mm
element diameter) was positioned so its focus coincided
axially and laterally with the laser focus. The transducer
was excited by a 400 MHz radio frequency (RF) bandwidth
pulser-receiver (5910PR, Panametrics, Waltham, MA). Ul-
trasonic probe pulses were synchronized with laser pulses,
repeated at 3.8 kHz, and had an adjustable delay line to Fig. 2. A typical acoustic waveeld of consecutive pulse-echo record-
probe microbubbles at variable times after the initiation ings illustrates dynamic events before, during, and after laser ex-
of photodisruption. For the experimental results reported posure, including acoustic emissions, pulse-echo signals from an
here, the transducer was excited approximately 729 ns be- LIOB bubble, and bubble lifetime. In this case, 20 laser pulses with
fore each laser ring, so that the ultrasound probe pulse 3.0 J/cm2 uence were delivered at 3.8 kHz. Individual pulse-echo
recordings are displayed as time (fast-time) relative to when acoustic
would arrive at the target site (the laser focus) after break- emissions are rst detected. Slow-time origin reects shutter opening.
down. The experimental system is illustrated in Fig. 1.
Multiple acoustic recordings were taken before, during,
and after laser exposure. When breakdown occurred, the ter is opened, however, acoustic emissions occur, signaling
transducer detected broadband pressure waves represent- microbubble formation. Then, because the transducer was
ing acoustic emissions generated at breakdown, and pulse- excited before the laser pulse to probe microbubbles af-
echo signals are reected from the resulting microbubble. ter breakdown, pulse-echo signals from the bubble appear
Data displayed in waveeld form illustrate these dynamic after emissions are detected. A bubble signal persists in
events and provide bubble lifetime information. An exam- consecutive recordings until ultimately decreasing to an
ple of a typical waveeld plot of consecutive pulse-echo amplitude below the baseline noise level. In Fig. 2, this is
recording is shown in Fig. 2. Individual pulse-echo record- observed to occur at 155 ms.
ings are displayed as time (fast-time) relative to when Specics about microbubble characteristics and dissolu-
acoustic emissions are rst detected. Each recording, which tion behavior, including relative bubble size and lifetime,
occurred 263 s apart (corresponding to 3.8 kHz repetition were determined by plotting backscatter power against
rate), are plotted vertically as time (slow-time) relative to time. Immediately after bubble creation, there was a
when laser exposure begins (the shutter is opened). While strong scattering peak, then decay. Below a threshold
the laser is blocked, no signals are detected. Once the shut- backscatter signal strength, dissolution rate rapidly in-
1964 ieee transactions on ultrasonics, ferroelectrics, and frequency control, vol. 52, no. 11, november 2005

creased and ultimately resulted in bubble signal decay to

baseline noise. The relatively slow data acquisition repeti-
tion rate (3.8 kHz) did not allow for visualization of bubble
oscillation. Because the high frequency of our system was
far from bubble resonance, we used maximum ultrasound
scattering intensity as a measure of microbubble size. The
decay time to the baseline noise limit, furthermore, gave a
measure of microbubble lifetime.
Using this setup, optical parameters, including laser u-
ence, total number of laser pulses, and period between
pulses, were varied to create and monitor bubbles with
a range of size, lifetime, and dissolution dynamics. We in-
vestigated how bubble characteristics varied in response to
three sets of conditions: variable pulse uence at constant
number and period, variable pulse number at constant u-
ence and period, and variable pulse period at constant u-
ence and number. Ranges of uence, pulse number, and Fig. 3. Example integrated backscatter versus time plots for four
pulse uences. In each case, 20 laser pulses were delivered at 3.8 kHz.
period were 0.95 to 4.9 J/cm2 /pulse, 20 to 1000 total laser
Note that integrated backscatter is dened as the backscattered
pulses, and 1.4 to 50 ms, respectively. Note that the max- acoustic power from the bubble normalized to the power recorded
imum uence was only 5.8 times above threshold. We ob- for a perfect planar reector using precisely the same transducer and
served that, for our focusing conditions, uences above this electronics.
value would create multiple laser-induced bubbles stacked
axially, aligned with the direction of the laser beam. There-
fore, the uence range was chosen to observe conditions
that created and stabilized only single bubbles.

III. Results

A. Size and Stability with Pulse Fluence and Number

For the rst set of conditions in which laser uence was

used as the main tuning parameter, bubble size and life-
time scaled with laser uence, as previously observed by
other researchers [6]. This relationship is demonstrated
by the example integrated backscatter plots of Fig. 3.
The integrated backscatter is dened as the backscattered
acoustic power from the bubble normalized to the power
recorded for a perfect planar reector using precisely the
same transducer and electronics. These plots show how
both scattering peaks and lifetimes increased with increas-
ing laser uence. Note that, although absolute bubble size
for each individual microbubble was not quantied from
these measurements, we estimated the size range from
backscatter measurements from a range of polystyrene
beads with known sizes. Bubbles reported in this study
ranged from 8 to 24 m in diameter, corresponding to a
40 to 25 dB backscatter range. In short, increasing laser
uence produced larger bubbles that correspondingly had
longer lifetimes.
Using pulse number as an additional tuning parame-
ter, however, we observed that longer bubble lifetimes did
not always have to be coupled with the same increases
in bubble size. In particular, for the second set of condi-
tions in which pulse number was used as the main tun-
ing parameter, we found that we could produce relatively
smaller, longer lived bubbles. Thus, bubble size and sta-
bility could be controlled more independently using both
Fig. 4. Example integrated backscatter versus time plots for four dif-
ferent total number of laser pulses. In each case, pulses were delivered
at 3.8 kHz with a 3.0 J/cm2 /pulse uence.
uence and total number of pulses as tuning parameters.
This is demonstrated in the example integrated backscat-
ter plots of Fig. 4, which show how bubble size does not
increase as dramatically even though lifetimes are compa-
rably increased.
Figs. 5 and 6 summarize the eects of these two optical
parameters (pulse uence and number) on bubble size and
stability. The six pulse uences used were 0.7, 1.25, 2.1,
2.5, 3.2, and 3.7 J/cm2 , and the eight pulse numbers used
were 20, 50, 100, 200, 400, 600, 800, 1000. For each g-
ure, data from eight bubbles were averaged for each of the
48 parameter combinations. Raw images were evenly up-
sampled (2 cubic interpolation in both lateral and axial
directions) for display purposes. In Fig. 5, the mean and
standard deviation of maximum integrated backscatter is
plotted for a range of uences and pulse numbers, with
deep red corresponding to the smallest bubble [Fig. 5(A)]
tse et al.: microbubble creation and behavior
Fig. 5. (A) Mean and (B) standard deviation of bubble maximum in-
tegrated backscatter (dB) for a range of uences and pulse numbers.
Pulses delivered at 3.8 kHz.
or size variability [Fig. 5(B)] and white corresponding to
the largest bubble [Fig. 5(A)] or size variability [Fig. 5(B)].
Clearly, uence is the primary parameter controlling size,
with maximum integrated backscatter saturating at the
higher uence values as bubble size approaches the ultra-
sound beam size. In addition, size variability generally de-
creases with pulse uence, with the standard deviation in
backscatter ranging from 0.2 to 1.4 dB. In Fig. 6, the mean
and standard deviation of bubble lifetime are plotted for
the same pulse uence and number ranges with blue cor-
responding to the shortest lived bubble or lifetime vari-
ability and pink corresponding to the longest lived bubble
or lifetime variability. For this bubble characteristic, pulse
number in addition to pulse uence is a controlling param-
eter. In addition, lifetime variability scales with these two
eects, with mean variability accounting for 10% of mean
bubble lifetime.
These gures suggest that bubble size and stability may
be more independently controlled using uence and puls-
ing together as tuning parameters. Consider the paramet-
ric plot in Fig. 7 showing size in relation to stability for
bubbles created and stabilized by two sets of conditions,
one in which pulse number was conserved and the other
1965
Fig. 6. (A) Mean and (B) standard deviation of bubble lifetime for
a range of uences and pulse numbers. Pulses delivered at 3.8 kHz.
in which pulse uence was conserved. This gure demon-
strates that a bubble of a particular lifetime does not nec-
essarily have to be of a particular size. For example, con-
serving lifetime, a 695 ms lifetime bubble can have 4 dB
reduced backscatter (a substantial size reduction) if cre-
ated at a lower 2.8 J/cm2 /pulse uence and stabilized by
100 additional pulses as compared to creation and sta-
bilization using a higher 4.8 J/cm2 /pulse uence and 20
additional pulses.
B. Pulse Period and Stochastic Bubble Behavior
Keeping pulse number constant, we varied the pe-
riod between consecutive pulses for three dierent supra-
threshold pulse uences (1.4, 2.8, and 4.2 J/cm2 ), deposit-
ing the same energy in a specic temporal manner to see
how it aected bubble behavior. Single-pulse bubble life-
times were measured to be 13, 43, and 97 ms for 1.4, 2.8,
and 4.2 J/cm2 /pulse, respectively. Because the pulse pe-
riod range studied was 1.4 to 50 ms, we considered pe-
riods far below single-pulse bubble lifetimes and periods
that were at least half the single-pulse bubble lifetimes.
Looking at integrated backscatter versus time plots, we
observed that the eect of subsequent pulses on bubble dy-
1966 ieee transactions on ultrasonics, ferroelectrics, and frequency control, vol. 52, no. 11, november 2005

Fig. 7. Parametric plot of maximum integrated backscatter versus
lifetime. Black diamonds correspond to bubbles created and main-
tained with a constant 20 pulses, but at variable pulse uence; red
circles correspond to bubbles created and maintained with a variable
number of pulses at a constant 2.8 J/cm2 /pulse. Arrows indicate
bubble examples with lifetime conserved.
Fig. 9. Variability in size versus pulse period for 30 pulses at three
dierent pulse uences. Arrows indicate how increasing uence de-
lays onset of stochastic bubble behavior. Squares, circles, and crosses
correspond to 1.4, 2.8, and 4.2 J/cm2 , respectively.
TABLE I
Average Maximum Integrated Backscatter and Lifetime
Values for Bubbles Exhibiting Typical Behavior for Each
of Three Fluence Conditions (30 Laser Pulses, Pulse
Periods Below the Stochastic Behavior Threshold).

Maximum
Pulse integrated
uence backscatter Lifetime Sample
(J/cm2 ) (dB) (ms) size
1.4 34.5 0.5 149 17 16
2.8 31.3 0.6 345 28 20
4.2 28.3 0.8 472 21 28

increasing uence delays the onset of stochastic behavior.

Fig. 8. Example integrated backscatter versus time plots for two pulse
periods, one of which exhibited typical behavior and one of which ex-
hibited stochastic behavior. Thirty laser pulses with 2.8 J/cm2 /pulse
delivered. Arrows indicate the end of laser exposure.
Table I summarizes the results from averaging bubble re-
sponses exhibiting typical behavior for each of the three
uence conditions, i.e., bubble responses for each set of
uence and pulse periods below the stochastic behavior
threshold.

namics is independent of pulse periods less than a uence- IV. Discussion

dependent threshold period value. Beyond this value, bub-
bles exhibit stochastic, random behavior resulting in large
size variability throughout their lifetimes. Fig. 8 gives ex-
ample backscatter plots for bubbles that exhibit typical
behavior and for bubbles that exhibit stochastic behav-
ior. Fig. 9 demonstrates how the period threshold value for
stochastic behavior scales with uence. Considering the
standard deviation () of integrated backscatter (or the
variability in bubble size) as a measure of stochastic be-
havior, we plotted average against pulse period for the
three pulse uences. For each parameter set of pulse period
and uence, four bubble responses were averaged. Arrows
in Fig. 9 mark the pulse period corresponding to the onset
of stochastic bubble behavior for each uence, showing how
Our high-frequency acoustic technique identied laser
irradiation parameters for controlled laser-induced mi-
crobubble creation inside tissue-mimicking, gelatin phan-
toms. For a given sample, initial cavitation conditions (ini-
tial cavitation size and inherent dissolution dynamics) are
controlled by pulse uence. Pulse uence determines ab-
sorbed laser energy and the size of the photodisruption
zone, which correspondingly yields a bubble of a certain
size and energy. Subsequent pulsing, with variable pulse
number and period, increases laser exposure and modies
the energy balance and transfer during the process lead-
ing to bubble dissolution and ultimate rapid decay. In-
terestingly, hundreds of laser pulses at lower laser uence
tse et al.: microbubble creation and behavior
have an equivalent eect on bubble lifetime as fewer laser
pulses at higher uence. Yet, those bubbles created and
stabilized with pulsing at lower uences are smaller than
those created using pulses with higher uence. Optimal en-
ergy, number, and timing of subsequent pulses for added
energy deposition and bubble stabilization depend on dy-
namic changes of bubbles produced by previous pulses. A
balance between pulse period and bubble dissolution rate
is required and sets a limit on the amount of time addi-
tional pulsing will stably inuence cavitation dynamics for
a given parameter set. The same total energy spread over
varying time periods had large eects on a bubbles stabil-
ity because pulses encountered bubbles at dierent stages
of dissolution.
Gas and gel dynamics (as associated with laser-induced
bubble dynamics) are inuenced by many eects such as
compressibility, heat, and mass transfer. With each laser
pulse, the energy transfer coecients governing these pro-
cesses are changed. Bubble characteristics and dynamics,
in short, are not simply related to the total laser energy de-
livered to a region of interest. Instead, the size, dynamics,
and lifetime of a bubble are determined by the interplay
between the eects of pulse uence, number, and period,
which all work together to create precise optical condi-
tions for bubble creation and maintenance in a particu-
lar medium. The mechanism of energy deposition of addi-
tional pulses is not clear from the results reported in this
study, but it may depend on a number of factors, including
nonlinear heat transfer to gas inside bubbles, additional
cavitation and coalescence stabilizing bubbles, tempera-
ture eects on surface tension and viscosity in the optical
zone, and sample elasticity eects on bubble stability. In
addition to the change in bubble dynamics, another indi-
cator of further energy deposition with additional pulses
was the presence of secondary acoustic emissions, which
were observed to occur during laser exposure to additional
pulses, but far earlier than the time of bubble signal decay
to baseline noise. An example of this may be observed in
the waveeld in Fig. 2; note the multiple emissions. The
intensity and frequency of these emissions varied, however,
even for the same optical parameter set that yielded bub-
bles with consistent characteristics.
The rapid decay of bubbles with a backscatter signal
strength below a certain threshold (bubble size) observed
in these studies was most likely caused by an ultimate im-
balance between pressure in the gelatin at the bubble wall
and the bubble vapor pressure. Because bubble expansion
in liquid and tissues occurs under stress connement, the
dissipation of bubble energy is highly inuenced by the
mechanical (viscosity and stiness) and thermal proper-
ties of the surrounding medium. Expanded bubbles even-
tually shrink in size due to both the properties and static
pressure of the surrounding medium, and bubble energy
and gas diusion characteristics of the medium determine
the rate of this process. For example, while laser-induced
bubbles produced by uences 10 threshold have been re-
ported to have lifetimes on the order of tens of microsec-
onds in water [7], cavitation bubbles created under similar
1967
Fig. 10. Example integrated backscatter versus time plots for two
gelatin stinesses. Twenty laser pulses with 3.0 J/cm2 uence deliv-
ered at 3.8 kHz.
optical conditions have lasted up to 30 s in corneal tissue
[6]. Preliminary results (see example backscatter plots in
Fig. 10) using our ultrasonic technique also have observed
a lengthening of bubble lifetime with increasing gelatin
concentration with relatively no dierence in bubble size.
Bubbles in 10% gelatin samples were twice as stable as
bubbles created in 5% gelatin with the same optical pa-
rameters (20 laser pulses, 3.0 J/cm2 uence delivered at
3.8 kHz ).
Low strain rate, direct mechanical measurements on
similar gels using methods as previously described [20] sug-
gest an elastic modulus in the ranges of 5.6 and 1.6 kPa
for the 10% and 5% gelatin medium [18]. Stability may be
inuenced by medium stiness through associated damp-
ing eects. Damping of bubble oscillations hinders bubble
collapse due to dissipation of bubble energy. Consequently,
bubbles may tend to persist longer when highly damped
by sti surrounding media. Alternatively, considerations
involving a mediums viscoelastic response to bubble for-
mation may provide an even more complete understand-
ing of the eect of mechanical characteristics. In future
studies, therefore, we intend to study modeling multipulse,
laser-induced bubble behavior in media of varying material
properties, as the dissipation of bubble energy is highly
inuenced by mechanical properties of the surrounding
medium. It also will be important to assess the exact dam-
age generated from breakdown in mechanically dierent
materials at dierent optical conditions. Potentially, for a
material with given mechanical properties, breakdown at
specic low power with many pulses imparts less stress,
generating a smaller amount of mechanical damage in the
sample than breakdown at a specic high power with few
pulses. When operating in either destructibility regime,
however, it is possible to generate strong acoustic signals
and scattering objects signifying the weak or strong break-
down event.
In addition, any diagnostic and/or therapeutic tech-
nology based on LIOB will depend on ultrafast optical
1968 ieee transactions on ultrasonics, ferroelectrics, and frequency control, vol. 52, no. 11, november 2005
pulses of sucient uence being successfully delivered to
the site of interest. To demonstrate applicability to tur-
bid biological tissues, we will investigate the eect of op-
tical scattering on maximal penetration and the process
and controllability of bubble creation at variable depths.
Wavelength and focal characteristics will be considered
to optimize breakdown in a realistic optical environment.
We also will begin studies using a biochemically targeted
LIOB model. Ultimately, detailed understanding of the
breakdown process of water-bearing materials will enable
a technology with the potential to target and create site-
activated acoustic contrast agents with controllable char-
acteristics that can be sensitively monitored with high-
frequency ultrasound.
V. Conclusions
Our current working hypothesis is that the creation of
LIOB bubbles is controllable through the careful selection
of laser parameters relevant to a particular medium, and
that this increases their use as site-activated ultrasound
contrast agents. Localized breakdown and a concomitant
bubble may be created by a single laser pulse, the inten-
sity of which mainly determines bubble size and inherent
dissolution dynamics. Subsequent pulses of variable num-
ber, intensity, and repetition period then may be used to
modify and maintain bubble stability by controlling a dy-
namic environment, due to gas and thermal diusion and
the generation of additional microbubbles, which helps to
stabilize the LIOB bubble, regardless of its size. Conse-
quently, it may be possible to operate site-targeted pho-
todisruption in controlled modes, creating site-activated
ultrasound contrast agents of selectable size, lifetime, de-
structive capability, and dissolution dynamics, allowing
useful imaging and manipulation windows.
Acknowledgment
We thank the NIH Resource Center at USC for supply-
ing the high frequency transducers. We also thank Todd
Erpelding for helpful discussions.
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Christine Tse received the dual B.S.E. de-
gree in biomedical and electrical engineering
from Duke University in 2001, and the M.S.
in biomedical engineering at the University
of Michigan, Ann Arbor, MI in 2003. She
is currently a Ph.D. candidate in biomedi-
cal engineering at the University of Michigan,
and is sponsored by the Whitaker Founda-
tion. Her research involves ultrasonic monitor-
ing of laser-induced microbubbles and the de-
velopment of LIOB-based imaging and ther-
apy applications. This work is being per-
formed in the Biomedical Ultrasonics Laboratory under Dr. Matthew
ODonnell.
tse et al.: microbubble creation and behavior
Marwa J. Zohdy received her B.S. degree
in electrical engineering in 2000, and her M.S.
degree in biomedical engineering in 2002, both
from the University of Michigan in Ann Ar-
bor, MI. She is a recipient of the Whitaker
Graduate Fellowship and past president of
the University of Michigan Biomedical En-
gineering Society. She is currently pursuing
her Ph.D. degree in the Biomedical Ultrason-
ics Laboratory at the University of Michigan,
where her current research activities involve
characterization of laser-induced microbub-
bles, investigating applications in cellular diagnostics and therapy.
Jing Yong Ye (M02SM02) received his
Ph.D. degree in applied physics from the Uni-
versity of Tsukuba, Japan, in 1997. Then he
joined the Joint Research Center for Atomic
Technology-Angstrom Technology Partner-
ship in the National Institute for Advanced
Interdisciplinary Research as a Research Sci-
entist, where he worked on single-molecule u-
orescence imaging and ultrafast time-resolved
spectroscopy. He received JRCAT Award in
1998 and was appointed as NEDO Fellow in
1999. In January 2000, Dr. Ye joined the Cen-
ter for Ultrafast Optical Science in the University of Michigan. He
is an Assistant Research Scientist and has a broad range of research
interests including ultrafast spectroscopy, multiphoton scanning con-
focal microscopy, ber-optic biosensing, nanotechnology, adaptive
aberration correction, single-molecule uorescence imaging and spec-
troscopy, etc. He is currently working on biosensing and triggering
of dendrimer-based nano-devices for noninvasive detection, diagnosis
and treatment of cancer for a NIH granted program, and develop-
ing biosensors for real-time monitoring of radiation induced biologic
eects in space for a NASA granted program. Dr. Ye is a senior
member of IEEE.
Theodore B. Norris is a professor in the
Electrical Engineering and Computer Science
Department at the University of Michigan.
He received his B.A. degree in physics (with
Highest Honors) from Oberlin College in 1982,
and his Ph.D. degree in physics from the Uni-
versity of Rochester in 1989, with a disser-
tation on time-resolved tunneling in semicon-
ductor heterostructures. He continued his in-
vestigations of time-resolved optical studies
of semiconductors at Thomson-CSF in France
19891990. During 19901992 he was an As-
sistant Research Scientist at the Ultrafast Science Laboratory and
from 19921996 an Assistant Professor and from 19962001 an As-
sociate Professor in EECS at the University of Michigan. His research
interests include the application of femtosecond optical techniques to
the physics of semiconductor structures, the development of new ul-
trafast optical and electronic probes with high spatial resolution for
applications to semiconductor nanostructures and biological imag-
ing, the application of ultrafast optics to biomedical imaging, in vivo
sensing, and cancer therapeutics, the generation of THz radiation,
and nanoacoustic imaging with picosecond coherent phonon pulses.
This work has appeared in over 110 journal and 160 conference pub-
lications. His research is performed at the Center for Ultrafast Op-
tical Science and the Electrical Engineering and Computer Science
Department at the University of Michigan. He is a Fellow of the Op-
tical Society of America, and a member of IEEE and the American
Physical Society.
1969
Lajos P. Balogh earned his Ph.D. degree in
chemical technology (1983) and his M.S. de-
gree in chemistry (1975) at the Kossuth L.
University of Sciences and Arts, Debrecen,
Hungary. He served as a Research Associate
Professor of both of Internal Medicine and
of Biomedical Engineering, and Research As-
sociate Professor of Biologic Nanotechnology
and of Macromolecular Science and Engineer-
ing at the University of Michigan, Ann Arbor,
MI. In January 2005, he joined the Roswell
Park Cancer Institute as Director of Nan-
otechnology Research. He is a professor of biomedical nanotechnol-
ogy, Department of Radiation Medicine, SUNY, Bualo. Dr. Balogh
specializes in the elds of organic synthesis, analytical chemistry,
chemical engineering, polymer chemistry and materials science. His
research involves conceptualization, synthesis, characterization and
utilization of polymers, dendrimers, organic/inorganic hybrid nano-
materials and engineered nanostructures for medical and materials
applications.
Kyle W. Hollman (S93M95) has been
an assistant research scientist in the Biomedi-
cal Engineering Department of the University
of Michigan since 2001. Currently, he is ex-
ploring biomedical applications of ultrasound
microscopy with particular interest in elas-
ticity measurements of corneas and arteries.
In 1998, the department originally hired him
as a postdoctoral research fellow. From 1996
through 1998 Dr. Hollman worked in the Ma-
terials Reliability Division of the NIST labora-
tory in Boulder, CO. He earned a M.A. degree
in 1990 and a Ph.D. degree in 1995 from the Physics Department of
Washington University in St. Louis where his doctoral thesis exam-
ined ultrasonic detection techniques of wavefront distortion caused
by rough surfaces or anisotropy. In 1988 he received a B.S. degree
from the University of Nebraska-Lincoln where he majored in both
mathematics and physics.
Matthew ODonnell (M79SM84F93)
EDUCATION: B.S. and Ph.D. in Physics,
University of Notre Dame, Notre Dame, IN,
1972 and 1976.
EXPERIENCE: Following his graduate
work, Dr. ODonnell moved to Washington
University in St. Louis, MO as a postdoc-
toral fellow in the Physics Department work-
ing on applications of ultrasonics to medicine
and nondestructive testing. He subsequently
held a joint appointment as a Senior Research
Associate in the Physics Department and a
Research Instructor of Medicine in the Department of Medicine at
Washington University. In 1980 he moved to General Electric Corpo-
rate Research and Development Center in Schenectady, NY, where
he continued to work on medical electronics, including MRI and ul-
trasound imaging systems. During the 19841985 academic year, he
was a visiting fellow in the Department of Electrical Engineering at
Yale University in New Haven, CT investigating automated image
analysis systems. In a bold move during 1990, Dr. ODonnell became
a Professor of Electrical Engineering and Computer Science at the
University of Michigan in Ann Arbor, MI. Since 1997, he has held a
joint appointment as Professor of Biomedical Engineering at Michi-
gan, and in 1998 he was named the Jerry W. and Carol L. Levin
Professor of Engineering. Currently, he is the Chair of the Biomed-
ical Engineering Department. His most recent work has explored
new imaging modalities in biomedicine, including elasticity imag-
ing, in vivo microscopy, optoacoustic arrays, optoacoustic contrast
agents for molecular imaging and therapy, thermal strain imaging,
and catheter based devices.