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Oscillating bubbles: a versatile tool for lab on a chip applications
Ali Hashmi, Gan Yu, Marina Reilly-Collette, Garrett Heiman and Jie Xu*
Received 28th April 2012, Accepted 6th June 2012
DOI: 10.1039/c2lc40424a
With the fast development of acoustic and multiphase microfluidics in recent years, oscillating
bubbles have drawn more-and-more attention due to their great potential in various Lab on a Chip
(LOC) applications. Many innovative bubble-based devices have been explored in the past decade. In
this article, we first briefly summarize current understanding of the physics of oscillating bubbles, and
then critically summarize recent advancements, including some of our original work, on the
applications of oscillating bubbles in microfluidic devices. We intend to highlight the advantages of
using oscillating bubbles along with the challenges that accompany them. We believe that these
emerging studies on microfluidic oscillating bubbles will be revolutionary to the development of next-
generation LOC technologies.
Introduction
Lab on a Chip (LOC) devices are rapidly finding applications in
diverse areas such as medicine, biology, chemistry, and physics,
with the notion that huge laboratory equipment and spaces can
be shrunk onto a tiny chip.1–10 However, getting small has its
own problems. In most applications, we need to acquire certain
reagents or species, transport and manipulate them using our
hands or robots; but at small scale it is extremely challenging to
effectively access, sort or manipulate samples. Many recent
studies have shown that oscillating bubbles may be one of the
promising candidates that can enable us to tackle these
challenges. For example, oscillating bubbles can carry, transfer,
direct and manipulate micro particles like drug molecules, cells
and even micro-organisms in an efficient way. Many other
applications are yet to be explored. Our attempt in this review is
to highlight the importance of the field by shedding some light
on the physics of oscillating bubbles and their relatively new-
found applications. We hope readers will be fascinated by
oscillating bubbles, their properties and potential applications.
Bubbles in microfluidics
Prosperetti11 has summarized the concept of a bubble in the most
artistic and richly detailed manner possible. Nevertheless, for
simplicity and for sake of science, a bubble is a vapor-phase
surrounded by a liquid-phase or a solid-phase, or a combination
of both. Thus, bubbles are ‘not’ the emptiness supposed in
ancient times. In microfluidics, bubbles come in a variety ofMechanical Engineering, Washington State University, Vancouver, USA.E-mail: [email protected]; Fax: 01 (360) 546-4138; Tel: 01 (360) 546-9144
Ali Hashmi graduated with a BSin Mechanical Engineering fromthe Ghulam Ishaq Khan Instituteof Engineering Sciences andTechnology, Pakistan in 2011.Since his graduation, Ali hasbeen doing research at Prof.Xu’s Microfluidics Laboratoryat Washington State UniversityVancouver. He describes himselfas an enthusiast of micro/nanos-cale heat and mass transfer withan interest in engineering sur-faces and understanding interfa-cial science for energy efficientsystems. Ali maintains a strong
interest in micro/nanofluidics and is especially fascinated by Lab ona Chip devices for biomedical applications. He intends to earn adoctorate in mechanical engineering.
Gan Yu obtained his bachelor’sdegree of Electrical Engineering atSun Yat-sen University, China in2010. He has been working inProf. Xu’s group for two years.He will be graduating with amaster’s degree in MechanicalEngineering at Washington StateUniversity Vancouver in July,2012. Gan’s research focuses onmicrofluidics, especially on acous-tic manipulation of biologicalspecimens, and biomedical devicedesign and testing.
Ali Hashmi Gan Yu
Lab on a Chip Dynamic Article Links
Cite this: Lab Chip, 2012, 12, 4216–4227
www.rsc.org/loc CRITICAL REVIEW
4216 | Lab Chip, 2012, 12, 4216–4227 This journal is � The Royal Society of Chemistry 2012
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shapes; for instance, they can be spherical if freely suspended in a
liquid owing to surface tension. They can be a truncated sphere if
attached to any solid-wall, with the shape primarily depending
upon the contact angle. Upon further confinement, such as in
microchannels, they can exist as a meniscus (refer to Fig. 1).
However, bubble deformation and contact line motion as
bubbles move via microchannels is complex.12–15
In microfluidics, numerous techniques have been realized
for generating bubbles, such as T-junctions,16–19 capillaries,20,21
flow focusing,22–25 cavitation,26–28 electrolysis,29,30 piezoelectric
actuation,31 heating,32–38 manual injection with microliter
syringes and passive methods.39–43 These techniques have their
advantages as well as disadvantages. Cavitation, heating and
electrolysis-induced microbubbles may exhibit a large variation
in size. T-Junction and flow focusing methods can generate
microbubbles with uniform sizes at high speeds, but they lack the
ability to control the volume of individual bubbles. Using a
piezoelectric actuator or a microliter syringe can generate
individual bubbles on demand with precise volume control, but
the former requires a complex system and the latter is inefficient.
Passive methods use microcavities to trap bubbles. It is a very
simple and reproducible method. However, the generated
bubbles are hard to transport or be removed using conventional
methods, such as venting membranes.44 To make bubbles
oscillate in a microfluidic device, the simplest method would be
a piezoelectric transducer that is arbitrarily coupled to the
device. The advantage of this powering mechanism is that the
source can be used to remotely control and actuate bubbles.
Other acoustic actuation and microbubble manipulation techni-
ques also exist, such as surface acoustic waves (SAW).45
An oscillating bubble
A common behavior exhibited by all of the bubble varieties
discussed earlier is the interesting response they show when
exposed to mechanical pressure waves like ultrasound. A bubble
can be thought of as a soft membrane able to vibrate under the
action of external excitation. The response of a bubble can be
linear or non-linear depending upon the amplitude of the
vibration.46 For example, the motion of a spherical bubble
under the action of a continuously oscillating pressure field can
be defined by the Rayleigh–Plesset Equation. Interested readers
are instructed to refer to Lauterborn and Kurz47 or classical text
by Brennen48 and Leighton.49 In simple words, insonated-
oscillating bubbles are a linear system for low amplitudes at
which they exhibit a stable motion known as ‘non-inertial
Fig. 1 A spherical bubble is freely suspended in a microfluidic channel;
attached to the wall of the channel is a smaller bubble; the entrapment of
gas within the liquid filled microchannel results in a meniscus.
Marina Reilly-Collette is agraduate student in OceanEngineering at the University ofRhode Island who completedher BSME at Washington StateUniversity Vancouver whileworking on this paper. Herprimary interests are fluid flow,heat exchange in fluid media, andmarine hydrodynamics, the lastof which led to her interest inengineering from a very youngage. She got involved in Prof.Xu’s Microfluidics Lab becauseshe was not being challenged inher regular classes with enough
fluidics study and wanted more work to do. In her private life sheenjoys hiking the Pacific coast and drinking too much coffee.
Marina Reilly-Collette
Garrett Heiman is a first-year gradu-ate student at WSU Vancouver, work-ing on his Mechanical EngineeringMaster’s degree. He graduatedfrom Prairie High School in BrushPrairie, Washington, in 2007. Garrettreceived his bachelor’s degree alsoin Mechanical Engineering fromWashington State University, Pullman,in 2011. Garrett currently doesresearch in Prof. Xu’s MicrofluidicsLaboratory at WSU Vancouver, withan emphasis on using acoustic bubblesin microfluidics.
Dr Jie Xu is an assistant professorof Mechanical Engineering atWashington State UniversityVancouver. He received his bache-lor’s degree in thermal engineeringfrom Tsinghua University inBeijing and his PhD degreein mechanical engineering fromColumbia University in the Cityof New York. He has beenrecognized by the 2011 DARPAYoung Faculty Award, 2011National New Faces of EngineeringProgram and 2009 ChineseGovernment Award. Dr Xu’sMicrofluidics Laboratory aims
at understanding micro interfacial sciences and building novelmicro/nanofluidic systems for energy, health and the environment.
Garrett Heiman Jie Xu
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cavitation’. However, as soon as the amplitude shoots above a
certain threshold, nonlinearities in the system begin to dominate.
At even higher amplitudes, bubbles may undergo violent
expansions and contractions over cycles, which may result in a
subsequent collapse—referred to as ‘inertial cavitation’; bubbles
at this stage also tend to accumulate mass. A rapid collapse can
cause the temperature inside bubbles to rise tremendously resulting
in emission of light—popularly known as sonoluminescence.50
These bubbles have detrimental consequences when they collapse
near a wall with pressures high enough to cause erosion (e.g. to
underwater propellers) or destruction (e.g. to biological cells). On
the other hand, insonated bubbles that undergo stable oscillations
are not ‘wild horses’ and can be controlled for the achievement
of a great many applications. Analytical models will be instru-
mental in designing bubble-based devices. However, current
theories are mostly for spherical bubbles. There is a need to
develop theories that conform to experimental studies so that the
bubble behavior, especially as affected by microgeometries, can be
well quantified.34,51,52 This can be extremely challenging, because
current theories regarding oscillating spherical bubbles are already
very complex.53
We would prefer not to bombard the readers with too many
equations. However, a few equations are important to be
‘discussed only’ to ensure a better understanding of oscillating
bubble and its dynamics. One such equation is assumed to be an
approximate representation of the bubble behavior. It is used to
determine the fundamental frequency of volume resonance of a
spherical bubble. Underlying theory states, for low amplitude
vibrations, a bubble of radius R will resonate at a unique
frequency, f, given by:48
f ~
ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
1
4rlp2R2
3k Poz2s
R
� �
{2s
R
� �
s
(1)
where r is the density, s is the surface tension, k is the
polytropic exponent of the gas and Po is the hydrostatic pressure
and the subscript l denotes liquid. The equation is not applicable
for higher amplitudes since the bubbles start to oscillate with
harmonics.
An interesting flow phenomenon occurring when a bubble is
oscillating is called microstreaming—a beautiful pattern in
nature with a rather unpleasant description54–59 (see Fig. 2).
Microstreaming is a second order non-linear dynamical system
which Marmottant et al.60 suggested exists owing to a difference
(phase-shift) between the radial expansion and contraction of a
bubble and its translational motion. Microstreaming is not only
produced by oscillations of bubbles in 3D but also by oscillations
of a 2D meniscus.52 The stream function of a microstreaming
pattern has been derived for oscillating bubbles in bulk fluid.57
For the condition when an oscillating bubble is attached to a
wall, the stream function, y, takes the form as shown below:
y~{3e2a2vsin(DQ)a
rcos2 h sin2 hz0 e2r{2
� �
(2)
where a represents the bubble radius, e represents the normalized
bubble amplitude, v denotes the angular frequency, DQ denotes the
phase-shift between radial and translational motion, h is the angle
coordinate with reference to the axis of translation and r is the
radial distance from the bubble centre.
This characteristic flow with very high velocity gradients is
what makes an oscillating microbubble unique for applications
in LOC devices. Moreover, the advantage oscillating micro-
bubbles have against conventional acoustic streaming—in which
ultrasound is used to excite liquids directly3,61–65—is that the
microstreaming flow field around oscillating microbubbles is
generated at much lower frequencies, which prevents the system
from generating excessive heat. The high velocity gradients result
in a shear drag force—along with another important force: the
secondary radiation force. Subsequent details will briefly discuss
them and their importance.
It is important to define the forces that are present near a
bubble undergoing oscillations. A particle moving in close
proximity of the vibrating liquid-gas interface will experience a
drag force, known as ‘Stokes Drag’, along the streamline. This
force arises by virtue of the relative motion between an object
and the fluid wherein it is immersed. For a particle with radius
Rp, the drag force it experiences can be calculated through a
relatively simple equation given below:66
FDrag = 6pmlRpUp (3)
where m represents the dynamic viscosity, R denotes the radius,
U represents the relative velocity and subscript p denotes particle.
The secondary radiation force, also called the Bjerknes force,49,67
is another force that a particle experiences near an oscillating
bubble. It is generated because of a scattering effect of the incoming
ultrasonic waves from the liquid–gas interface. It tends to issue forth
from the centre of the bubble and affects the particles that are
present within the flow field. It is generally believed that the particles
absorb this scattered radiation, which imparts momentum68
FRadiation~4prl{rp
rlz2rp
R4R3p
d5v2j2 (4)
where d represents the centre-to-centre separation between the
bubble and the particle; v denotes the angular frequency and j
represents the bubble displacement.
Fig. 2 The image shows superimposed streamlines generated around an
oscillating microbubble as predicted by theory and the actual paths of the
vesicles in experiments conducted by Marmottant et al. Reprinted with
permission from ref. 60.
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From the equation above, we might be able to conclude that
the magnitude of the secondary radiation force depends upon the
geometries of the particle as well as the amplitude and the
frequency at which a bubble is actuated. Also note, the sign that
determines the direction of the force i.e. whether attractive or
repulsive depends on the ratio of the particle and fluid densities.
For most of the time and for most applications we will be
discussing in the next section, it is generally the interaction
between the drag (eqn (3)) and secondary radiation force (eqn
(4)) that is important and more meaningful.
Emerging applications of oscillating microbubbles
Oscillating bubbles is an old field of study; however, its use in
microfluidics is a relatively nascent field and much remains to be
understood and explored in terms of bubble behavior and novel
applications. Over the past decade, oscillating microbubbles have
shown a huge potential for numerous applications that could
be easily incorporated into existing microfluidic platforms to
achieve various tasks. In LOC devices, Fair has defined an
elemental set of operations.69 For example, flow needs to be
controlled (e.g. flushing and mixing); objects need to be
controlled (e.g. trapping, enrichment, filtering, transport, and
manipulation); mass transfer across cell membrane needs to be
controlled (e.g. gene extraction, gene/drug delivery). Oscillating
microbubbles seem to be versatile in all such operations. This
section introduces the summary and a critical analysis of up-
to-date research pertaining to the applications of oscillating
microbubbles. Our purpose remains to attract the attention
of a broader scientific community toward this promising area.
Table 1 provided at the end summarizes emerging LOC
applications based on oscillating microbubbles.
Flow control
1. Pump. At small length scales—where viscous effects
dominate—there is an exigency of developing efficient pumps
for the LOC devices in order to aid in fast bulk fluid
transportation. A comprehensive review70 suggests that most
of the mechanisms realized for micropumps are inefficient.
However, the acoustically pulsating bubbles have demonstrated
the capability of being used as an efficient pumping mechanism
for LOC. As a forerunner, Ryu et al.71 realized a microfluidic
pump by taking advantage of an oscillating bubble’s flow field.
By placing a small capillary tube over a bubble undergoing
volume resonance, they were able to pump water through the
tube (Fig. 3 top-left). They quantified their studies and noticed
that the pumping curve generated by the oscillating bubble had
the same characteristics as a conventional pump (Fig. 3 top-
right), which makes these novel pumping systems easy to
analyze. In their study, a strikingly high flow rate (approximately
0.6 mL s21) was attained with the use of a millimetre-sized
bubble, with the fluid flow being strongly affected by the tube’s
diameter and the distance from the bubble. Further advancing
the studies on acoustic pumps based on microbubbles, Tovar and
Lee40 showed that bubbles trapped at junctions fabricated along
Table 1 Emerging applications of oscillating microbubbles
ApplicationsBubbleconfiguration Bubble generation Substrate Notes Ref.
Pump Single Micropipette Parylene coatedglass plate
Capillary tube over bubble 71
Multiple Lateral cavity PDMS Bubble pair at a junction 40Mixer Single Horse-shoe cavity PDMS Microstreaming responsible
for ultra-fast mixing time42
Multiple Vertical or bottomwall cavities
Polycarbonate Staggered grid arrangementfor better mixing result
74,75
Multiple Pressure , vaporpressure
PMMA Mixing of highly viscous liquid 77
Multiple Lateral cavities PDMS Staggered arrangement utilized 43Filter Single Microliter syringe Silicon Competition between drag and
secondary radiation force79
MobileTransporter
Single pipette Glass plate coatedwith Teflon
EWOD for bubble migration in 1 D 83
Single Electrolysis Teflon coatingon glass rod
Bubble attached to hydrophobic tipsof a rod for 3 D manipulation
85
Multiple Electrodes/Microlitersyringe
Teflon coatingon glass rod
Twin bubbles attached to a U shaped rod 86
StaticTransporter
Multiple Squirting air,Vertical cavities
Quartz PDMS/Silicon A break in flow symmetry enablesbubble chains to transfer mass
87,88
Rotation Single Microheater Glass Rotor motion presumablydue to microstreaming
33
Live organisms Multiple Vertical cavity Aluminium Competition between drag andsecondary radiation force
80
Propeller Multiple Microliter syringe Aluminium Microstreaming imparts momentum 92Switching andenrichment
Single Vertical cavity PDMS Superposition of Poiseuille flowand microstreaming
93
Temporal actuation of bubble 41Cell lysis Single Microliter syringe Quartz Shear stress due to high velocity
gradient in microstreaming60
Multiple Gas injection into the channel PDMS Exposure time to bubble cavitationdetermines lysis
107
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a microchannel side wall could be actuated to drive fluid flow in
the channel, if these junctions are inclined at an angle (Fig. 3
bottom-left). The flow rate was found to increase with the
amplitude of bubble oscillation and was most noticeable for the
15u inclination of the junctions (Fig. 3 bottom-right); the highest
flow rate obtained was as high as 0.0042 mL s21. The other
configurations were not as effective primarily due to the
proposed cancellation effect of the microstreaming flow fields.
Further experimentations have been performed with the 15uconfiguration.39 In future, simulation tools could be developed
and used for optimization studies. However, it would be a
challenging task, because of the multiple spatial and temporal
scales involved.72 Other potential challenges include reliability/
long-term stability of the pump performance.
2. Mixer. Mixing is one of the most crucial factor that
determines the homogeneity of a sample and the rate at which
chemical reactions proceed. At the small length scale of an LOC,
mixing is governed by diffusion, a very slow process. Therefore,
addressing this problem could mean a difference between hours
or a few milliseconds. Different micromixers have been studied
for use in microfluidic platforms,73 but acoustically actuated
microbubbles could prove to be a holy grail for achieving fast
convective mixing at micro scale lengths. The first of a kind
acoustic bubble-based micro-mixer74 was realized using an array
of sonicated microbubbles with a microstreaming flow field
(Fig. 4 top-left). In addition, the array was optimized for efficient
mixing, and it was discovered that a staggered grid arrangement
eliminated a build-up of stagnation points within the flow due to
interferences (Fig. 4 top-right). Enhanced microfluidic mixing
has also been achieved using an array of trapped bottom-wall
bubbles,75 sidewall bubbles,43 and more recently, top-wall
bubbles.76 An advantage of such designs in contrast to
mechanical micro-mixers is that the mixing takes place more
thoroughly because the microstreaming flow is driven well
beyond the Stokes boundary layer, probably because of slip
boundary conditions at the bubble surface. Furthermore, a
micromixing device that relies on oscillating bubbles does not
require much energy in overcoming resistances. However, an
associated drawback with these designs is that they contain too
many bubbles. This shortcoming has been fixed by utilizing a
single acoustically excited bubble trapped within a horseshoe
shaped cavity to mix two fluid streams flowing parallel to each
other in a microchannel42 (Fig. 4 bottom-left). The mixing
intensity has been shown to be appreciable both along the length
and the width of the microchannel (Fig. 4 bottom-right). The
microstreaming around this trapped bubble results in a uniform
mixing of these parallel running fluid streams within a matter of
milliseconds. Such novel micromixers could allow an increas-
ingly faster rate of chemical mixing at smaller length scales and
could prove viable for applications in LOC, especially where
mixture uniformity is critical, or in potential microfluidic
applications where mixing highly viscous fluids is of importance.77
Potential challenges that linger around these oscillating bubble
micro-mixers is to better quantify mixing effectiveness especially
when microstreaming is coupled with strong external flow;
optimize the design; and improve the mixing time further down
to the micro-second range.
Handling of micro-objects
1. Filter. One of the most important pieces of research in
existing micro/nanofluidics is the ability to sort particles
according to various properties, such as size and density. It
would be revolutionary for biomedical applications if we can
devise an efficient and cost effective way of sorting biological
cells on an LOC; a potential candidate could be sonicated
microbubbles, with Ryu et al.78 having first demonstrated the
Fig. 4 (Top-left) Mixing occurs due to oscillations of a multiple bubble
system. (Top-right) The simulation result shows a better mixing
performance with a staggered grid arrangement of bubbles. Reprinted
with permission from ref. 74. (Bottom-left) (a) A non-oscillating bubble
trapped in a horseshoe shaped cavity (b) mixing taking place when the
bubble in the horse shoe cavity is actuated. (Bottom-right) Curves show
mixing (normalized concentration) along both the length and the width
of the microchannel. Reprinted with permission from ref. 42.
Fig. 3 (Top-left) A single bubble microfluidic pump drives a flow
through a small capillary tube along with its pumping curve shown on the
(top-right); notice that the curve resembles a typical pumping curve.
Reprinted with permission from ref. 71. (Bottom-left) A microfluidic
pump utilizes a trapped bubble pair at a junction excited by an off-chip
power source to pump fluid; the flow-rate is a maximum for the 15ujunction angle for all voltages (bottom-right). Reprinted with permission
from ref. 40.
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possibility of size-based particle separation utilizing bubbles. In a
more recent study, Rogers and Neild79 took advantage of the
competition between the drag force and the secondary radiation
force to separate particles according to sizes and densities. In
observation, acoustic excitation caused small particles to repel
away from the bubble and trace motion along their streamlines
since the drag force dominated the radiation force (Fig. 5 top).
On the other hand, larger sized particles were noted to experience
an attractive force because of a dominant radiation force. They
also achieved particle trapping based on density variations
(Fig. 5 bottom-left) that agreed well with their theoretical
predictions. The study also quantifies frequencies at which
specific sized particles can be trapped. Bigger particles are shown
to be trapped at relatively lower frequencies whereas the smaller
particles could be trapped only by employing a higher actuation
frequency, which in effect means smaller bubbles (Fig. 5 bottom-
right). Very possibly, this is owing to increased secondary
radiation force at higher frequencies. This novel and relatively
simple concept can be implemented for inventing a new breed of
non-contact based particle sorters, for cell sorting based on size
and density. Our group has recently found that oscillating
bubbles can be used to trap C. elegans, one of the most
important model animals for biomedical studies; and by steadily
reducing the excitation intensity, we can gradually release the
trapped worms from the biggest to the smallest, so that size-
based selection is realized.80 This is probably due to the fact that
bigger worms are stronger and more likely to escape from the
radiation force field. Future directions of bubble-based filters
dictate caution: careful studies need to be done as most cells have
relatively small cellular density differences. Moreover, since
studies suggest that size and shape of a particle or a cell has a
direct relation with the magnitude of the shear stress it
experience in flow, a careful quantification must be done to
prevent cell lysis or distortion to the verge of denaturing cells.
2. Transporter. For most applications in microfluidic plat-
forms such as LOC, we are usually concerned with transporting
samples from one location to another while ensuring that the
sample remains intact. An oscillating bubble can act as a
potential tweezer for manipulating micro-sized objects, like
biological cells. The secondary radiation force can be used to
capture the particle, and another mechanism can be used to
move the bubble to a desired location for particle release. The
first such application was demonstrated by Sang Kug et al.81 and
later elaborated by Chung et al.82 Using the Electrowetting on
Dielectric (EWOD) method, they selectively switched electrodes
to move bubbles along a desired path. The acoustically actuated
microbubbles carried along with them the macromolecules and
cells during their lateral migration. Mobile manipulating
robots83,84 have been created using the same principle (Fig. 6
top-left). It has been found that the bigger objects (fish eggs,
water fleas) are the ones more likely to be trapped around
bubbles than microparticles that tend to follow the streamlines.
As explained before, the reason can be attributed to the
competition between the radiation force and the drag force. In
principle, the trapping range increases with bubble oscillation
amplitude and that trapping gets strongest when the bubbles are
Fig. 5 (Top) The image delineates the principle of particle sorting on
basis of size. The larger particles are attracted toward the bubble whereas
the smaller sized ones continue following the micro streamlines, as a
result of the competition between the drag and the secondary radiation
force. (Bottom-left) shows trapping of a 5 mm silica particle (grey) on the
bubble surface, whereas the similar size polystyrene particle (red) follows
the streamline, hence realizing trapping based on density difference.
(Bottom-right) Particle size based trapping is plotted against actuation
frequency; notice that for trapping smaller particles we need to utilize
smaller sized bubbles. Reprinted with permission from ref. 79.
Fig. 6 (Top-left) An acoustically actuated microbubble carrying micro-
objects while being forced to traverse laterally over the substrate using
EWOD. Adapted with permission from ref. 83. (Top-right) A single
actuated bubble on the hydrophobic tip of a rod is being used to
manipulate micro-objects with a 3D freedom in space. Reprinted with
permission from ref. 85. (Bottom-left) A pair of twin bubbles is used to
attain a better control for manipulating objects in space. The nature of
the force and its strength depends on the distance of the micro-objects
from the bubble-pair (Bottom-right). Reprinted with permission from
ref. 86.
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forced to vibrate at their respective resonant frequency. An
acoustically actuated single bubble has been shown to carry
objects with a greater degree of freedom in space by placing it on
the hydrophobic tip of a rod85 (Fig. 6 top-right). The novel
mechanism of using a single bubble for micro manipulation
seems promising. However, there is an inherent problem with its
usage: the direction of the manipulating force cannot be precisely
controlled. Recently this problem has been overcome by
employing twin bubbles on the tips of a U-shaped rod86 (see
Fig. 6 bottom-left); experiments have demonstrated that the duo
gives a better control over the direction of manipulation.
Furthermore, it has been noticed that the distance of the object
from the twin bubbles in effect determines whether manipulating
forces would be attractive or repulsive (Fig. 6 bottom-right).
The aforementioned details aim to categorize different bubble
tweezer designs. Generally, the major advantage associated with
bubble tweezers is its working mechanism, which relies on a non-
contact based approach i.e. the bubble tweezer manipulates
micro-objects via action-at-a-distance principle. Nevertheless,
improvement in bubble tweezer design stipulates further research
on novel lines that include quantifying the maximum load
that the bubble tweezers can carry and exploring other
potential methods to move and manoeuvre oscillating bubbles
around complex pathways, especially in conditions of maximum
payload.
On the other hand, use of bubble tweezers may not be effective
for locations in LOC devices that are somewhat inaccessible.
However, acoustically actuated microbubbles are a wonderful
agent for transporting matter even if they are themselves
immobile. Marmottant et al.87 have reported that by creating a
surface protrusion the symmetry of microstreaming flow field in
proximity of an acoustically actuated bubble could be broken,
thus giving rise to a secondary induced flow (Fig. 7a). Since
streamlines of the secondary flow are linear and parallel to the
substrate on which a bubble is attached, rather than vortical;
such a flow is shown as a viable transport mechanism for
particles and biological cells to direct them along straight lines
(Fig. 7b). In a later study88 it has been shown that an array of
three doublets (bubble–protrusion pairs) could form a chain for
directing and transporting particles from one location to another
(Fig. 7c). The direction of the flow can be controlled by fixing a
protrusion around the bubble to break symmetries for a desired
direction. This method is promising in context that the
microparticles could be directed at fast speeds (approximately
1 mm s21) that would otherwise flow slowly through the
microchannels in an LOC. Our group has recently found that a
teardrop shaped cavity can also be used to produce non-
symmetric oscillating bubbles, which can be used as a particle
transporter according to the same principle (refer to Fig. 8).
3. Micro-rotor
The vortical flow field generated around an oscillating bubble is
a potential source of energy. Power can be extracted from this
reservoir if a rotor can be attached to the bubble interface. Wang
et al.89 and Kao et al.33 realized such micro-rotors based on this
concept. They observed microrotors suspended in a liquid to
move toward an acoustically actuated bubble, probably due to
the secondary radiation force. Then these rotors self-aligned on
Fig. 7 Image (a) shows two doublets; notice vortical streamline dying
around the protrusion giving rise to a straight streamline, hence
transporting the particles along with it. Reprinted with permission from
ref. 87. Image (b) shows the path a small bead takes around a bubble–
protrusion pair (a doublet); (c) shows a transport chain of microparticles
from the first bubble to the last. Reprinted with permission from ref. 88.
Fig. 8 A bubble in a tear drop shaped hole with preferential direction of
flow as a result of a break in symmetry. The velocity profile of
microparticles along the line of symmetry of the teardrop is obtained at
two different voltages by tracking seeded microparticles in the flow.
Fig. 9 (Top image) The image shows rotation of a self-aligned rotor (R)
on top of an acoustically actuated bubble (B) attached to a substrate (W).
(Bottom) The plot between rotation speed and excitation frequency
depicts the speed of the rotor is a maximum at the volume resonance of
the bubble. Rotor speed is also shown to vary linearly with the voltage
supplied to the transducer. Reproduced with permission from ref. 33.
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top of the microbubbles and rotated once a balance was found
(refer to Fig. 9 top). An optimization study was performed to
determine the system’s performance with the shape of the rotor.
In their experiments they found the rotor to rotate as high as 625
rpm. Furthermore, the rotor speed turned out to be a maximum
when the bubble was forced to vibrate at its resonance (Fig. 9
bottom-left) and it increased with voltage (Fig. 9 bottom-right).
They used the dimensions of the rotor and the bubble actuation
frequency at volume resonance, along with a few other
parameters to calculate the maximum theoretical power that
could be extracted. Though there is a huge loss in power when
the input is compared to the output, even a femtowatt of power
that is generated this way might be sufficient as well as
advantageous to power the in-house electrical components on
the micro electromechanical systems (MEMS) and nano-electro-
mechanical systems (NEMS). In comparison to a mechanical
motor, the reduced friction outweighs the reduced efficiency
concerns. Secondly, the power source for actuation is not located
internally on the chip, which allows space saving in an
environment where judicious use of space is required. Kao et al.
has suggested that such a bubble-rotor system could be used as an
alternative to a mechanical pump. With a different arrangement,
multiple bubble-rotor systems could be connected together in
series with a single walled-nanotube and be utilized as a mixing
chamber in future LOC devices. However, to realize these future
concepts tremendous fabrication challenges need to be overcome.
4. Manipulation of live animals. Particle and cell manipulation
is at the heart of most microfluidic technologies. The ability to
precisely trap and manipulate particles can be extended to larger
dimensions, enabling us to manipulate an entire microorganism;
sonicated microbubbles have the ability to achieve such
manipulation. We have previously shown that primary radiation
force in an acoustic standing wave field can be used to
manipulate a collection of C. elegans.90 In a recent effort, we
found that the secondary radiation force generated from an
array of insonated microbubbles can be used to precisely
manipulate the pathways of a single C. elegans80 (see Fig. 10).
These worms experience a strong enough secondary radiation
force and they are attracted and are bonded to the oscillating
bubbles. Because the worms are alive and they have the ability to
swim, they will eventually keep rotating about the pulsating
bubbles. Therefore by turning bubbles on and off, the motion of
worms can be directed. This method can be potentially used for
various other biological creatures of interest—especially those
with flagella. We hope that with an improvement to this
manipulation technique in future, an inexpensive simple logic
device could be designed that will enable scientists and engineers
to study important physical properties of microorganisms or
monitor their behavioural characteristics either in isolation or
as part of an ensemble. The concurrent issue with such a
manipulative system is to check whether the organisms can be
made to move in complicated circuits. Furthermore, since the
description for the radiation force (eqn (4)) is only applicable for
spherical particles much smaller than the wavelength of the
ultrasound, successful manipulation of C. elegans emphasizes the
need for a new mathematical model applicable for explaining
the manipulation of larger non-spherical organisms.
5. Propeller. Propellers have long been used to force objects
through fluids by imparting them with momentum and enabling
them to have some degree of manoeuvrability. Propulsion of
miniature objects is proved to be very challenging, because of the
low Reynolds number associated.91 It is extremely hard to
conceive a mechanism that can propel micrometer-sized objects
through fluids without adding weight to the system. A
remarkable feature about eddies generated around pulsating
bubbles is that they can act as propellers to drive floating objects
through fluids.92 The novel approach does not utilize a rotor
system and in turn relies only on a vortex pair to impart
momentum to the objects to which the bubble is attached. The
vortical flow not only propels micro-sized objects, but also is
strong enough to exert a considerable propulsive force on
millimetre-sized objects. In addition, these bubbles can be used
for manoeuvrability in a two-dimensional plane. Miniature
bubble-propelled systems would preclude the need for an in-
house power source, making them first-of-a-kind, cost-effective
wireless propulsion technology for LOC and other microfluidic
platforms. In future, it is hoped that micro-sized robots can be
integrated with this propulsive mechanism instead of flagella-
based propulsion for surveillance in microchannels.
6. Switching and enrichment. The future of LOC would
inevitably require faster computation and in that perspective, a
faster switching mechanism to handle or sort a large amount of
particles with considerable variation in sizes and densities. Since
most of the samples analyzed by the microfluidic platforms,
including LOC devices, exhibit a large variation in terms of size
and densities, segregation and enrichment is required for pre-
processing. Microfluidic switches for LOC based on acoustically
actuated bubbles seem to have an answer for this. In a study,
Wang et al.93 have utilized a superimposed Poiseuille flow and a
vortical flow to act as a switch for particle separation based upon
dimensions (Fig. 11 top-left). In their experiments, they observed
selective trapping of some particles in closed streamlines
whereas the others pass over the oscillating bubble unaffected.
Furthermore, with the superimposed flows, particles of sizes
much smaller than that defined by the design limitation could be
trapped and released after they pass through a narrow gap above
the bubble. Since the particles are released at different locations
when they pass along the critical streamline, this technique can
serve as a very convenient switching, trapping and particle
sorting mechanism (Fig. 11 top-right) with spatial resolution on
the order of 1 mm.94 The advantage also resides in the fact
that we need not change the geometric characteristics of the
Fig. 10 A C. elegans being manipulated to travel along a closed loop by
turning the acoustic field on and off with proper timing control.80
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microfluidic channel, as the only controlling variables are the
driving frequency, the amplitude of bubble oscillation and
the relative strengths of the superimposed flows. Furthermore,
the bubble’s position can be adjusted easily rather than looking
for mobility in the solid components of the design. Patel et al.41
have developed a switch based on an oscillating lateral bubble at
the mouth of a bifurcated channel for collecting particles and
cells in a specified outlet (Fig. 11 bottom-left). Fundamentally,
oscillations induce microstreaming around the bubble, which in
effect mediates the direction by deflecting the incoming particles.
The time of actuation of the bubble is the most critical factor in
determining the width of the switching zone and hence deciding
whether a given particle will make it to the collection outlet. This
switching mechanism is different from the former; instead of
relying on continuous bubble oscillations, the bubble is only
actuated at specific instances. Theoretical switching rates are
about 800 particles per second and experimental results have
shown a viability of 94%. The advantages of such a system
include, but not limited to, an off-chip and a low power voltage
source. However, the trickiest part to realize this switching
mechanism is about knowing the right actuation time with
reference to an incoming particle’s initial position and its
velocity, because even a small deviation can tremendously affect
the efficiency (Fig. 11 bottom-right). Although the authors
reported that the particles were not attracted to the liquid–air
interface, experimentation may be performed with particles of
varying sizes to determine whether the radiation force could
exceed the drag force. An understanding of a bubble’s surface
modes of vibration will also be necessary.95,96
Mass transfer across lipid bilayer membranes
1. Cell lysis. For most biomedical applications where an in-
depth study of cell content and structure is required, cells need to
be ruptured. The mechanical process of rupturing membranes is
generally time-consuming, whereas rupturing via electrical means
may result in hydrolysis or ionization of cell’s content, impacting
study results. On the other hand, oscillating microbubbles—
whether in inertial cavitation or non-inertial cavitation—are
efficient surgeons in their own right and have shown good
promise in this application for future biomedical LOC devices.
The first documented report of cell disruption as a result of
oscillating bubbles in inertial cavitation was published in 1962.97
Ever since then, attempts have been made to explain and achieve
a controlled cell-lysis (disruption) by exposing cells to short-lived
cavitating bubbles.98–106 More recently, Tandiono et al.107
managed to expose a colony of E. coli to a controlled ‘inertial-
cavitation’; in their results, exposure time has been found to
significantly influence cell lysis and a control over this key factor
led to a desired extent of cell disruption. Bubbles in non-inertial
cavitation have also been used for cell lysis with the first reported
study of hemolysis.108 Release of haemoglobin molecules was
thought to be due to the high shear stress or high velocity
gradients present near the actuated bubbles. However, the report
lacked quantitative description sufficient to justify any claims.
Even though observations of cell lysis due to stably oscillating
bubbles were reported long ago, it seems that the microstreaming
generated around these bubbles is not strong enough to shear
cells effectively as compared to inertial-cavitation. An interest
in this area has been triggered more recently with a rather
quantitative description of the phenomenon by Marmottant
et al.60 They noticed cell lysis occurring when a vesicle passed in
close proximity of a vibrating bubble, especially near regions
where the shear stresses were predominantly high due to
microstreaming (see Fig. 12).
Although promising, the aforementioned techniques of cell-
lysis face certain challenges. For example, there is much need for
quantifiable results and experiments that could correlate micro-
streaming around a stably vibrating bubble with the shear
Fig. 12 The image above shows cell deformation and subsequent
rupturing caused by an acoustically actuated bubble due to the presence
of high velocity gradients in the microstreaming flow field. Reproduced
with permission from ref. 60.
Fig. 11 (Top-left) Particle separation and switching is due to a
superimposed Poiseuille flow and microstreaming. (Top-right) We see
the different sized particles (represented by different coloured lines) being
released at different locations after passing the critical streamline.
Reproduced with permission from ref. 93. (Bottom-left): A microfluidic
bubble switch deflects particles into the collection outlet via temporal
actuation of the microbubble. (Bottom-right) The switching efficiency of
the device is strongly dependent on the incoming particle’s velocity and
position. Reproduced with permission from ref. 41.
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strength required to cause cell lysis for different cell varieties. A
lysis study98 with cavitating bubbles suggests cell size might be a
crucial parameter for determining the rupturing strength of a cell
membrane. Therefore, an extensive amount of experimentation
needs to be conducted to tabulate the required shear strength for
different cell sizes and types. Furthermore, for biomedical LOC
devices, usually many functional units are desirable to be
integrated on a same chip for multi-step assays. Thus future
research efforts to integrate oscillating bubbles for cell lysis in
LOC devices may need to look into an optimal acoustic
actuation scheme to ensure that acoustic energy is delivered
only to the point of interest, and does not interfere with other
functions on the same device.
2. Drug and gene delivery. If complete disruption of cells can
prove effective in obtaining cellular content on the one hand,
then on another hand actuated microbubbles can aid in
transferring mass into the cells by creating pores in membranes.
As capsules, microbubbles are miniature laboratories for
synthesizing molecules109,110 and delivering them to target
zones,111 thus microbubble architecture can serve as a harmless
delivery system for drug molecules and genes.112 Viruses, even
if notionally rendered harmless, present serious concerns of
hybridization, mutation and spread of new diseases in the human
population. Oscillating microbubbles offer an alternative gene
delivery method113–115 for combating various diseases/tumours
which subsequently can help avoid the pitfalls of viral based gene
therapy. Drug molecules can either be introduced within the
bubbles using a perfluoride gas, or be coated as nanoparticles116
on the bubble surface using ligands. These small capsules can be
forced to undergo inertial cavitation once they are at desired
locations for effective drug delivery. Microbubbles are a
promising smart carrier of drug molecules for minimizing impact
from invasive therapies: the ideal thing about them is that they
can be traced conveniently since they are already being used for
enhancing image contrast.117–119 Cavitating microbubbles can
ensure a localized and controlled release of drug molecules that
can help drastically lower the issue of cytotoxicity associated
with some types of drugs. Moreover, the process of sonoporation
accompanying cavitation presumably enhances the uptake of
drug molecules in the affected regions.120 Sonoporation using
oscillating bubbles has already been shown as a viable alternative
to electroporation of cells in LOC devices,103 and studies suggest
that this novel mechanism increases cell permeability to
molecules without affecting the cell’s viability.121 A few
challenges that are to be dealt with before this method can be
widely adopted for LOC devices include: increasing payload of
the carriers with sufficient life-time to realize delivery of drug
molecules or genes; preparation of monodispersed bubbles that
can respond to a unique frequency; and precise control and
manipulation of microbubbles in a microchannel. Nevertheless,
research in realizing the full potential of oscillating bubbles can
revolutionize our arsenal for the safe delivery of drugs and genes
for various LOC applications.
Conclusion and future perspective
To summarize, we have presented to the best of our knowledge
the state-of-the-art LOC technologies that are based on
acoustically actuated microbubbles. We have shown how the
acoustically actuated bubble is an extremely powerful tool for
realizing several microfluidic applications in LOC devices
including cell lysis, drug delivery, tweezers for soft-matter, mini
transporters, particle sorting, manipulating organisms, develop-
ing micro-rotors for power generation, micro-mixers, propellers,
microfluidic switch and microfluidic pumps. We presented the
advantages that pulsating bubbles hold, some of which include
but not limited to a higher velocity field, wireless power source
for actuation, and small size. However, to fully extract the
potential of oscillating bubbles, more quantitative comparison
with existing technologies needs to be conducted. Despite the
benefits, we critically analyzed some of the existing literature
pertaining to microfluidic applications realized via oscillating
bubbles. We highlighted challenges present in realizing applica-
tions wherein bubbles act as the driving agents, and we pointed
out the need to further study into this promising field: the
physics of oscillating bubbles is not well understood. Specifically,
the dynamics of oscillating bubbles interacting with microgeo-
metries in LOC devices needs an in-depth quantitative char-
acterization. In this regard, numerical tools for multiscale
modelling could be instrumental in the design, prediction and
analysis of microfluidic devices utilizing oscillating bubbles.
With a better scientific understanding and more powerful
simulation tools we believe oscillating bubbles are one of the
strongest bets for improving current LOC applications, and for
developing new ones, especially for biomedical and micro-
mechanical purposes.
Acknowledgements
We thank the financial support from DARPA Young Faculty
Award through grant N66001-11-1-4127.
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