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: jie.xu@wsu.edu; 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

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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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