Multi-Layer Microbubbles by Microfluidics

doi:10.4236/eng.2013.510B031

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Engineering, 2013, 5, 146-148

http://dx.doi.org/10.4236/eng.2013.510B031 Published Online October 2013 (http://www.scirp.org/journal/eng)

Multi-Layer Microbubbles by Microfluidics

Hongbo Zhang*, Haosu Meng, Qian Sun, Jianpu Liu, W. J. Zhang

Complex and Intelligent Research Centre, East China of Science and Technology, Shanghai, China

Email: *[email protected]

Received April 2013

ABSTRACT

Multi-layer microbubble has great potential in enabling the corporation of medical imaging with tumor therapy such as

drug and gene delivery of therapeutics or other functional materials in medical applications. Microfluidic technique has

advanced over the last decade and showed great promise in replacing traditional microbubble generating method. In this

paper, a multi-layer microbubble structure was produced with the aspect as potentially used for drug loaded microbub-

ble contrast agents.

Keywords: Microfluidic; Multi-Layer; Microbubbles; Medical Imaging

1. Introduction

Microbubble as contrast agents in medical imaging is

first invented in 1970s and it has greatly improved the

quality of medical imaging over the decades. Recently, it

has been found that microbubbles can be used to kill ma-

lignant cells by releasing preloaded drugs and also by

enhancing the drug transfer efficiency in ultrasound filed.

It can also assist the drug targeting to the cells by the

micro-jetting emitted by the microbubble when it col-

lapses subjected to an intense ultrasound filed. This con-

cept has encouraged researches to gener ate microbubbles

with unique structures that meet the demand, but so far,

there are still numerous obstacles remained.

Microfluidic technique has been a promising tool to

generate microbubbles owing to its number of merits,

such as high monodispersity and controllable size distri-

bution [1,2]. New attempts have been made to increase

the production, for example, multi-array microchips [3]

and sudden deepened configuration in the micro-channel

[4]. The mechanism of microbubble generation by micro -

fluidic is still not fully understood, but the most accepted

theory is that in flow focusing (or co-flow) configuration,

the microbubbles are generated by the instability of gas-

liquid jets. Therefore, it can produce much smaller mi-

crobubbles compared with the T-junction geometry [5].

The mechanism of the microbubble formation has been

studied by the ultra high speed camera [6]. Their obser-

vation suggests that the final moment of microbubble

pinch-off in a cross focusing system is purely liquid iner-

tia driven; however, surface tension is still important.

The drug loaded microbubbles are mainly produced by

attaching functional groups to the microbubble surface,

which suffers the major defect that only selects group of

drugs can be loaded [7]. Multilayer microbubbles might

hold the key to succeeding drug loading function with

high efficiency. The drug or gene can be encapsulated in

the middle layer with a protection ou ter layer in the shell.

Also due to the i mmer si on of the two layers, the outer

layer can be liposome while the drug or gene aqueous

liquid is in the middle. In this paper, a multi-channel mi-

crofluidic device was constructed to generate multi-layer

microbubbles.

2. Material

The middle layer of the microbubble is between 80

(Amresco, Ltd.) and ionized water mixture (2% w/v), the

outer layer is composed of liquid paraffin (Shanghai

Lingfen g L t d.) and air is chosen as the gas phase.

3. Microbubble Generation

The microfluidic configuration is shown in Figure 1. The

depth of the channel is 25 μm, the width of the channel is

100 μm, the width of the joint is 20 μm and the length of

the channel for each input is 7 mm.

4. Experiments

The experimental setup is shown in Figure 2. Com-

pressed air was regulated by a valve (Swagelok B-SS4-

VI, USA) and a pressure sensor was used to monitor the

pressure. Liquid phases were supplied by Syringe pumps

(Stoelting 53100, USA). High speed camera (Microview

MVC610DAM-GE110, USA) and microscopy (Sharp-

scope SF-1, USA) was used to evaluate the microbubble

generation process and s ize dist ribution of microbubbles.

*Corresponding a uthor.

H. B. ZHANG ET AL.

147

Figure 1. Microfluidic configuration.

Figure 2. Experimental setup.

5. Results and Analysis

The air pressure was fixed at 23 psi, while the flow rate

of the middle layer (tween 80 and water mixture) was set

at 20 μl/min, the flow rate of the outer layer of liquid

paraffin varied between 5 - 15 μl/min, multi-layer mi-

crobubbles were generated. Figure 3 shows the micro-

bubble generating process. The microbubbles with much

smaller size compared with the width of the channels

were produced. Due to the secondary encapsulation, the

final multi-layer microbubbles (as shown in Figure 4)

have a relative larger size compared with monolayer mi-

crobubbles. The inserted photo clearly showed the mul-

ti-layer structure. The scale bar is 100 μm. The mul-

ti-layer microbubbles have a relative uniform size. The

core of the microbubbles tends to move to the edge of the

mul ti-layer stru cture, it is more likely because of the van

der Waals force.

The flow ratio of two liquid phases plays an important

role in determine the microbubble size and distribution

when the gas phase pressure is fixed. At lower flow ratio

of 0.25 and 0.4, the microbubble production is low, at the

ratio of 0.5 between 80 and liquid paraffin, the micro-

bubbles size is becoming smaller as shown in Figure 5,

with the increase of the both liquid phase flow rate, the

microbubble becomes larger, but the dispersity of the

microbubbles reduces (as shown in Figure 6). Due to

higher flow rates, the process is becoming more stable.

As the increase of the outer layer flow rate, the outer

layer in the microbubble is becoming thicker as shown in

Figure 4 compared with Figure 5. The scale bar in Fig-

ure 5 is 50 μm. It is possible to modify the membr an e

thickness of the microbubbles, therefore, it is likely to

Figure 3. Microbubble generation.

Figure 4. Multi-layer microbubbl es (flow ratio of 0.75).

Figure 5. Microbubbles at liquid phase flow ratio of 0.5.

Figure 6. Microbubble dispersity.

adjust the amount of drugs and genes being carried by

the microbubbles.

The dispersity index was calculated by the formula

(1):

10%

20%

30%

40%

50%

0.25

0.4

0.5

0.6

0.75

Dispersity

Flow rate rationof Two liquid Phases

Tween 80/Paraffin

H. B. ZHANG ET AL.

148

CV D

= (1)

where

is the standard derivation, and

is the

mean diameter of microbubbles.

Due to the higher surface tension of liquid paraffin to

water of 72 dyn/cm, the multi-layer microbubbles cannot

survive for more than 10 minute. The properties of the

immiscible two liquid could play an important role in

prolonging th e life time of microbubbles .

6. Conclusion

Multi-layer microbubble structures have been produced

by microfluidics. By adjusting the operating parameters,

such as flow rate ratio, the microbubble size can be va-

ried, so as the thickness of the microbubble membrane

and it could offer a potential mean for gen eration of drug

and gene loaded microbubble contrast agents to accom-

plish the dual function as imaging and therapy of can-

cers.

7. Acknowledgements

This work is supported by the “One Thousand Talented

Scheme” and the Fundamental Research Funds for the

Central Universities in Chin a.

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