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Dynamics of Bubble Formation in Highly Viscous Liquids Ketan Pancholi, Eleanor Stride,* and Mohan Edirisinghe Department of Mechanical Engineering, Uni Versity College London, Torrington Place, London WC1E 7JE, United Kingdom ReceiVed December 10, 2007. In Final Form: Ja nuary 14, 2008 There has recently been considerable interest in the development of devices for the preparation of monodisperse microbubble suspensions for use as ultrasound contrast agents and drug delivery vehicles. These applications require not only a high degree of bubble uniformity but also a maximum bubble size of 8 µm, and this provides a strong motivation for developing an improved understanding of the process of bubble formation in a given device. The aim of this work was to investigate bubble formation in a T-junction device and determine the influence of the different processing parameters upon bubble size, in particular, liquid viscosity. Images of air bubble formation in a specially designed T-junction were recorded using a high-speed camera for different ratios of liquid to gas flow rate ( Q l / Q g ) and different liquid viscosities ( µ l ). It was found that theoretical predictions of the flow profile in the focal region based on analysis of axisymmetric Stokes flow were accurate to within 6% when compared with the experimental data, indicating that this provided a suitable means of describing the bubble formation process. Both the theoretical and experimental results showed that Q l / Q g and µ l had a significant influence upon bubble formation and eventual size, wit h hig herflow rat es andhighe r viscos iti es pro duc ingsmall er bubble s. The re were, howeve r, found to be limiti ng values of Q l / Q g and µ l beyon d which no furthe r reduc tion in bubble size was achi eved. Introduction The use of gas microbubbles stabilized by a surfactant or polymer coating as contrast agents for ultrasound imaging is well established, and there has been increasing interest in their use as vehicles for ultrasound-mediated targeted drug delivery and gene ther apy. 1-3 Thislatterapplication requ iresa highdegree of control over the size and uniformity of microbubbles in order to ens ure accurate dos ing of a given dru g andmaximizedel ive ry eff ici enc y. T-junc tio n devices pro vid ea mea ns of achieving thi s control, enabling monodisperse microbubble suspensions to be prepared by the impingement of a gas stream into a liquid flow at a narrow orifice. 3 A further requirement for microbubbles which are to be administered intravenously, however, is that they are smaller than 8 µm in diameter in order to minimize the risk of embolism. There is consequently a significant need for impro ved unders tandin g of bubble for mat ion in ter ms of the key parameters controlling the process. The dynamics of bubble formation have been studied widely, both theoretically and experimentally, and it has been shown tha t bubblesare for medvia a “pi nch- off ” pro ces s due to ins tab ili ty of the gas/liquid interface. 4-6 The wavelength of this instability determines the size of the bubble formed, 7 with more rapid pinching-off producing smaller bubbles. This, in turn, depends upon the liquid:gas flow rate ratio, which must be increased in order to reduce bubble size. For a fixed gas pressure, however, there will be a maximum liquid flow rate above which the gas fl ow wil l bec ome choked and no bubble s can be for med . 4 Simi larl y, the gas pres sure cannot be incre ased indefinite ly with out resulting in atomization of the liquid. Moreover, the maximum li qui d fl owratewill als o be limited by thediamete r of thechannel through which it is flo win g. The aimof this stu dy,there for e, was * To whom correspon dence should be addre ssed. Phone: +44(0)- 207679393 8. Fax: +44(0)20738 80180. E-mail: [email protected]. (1) Talu, E.; Lozano, M. M.; Powell, R. L.; Dayton, P. A.; Longo, M. L. Long-term stability by lipid coating monodisperse microbubbles formed by a flow-focus ing device. Langmuir 2006, 22 (23), 9487-9490. (2) Unger, E. C.; Porter, T.; Culp, W.; Labell, R.; Matsunaga, T.; Zutshi, R. Therapeuti c applicatio ns of lipid-coat ed microbubbles. Ad V. Drug DeliVery ReV. 2004, 56 (9), 1291-1314. (3) Pancholi, K.P.; Farook, U.; Moaleji, R.; Stride, E.; Edirisinghe, M. Novel methods for preparing phospholipid coated microbubbles. Eur. Biophys. J. 2008, in press; DOI 10.1007/s00249-007-0211-x. (4) Ganan-Ca lvo, A. M.; Gordillo, J. M. Perfect ly monodi spersemicrobubbli ng by capillary flow focusing. Phys. ReV. Lett. 2001, 87 (27), 274501-274504. (5) Gordillo, J. M.; Cheng, Z. D.; Ganan-Calvo, A. M.; Marquez, M.; Weitz, D. A. A new device for the generation of microbubbles. Phys. Fluids 2004, 16 (8), 2828-2834. (6) Jensen, M. J.; Stone, H. A.; Bruus, H. A numerical study of two-phase Stokes flow in an axisymmetric flow-focus ing device. Phys. Fluids 2006, 18 (7), 077103-077113. (7) Garstecki,P.; Fuerst man,M. J.;Whiteside s, G. M. Oscil latio ns withuniquely longperiodsin a micr oflu idicbubble gene rato r. Nat . Phys. 2005, 1 (3),168-171. Figur e 1. Sche mati c of the T-jun ctiondevice: (a) syste m appar atus and (b) junction geometry. 4388 Langmuir 2008, 24, 4388-4393 10.1 021/ la703849 x CCC: $40 .75 © 2008 America n Chemi cal Soci ety Published on Web 03/11/2008

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