pubs.acs.org/Langmuir © 2009 American Chemical Society
Microfluidic Fabrication of Stable Nanoparticle-Shelled Bubbles Myung Han Lee,† Varesh Prasad,‡ and Daeyeon Lee*,† †
Department of Chemical and Biomolecular Engineering, and ‡Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104 Received November 23, 2009. Revised Manuscript Received December 20, 2009
We introduce a microfluidic approach to generating monodisperse, stable nanoparticle-shelled bubbles using air-inoil-in-water (A/O/W) compound bubbles as templates. The oil phase of the A/O/W compound bubbles comprises a volatile organic solvent and a hydrophobic silica nanoparticle. Upon evaporation of the organic solvent, the nanoparticles in the oil layer form a stiff shell at the air-water interface, which drastically enhances the stability of the bubbles against dissolution and coarsening. On the basis of this approach, we demonstrate that it is also possible to generate functional bubbles stabilized by composite shells that are composed of mixtures of hydrophobic materials and nanoparticles with unique properties.
A bubble is a globular body of air or gas dispersed in a liquid. Monodisperse, stable bubbles have potential applications in the fabrication of functional lightweight materials with hierarchical structure and in the encapsulation of flavors and fragrances for food and cosmetics additives.1-4 Bubbles are also used in medical applications such as contrast-enhanced ultrasonography and drug delivery.5-10 It is, however, not trivial to generate gas bubbles with high uniformity in size and properties and store them without significant changes in size for an extended period of time. Conventional methods of preparing bubbles involve the production of a dispersion of gas in a solution containing amphiphilic molecules such as phospholipids and surfactants by sonication, mechanical agitation, or high shear mixing.11-13 Bubbles generated using these methods tend to be very polydisperse in size. A recently developed electric bubble generation method provides better control of the size distribution but nevertheless generates bubbles with a polydispersity index (δ) of 30-40% (δ (%) = σ/D 100 where σ and D are the standard deviation and average diameter of bubbles, respectively).14 In addition to their polydispersity, gas bubbles stabilized by amphiphilic molecules undergo dissolution and coarsening via Ostwald ripening because of the effects of Laplace pressure across the *Corresponding author. E-mail:
[email protected]. Tel: (215) 5734521. Fax:(215) 573-2093.
(1) Binks, B. P.; Murakami, R. Nat. Mater. 2006, 5, 865–869. (2) Campbell, G. M.; Mougeot, E. Trends Food Sci. Technol. 1999, 10, 283–296. (3) Bala Subramaniam, A.; Abkarian, M.; Mahadevan, L.; Stone, H. A. Nature 2005, 438, 930. (4) Alargova, R. G.; Warhadpande, D. S.; Paunov, V. N.; Velev, O. D. Langmuir 2004, 20, 10371–10374. (5) Unger, E. C; Porter, T.; Culp, W.; Labell, R.; Matsunaga, T.; Zutshi, R. Adv. Drug Delivery Rev. 2004, 56, 1291–1314. (6) Klibanov, A. L. Adv. Drug Delivery Rev. 1999, 37, 139–157. (7) Unger, E. C.; Matsunaga, T. O.; McCreery, T.; Schumann, P.; Sweitzer, R.; Quigley, R. Eur. J. Radiol. 2002, 42, 160–168. (8) Ke, H.; Xing, Z.; Zhao, B.; Wang, J.; Liu, J.; Guo, C.; Yue, X.; Liu, S.; Tang, Z.; Dai, Z. Nanotechnology 2009, 20, 425105. (9) Ferrara, K.; Pollard, R.; Borden, M. Annu. Rev. Biomed. Eng. 2007, 9, 415– 447. (10) Linder, J. R. Nat. Rev. Drug Discovery 2004, 3, 527–532. (11) Pancholi, K. P.; Farook, U.; Moaleji, R.; Stride, E.; Edirisinghe, M. J. Eur. Biophys. J. 2008, 37, 515–520. (12) Xu, Q.; Nakajima, M.; Ichikawa, S.; Nakamura, N.; Roy, P.; Okadome, H.; Shiina, T. J. Colloid Interface Sci. 2009, 332, 208–214. (13) Stride, E.; Edirisinghe, M. Soft Matter 2008, 4, 2350–2359. (14) Farook, U.; Stride, E.; Edirisinghe, M. J. J. R. Soc. Interface 2009, 6, 271– 277.
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air-water interface, making it very difficult to retain size uniformity for an extended period of time.15,16 Recently, microfluidic approaches have been utilized to generate stable, monodisperse bubbles with controlled dimensions.17-23 The polydispersity (δ) of these bubbles is typically less than 5%. In these approaches, monodisperse bubbles generated in a microfluidic device are stabilized by the adsorption of amphiphilic molecules or partially hydrophobic particles from an aqueous phase to the air-water interface.17-22 In particular, the stability of bubbles has been drastically improved by the formation of close-packed layers of colloidal particles at the air-water interface.3,4,20,24 Monodisperse bubbles with a hydrogel shell suspended in oil have also been generated using a microfluidic technique.25 A hydrogel shell was generated by photopolymerizing water-soluble monomers to encapsulate gas bubbles. These approaches, however, are limited to the use of amphiphilic or water-dispersible materials for the stabilization of the air-water interface. This limitation restricts the formation of composite shells that are composed of mixtures of hydrophobic molecules and nanoparticles with unique properties. The incorporation of non-water-soluble materials such as drugs and nanomaterials would significantly enhance the versatility of composite bubbles in various applications. In this work, we demonstrate that monodisperse nanoparticleshelled bubbles can be created using an air-in-oil-in-water (A/O/ W) compound bubble as a template. These A/O/W compound (15) Norde, W. Colloids and Interfaces in Life Sciences; Marcel Dekker: New York, 2003. (16) Dutta, A.; Chengara, A.; Nikolov, A. D.; Wasan, D. T.; Chen, K.; Campbell, B. J. Food Eng. 2004, 62, 177–184. (17) Talu, E.; Hettiarachchi, K.; Powell, R. L.; Lee, A. P.; Dayton, P. A.; Longo, M. L. Langmuir 2008, 24, 1745–1749. (18) Xu, J. H.; Li, S. W.; Wang, Y. J.; Luo, G. S. Appl. Phys. Lett. 2006, 88, 133506. (19) Garstecki, P.; Gitlin, I.; DiLuzio, W.; Whitesides, G. M.; Kumacheva, E.; Stone, H. A. Appl. Phys. Lett. 2004, 85, 2649. (20) Park, J. I.; Nie, Z.; Kumachev, A.; Abdelrahman, A. I.; Binks, B. P.; Stone, H. A.; Kumacheva, E. Angew. Chem., Int. Ed. 2009, 48, 5300–5304. (21) Dollet, B.; van Hoeve, W.; Raven, J. P.; Marmottant, P.; Versluis, M. Phys. Rev. Lett. 2008, 100, 034504. (22) Martinez, C. J. J. Bubble Sci. Eng. Technol. 2009, 1, 40–52. (23) Pancholi, K.; Stride, E.; Edirisinghe Langmuir 2008, 24, 4388–4393. (24) Wege, H. A.; Kim, S.; Paunov, V. N.; Zhong, Q.; Velev, O. D. Langmuir 2008, 24, 9245–9253. (25) Wan, J.; Bick, A.; Sullivan, M.; Stone, H. A. Adv. Mater. 2008, 20, 3314– 3318.
Published on Web 12/29/2009
DOI: 10.1021/la904425v
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Figure 1. (a) Schematic diagram and (b) optical microscopy image of A/O/W compound bubbles generated in a capillary microfluidic device. (c) Dependence of the encapsulated bubble size (Dbubble) (open) and oil thickness (Loil) (closed) on the flow rates of middle (Qm) and outer phases (Qo) and the pressure of the inner phase (Pi). We note that Dbubble and Loil are determined by the oil flow rate (Qm), compoundbubble generation frequency (fbubble), and compound-bubble size (Dave), which are given by Dbubble = (Dave3 - (6Qm/fbubbleπ))1/3 and Loil = (Dave - Dbubble)/2, respectively.
bubbles are generated using a glass-capillary microfluidic device combining both hydrodynamic flow-focusing and coflowing geometry,26-28 as shown in Figure 1a. The inner phase (A) is typically nitrogen, and the outer phase (W) is a 2 wt % poly(vinyl alcohol) (PVA) aqueous solution. The middle phase (O), which is immiscible with both the inner and outer phases, is a toluene solution containing hydrophobic silica nanoparticles. The outer phase hydrodynamically focuses the middle and inner fluid streams, breaking them into monodisperse A/O/W compound bubbles with a core-shell structure upon entering the collection tube as shown in Figure 1b. In the microfluidic device, highly uniform A/O/W compound bubbles with a very low polydispersity (δ < 3%) are generated at a typical frequency of several thousand hertz. PVA in the outer aqueous phase adsorbs to the oil-water interface and prevents the coalescence of the generated compound bubbles. For a given device, the dimensions of the compound bubbles strongly depend on the flow rates of the middle (Qm) and outer phases (Qo) as well as the pressure of the inner phase (Pi), as shown in Figure 1c. An increase in the flow rate of the middle oil phase (Qm) generally leads to an increase in the thickness of the oil layer with no significant changes in the encapsulated bubble size. A drastic increase, however, leads to the encapsulation of multiple gas bubbles that eventually coalesce, forming polydisperse compound bubbles. (See Supporting Information for optical microscope images, Figure S1). Changes in the flow rate of the continuous phase (Qo) and the pressure of the inner phase (Pi) change the size of the encapsulated bubbles, but they do not (26) Shah, R. K.; Kim, J. W.; Agresti, J. J.; Weitz, D. A.; Chu, L. Y. Soft Matter 2008, 4, 2303–2309. (27) Utada, A. S.; Lorenceau, E.; Link, D. R.; Kaplan, P. D.; Stone, H. A.; Weitz, D. A. Science 2005, 308, 537–541. (28) Lee, D.; Weitz, D. A. Small 2009, 5, 1932–1935.
2228 DOI: 10.1021/la904425v
significantly influence the thickness of the oil shell as shown in Figure 1c. By tuning the flow rates of the three phases independently, we are able to control the dimensions of A/O/W compound bubbles, thereby providing a method to tune the dimensions of nanoparticle-shelled bubbles. To generate highly uniform bubbles encapsulated by a nanoparticle shell, it is critical to make and retain monodisperse, stable compound bubbles with a gas core and an oil shell suspended in water as a template. Previous studies, for example, have reported that the dewetting instability of the oil layer in the water-in-oil-inwater (W/O/W) double emulsions prevented the generation of polymersomes, which are vesicles of amphiphilic diblock copolymers.29,30 To generate thermodynamically stable core-shell structures from three fluids, the spreading coefficient, defined as Si=γjk - γij - γik (i ¼ 6 j 6¼ k=op, ip, mp) (where γjk, γij, and γik are the surface and interfacial tensions between j and k, i and j, and i and k fluids), of the three phases must satisfy the following relationship: Sop < 0, Sip < 0, and Smp > 0 (subscripts op, ip, and mp indicate the outer, inner, and middle phases, respectively).31 In our system, the spreading coefficients, determined using pendant drop tensiometry,32 are Sop=-27.1 < 0 mN/m, Sip =-66.4 < 0 mN/m, and Smp =18.7 > 0 mN/m, satisfying the conditions for the engulfment of one dispersed phase in the second phase.31 Because of the favorable wetting properties at each interface, the initial template configuration remains stable until the complete evaporation of the solvent. (29) Shum, H. C.; Kim, J. W.; Weitz, D. A. J. Am. Chem. Soc. 2008, 130, 9543– 9549. (30) Hayward, R. C.; Utada, A. S.; Dan, N.; Weitz, D. A. Langmuir 2006, 22, 4457–4461. (31) Torza, S.; Mason, S. G. J. Colloid Interface Sci. 1970, 33, 67–83. (32) Andreas, J. M.; Hauser, E. A.; Tucker, W. B. J. Phys. Chem. 1938, 42, 1001– 1019.
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Figure 2. (a) Schematic of the formation of bubbles with the rigid shell of close-packed nanoparticles from microfluidic-generated A/O/W compound bubbles. (b) Long-term stability of bubbles generated at Qo=120 000 μL/h, Qm=1000 μL/h, and Pi=82.7 kPa. An optical microscopy image shows bubbles 1020 h after preparation. The inset is a histogram showing the size distribution of bubbles.
Nanoparticle-shelled bubbles generated upon the evaporation of the solvent, as shown in Figure 2a, are extremely stable against dissolution and coarsening. Figure 2b displays the long-term stability of bubbles after collection from microfluidic device; the average diameter (Dave) and polydispersity (δ) of bubbles produced at Qo=120, 000 μL/h, Qm=1000 μL/h, and Pi=82.7 kPa are plotted as a function of storage time ta. The initial diameter of compound bubbles, generated at the orifice of the collection tube, was 36.2 μm (δ = 1.2%). The diameter of compound bubbles decreased to 28.0 μm one hour after collection and did not undergo further change. Also, the polydispersity of bubbles increased from 1.2% to approximately 5.2% in the first 24 h after collection and did not change significantly thereafter. The decrease in diameter and the increase in polydispersity in the early stages after collection likely result from the dissolution of gas into the continuous phase and the evaporation of oil. The formation of stiff nanoparticle shells, as evidenced by the presence of intact spherical hollow shells in the scanning electron microscopy (SEM) images in Figure 3, arrests the shrinkage of bubbles, leading to long-term stability for several months. The average diameter of hollow capsules as determined using SEM is 29.0 μm (δ=4.5%), consistent with the diameter of nanoparticle-shelled bubbles in solution (∼28 μm), as seen in Figure 2b. This observation indicates that the compound bubbles decrease to a terminal size upon removal of the solvent and that this event is accompanied by the formation of a stiff shell of randomly packed nanoparticles, providing excellent stability against dissolution and coarsening. The unique feature of our approach is in the possibility of generating multicomponent bubbles by incorporating a variety of materials into the silica nanoparticle shell. This can simply be achieved by suspending or dissolving functional materials into the oil layer containing silica nanoparticles and subsequently removing the solvent. A magnetically responsive bubble was generated, for example, by adding magnetic nanoparticles to the oil layer, as shown in Figure 4a. These magnetic bubbles could be readily manipulated using a magnetic field. In the absence of a magnetic field, the magnetic bubbles drifted in the x direction, likely because of the curved water surface. Upon application of a magnetic field in the direction perpendicular to the spontaneous drift, the bubbles moved at a velocity of 12.8 μm/s in the direction Langmuir 2010, 26(4), 2227–2230
Figure 3. SEM images of hollow shells obtained after bubbles generated at Qo = 120 000 μL/h, Qm = 1000 μL/h, and Pi = 82.7 kPa were completely air dried at room temperature.
of the field gradient. In addition to magnetic nanoparticles, a hydrophobic fluorescent dye, Nile red, and a free fatty acid, palmitic acid, could be incorporated into the silica nanoparticle shells, as shown in Figures 4b and c, respectively. We believe that these molecules coat the silica nanoparticles that form the shell surrounding the gas bubbles after the removal of the solvent. Incorporating hydrophobic molecules into the shell of bubbles and controlling the composition of the shell are not trivial tasks when using previously reported methods of bubble generation.17-21 With our approach of using A/O/W compound bubbles as templates, however, we can readily achieve these goals. Our strategy to control the shell composition could also be useful in tuning the mechanical properties of these bubbles to optimize their deformability for contrast-enhanced ultrasonography applications.10 In summary, we demonstrated a novel approach to fabricating highly monodisperse, stable bubbles with an elastic shell comprising silica nanoparticles and other functional materials. The microfluidic technique was used to generate precisely controlled air-in-oil-in-water (A/O/W) compound bubbles as a template. Upon the evaporation of the solvent from the oil layer, the nanoparticle-oil suspension that encapsulated the gas bubbles underwent a liquid-to-solid transition, resulting in the formation of a stiff shell and conferring great stability to the bubble for several months. Finally, the generation of bubbles with composite shells incorporating hydrophobic materials demonstrates the great potential of our approach to using A/O/W compound bubbles as drug-delivery vehicles in therapeutic applications. Furthermore, these functional bubbles with precisely controlled composition can be utilized to fabricate hierarchical porous structures with desirable physicochemical properties.33 In the (33) Backov, R. Soft Matter 2006, 2, 452–464.
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Figure 4. Generation of bubbles with multicomposite shells: (a) (left) optical images of magnetic bubbles moving parallel to a magnetic field gradient; (right) x and y trajectories as a function of time for the magnetic bubble motion induced by the magnetic field gradient. (b) Fluorescent image of bubbles with the silica shell containing fluorescent dye Nile red. (c) SEM image of air-dried bubbles with a palmitic acid/silica nanoparticle composite shell.
future, we will explore the possibility of using external stimuli such as ultrasound to trigger the release of incorporated materials from the bubble shell for drug-delivery applications.5,9
Experimental Section Fabrication of Microfluidic Devices. The glass-capillary microfluidic device with hydrodynamic flow-focusing and coflowing geometry was fabricated as described previously.27,34 Two circular capillary tubes with inner and outer diameters of 0.58 and 1.0 mm (World Precision Instrument Inc.) were tapered for the injection of a gas phase and the collection of bubbles, using a micropipet puller (P-1000, Sutter Instruments Inc.) and a microforge (Narishige MF-830). The diameter of the inner orifice ranged from 2 to 5 μm, and that of the collection tube ranged from 100 to 150 μm. The two capillaries were inserted into a square capillary with an inner dimension of 1.0 mm. Generation of Compound Bubbles. For the generation of A/O/W compound bubbles with a gas core and oil shell suspended in water, two liquids and one gas were introduced into a microfluidic device. Nitrogen (N2) as the inner phase was delivered to the device via flexible Tygon tubing with a pressure regulator (ControlAir Inc.). A 2 wt % poly(vinyl alcohol) aqueous solution (PVA, 87-89% hydrolyzed, average Mw = 13 000-23 000, Aldrich) as the outer phase and a toluene solution containing hydrophobic silica nanoparticles (average diameter = ∼15 nm, Nisan Chemical Inc. Tol-ST) as the middle phase were loaded into two syringes (SGE or Hamilton Gastight) and introduced into the device using syringe pumps (PHD, Harvard Apparatus). For the fabrication of bubbles with magnetic, fluorescent, and free fatty acid-containing shells, the middle oil phases were prepared by dissolving 14 μL of toluene-based ferrofluid (Ferrotec Corp.), 20 μL of toluene-based Nile red solution (1 mg/mL), and 500 μL of toluene solution containing palmitic acid (100 mg/mL) in 5 mL of toluene solution containing silica particles (volume fraction= 0.12), respectively. (34) Lee, D.; Weitz, D. A. Adv. Mater. 2008, 20, 3498–3503.
2230 DOI: 10.1021/la904425v
Characterization of Bubbles. The generation of compound bubbles in a device was monitored with a 10 objective using an inverted optical microscope (Nikon Diaphot 300) equipped with a high-speed camera (Phantom V7.1). The size distribution of bubbles upon collection was analyzed using an upright microscope (Carl Zeiss Axio Plan II) with a CCD camera (Qimaging Retiga 2000R Fast 1394). The average bubble size (Dave) and polydispersity index (δ) were determined by measuring the sizes of at least 150 bubbles with ImageJ software. The scanning electron microscope (SEM) images were taken using a Quanta 600 FEG Mark II. To prevent the accumulation of electric charge on the samples, samples were coated with a thin layer of gold. Fluorescent images were taken using a Nikon Diaphot 300 inverted microscope with a CCD camera and 75 W xenon lamp (Nikon). Surface and Interfacial Tension Measurements. Surface (air-liquid) and interfacial (liquid-liquid) tension measurements were performed using the pendent drop technique32 on a RameHart model 200 goniometer with DROPimage Advanced software to determine the spreading coefficients. Surface/interfacial tensions were measured from the shape of a droplet created at the flat tip of a stainless steel needle using a micrometer syringe (GS1200, Gilmont Instruments). The reproducibility of tension measurements was within (0.5 mN/m. Acknowledgment. This work was supported by the PENN MRSEC DMR-0520020, the Nano/Bio Interface Center through the National Science Foundation (NSEC DMR-0425780), and the Amore-Pacific Co. V.P. and D.L. acknowledge financial support for this project provided by the University of Pennsylvania’s Provost’s Undergraduate Research Mentorship (PURM) program. We also thank Professor Shu Yang and Dr. Rong Dong at the University of Pennsylvania for the use of their goniometer. Supporting Information Available: Optical microscopy images of compound bubbles generated in a microfluidic device. This material is available free of charge via the Internet at http://pubs.acs.org. Langmuir 2010, 26(4), 2227–2230
