Publications

2012
Vladisavljevic, G. T. ; Duncanson, W. J. ; Shum, H. C. ; Weitz, D. A. Emulsion templating of poly(lactic acid) particles: Droplet formation behavior. Langmuir 2012, 28, 12948-12954.Abstract

Monodisperse poly(DL-lactic acid) (PLA) particles of diameters between 11 and 121 mu m were fabricated in flow focusing glass microcapillary devices by evaporation of dichloromethane (DCM) from emulsion droplets at room temperature. The dispersed phase was 5% (w/w) PLA in DCM containing 0.1-2 mM Nile Red and the continuous phase was 5% (w/w) poly(vinyl alcohol) in reverse osmosis water. Particle diameter was 2.7 times smaller than the diameter of the emulsion droplet template, indicating very low particle porosity. Monodisperse droplets have only been produced under dripping regime using a wide range of dispersed phase flow rates (0.002-7.2 cm(3).h(-1)), continuous phase flow rates (0.3-30 cm(3).h(-1)), and orifice diameters (50-237 mu m). In the dripping regime, the ratio of droplet diameter to orifice diameter was inversely proportional to the 0.39 power of the ratio of the continuous phase flow rate to dispersed phase flow rate. Highly uniform droplets with a coefficient of variation (CV) below 2% and a ratio of the droplet diameter to orifice diameter of 0.5-1 were obtained at flow rate ratios of 4-25. Under jetting regime, polydisperse droplets (CV > 6%) were formed by detachment from relatively long jets (between 4 and 10 times longer than droplet diameter) and a ratio of the droplet size to orifice size of 2-5.

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Schmid, L. ; Wixforth, A. ; Weitz, D. A. ; Franke, T. Novel surface acoustic wave (SAW)-driven closed PDMS flow chamber. Microfluidics and Nanofluidics 2012, 12, 229-235.Abstract

In this article, we demonstrate a novel microfluidic flow chamber driven by surface acoustic waves. Our device is a closed loop channel with an integrated acoustic micropump without external fluidic connections that allows for the investigation of small fluid samples in a continuous flow. The fabrication of the channels is particularly simple and uses standard milling and PDMS molding. The micropump consists of gold electrodes deposited on a piezoelectric substrate employing photolithography. We show that the pump generates a pressure-driven Poiseuille flow, investigate the acoustic actuation mechanism, characterize the flow profile for different channel geometries, and evaluate the driving pressure, efficiency and response time of the acoustic micropump. The fast response time of our pump permits the generation of non-stationary flows. To demonstrate the versatility of the device, we have pumped a red blood cell suspension at a physiological rate of 60 beats/min.

2012_microfluidnanofluid_saw.pdf
Romeo, G. ; Imperiali, L. ; Kim, J. - W. ; Fernandez-Nieves, A. ; Weitz, D. A. Origin of de-swelling and dynamics of dense ionic microgel suspensions. Journal of Chemical Physics 2012, 136.Abstract

A direct consequence of the finite compressibility of a swollen microgel is that it can shrink and deform in response to an external perturbation. As a result, concentrated suspensions of these particles exhibit relaxation dynamics and rheological properties which can be very different with respect to those of a hard sphere suspension or an emulsion. We study the reduction in size of ionic microgels in response to increasing number of particles to show that particle shrinkage originates primarily from steric compression, and that the effect of ion-induced de-swelling of the polymer network is negligible. With increasing particle concentration, the single particle dynamics switch from those typical of a liquid to those of a super-cooled liquid and finally to those of a glass. However, the transitions occur at volume fractions much higher than those characterizing a hard sphere system. In the supercooled state, the distribution of displacements is non-Gaussian and the dependence of the structural relaxation time on volume fraction is describable by a Volger-Fulcher-Tammann function. (C) 2012 American Institute of Physics. [http://dx.doi.org/10.1063/1.3697762]

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Rubinstein, S. M. ; Kolodkin-Gal, I. ; Mcloon, A. ; Chai, L. ; Kolter, R. ; Losick, R. ; Weitz, D. A. Osmotic pressure can regulate matrix gene expression in Bacillus subtilis. Molecular Microbiology 2012, 86, 426-436.Abstract

Many bacteria organize themselves into structurally complex communities known as biofilms in which the cells are held together by an extracellular matrix. In general, the amount of extracellular matrix is related to the robustness of the biofilm. Yet, the specific signals that regulate the synthesis of matrix remain poorly understood. Here we show that the matrix itself can be a cue that regulates the expression of the genes involved in matrix synthesis in Bacillus subtilis. The presence of the exopolysaccharide component of the matrix causes an increase in osmotic pressure that leads to an inhibition of matrix gene expression. We further show that non-specific changes in osmotic pressure also inhibit matrix gene expression and do so by activating the histidine kinase KinD. KinD, in turn, directs the phosphorylation of the master regulatory protein Spo0A, which at high levels represses matrix gene expression. Sensing a physical cue such as osmotic pressure, in addition to chemical cues, could be a strategy to non-specifically co-ordinate the behaviour of cells in communities composed of many different species.

2012_molemicro_osmotic_pressure_regulate_matrix_gene_expression_in_bacillus_subtilis.pdf
Seminara, A. ; Angelini, T. E. ; Wilking, J. N. ; Vlamakis, H. ; Ebrahim, S. ; Kolter, R. ; Weitz, D. A. ; Brenner, M. P. Osmotic spreading of Bacillus subtilis biofilms driven by an extracellular matrix. Proceedings of the National Academy of Sciences of the United States of America 2012, 109, 1116-1121.Abstract

Bacterial biofilms are organized communities of cells living in association with surfaces. The hallmark of biofilm formation is the secretion of a polymeric matrix rich in sugars and proteins in the extracellular space. In Bacillus subtilis, secretion of the exopolysaccharide (EPS) component of the extracellular matrix is genetically coupled to the inhibition of flagella-mediated motility. The onset of this switch results in slow expansion of the biofilm on a substrate. Different strains have radically different capabilities in surface colonization: Flagella-null strains spread at the same rate as wild type, while both are dramatically faster than EPS mutants. Multiple functions have been attributed to the EPS, but none of these provides a physical mechanism for generating spreading. We propose that the secretion of EPS drives surface motility by generating osmotic pressure gradients in the extracellular space. A simple mathematical model based on the physics of polymer solutions shows quantitative agreement with experimental measurements of biofilm growth, thickening, and spreading. We discuss the implications of this osmotically driven type of surface motility for nutrient uptake that may elucidate the reduced fitness of the matrix-deficient mutant strains.

2012_pnas_osmotic_spreading_of_bacillus_subtilis.pdf
2011
Zhao, Y. ; Shum, H. C. ; Adams, L. L. A. ; Sun, B. J. ; Holtze, C. ; Gu, Z. ; Weitz, D. A. Enhanced encapsulation of actives in self-sealing microcapsules by precipitation in capsule shells. Langmuir 2011, 27, 13988-13991.Abstract
Microcapsules with core-shell structures are excellent vehicles for the encapsulation of active ingredients; however, the actives often leak out of these structures over time, without observable damage to them. We present a novel approach to enhancing the encapsulation of active ingredients inside microcapsules. We use two components that can form solid precipitates upon mixing and add one each to the microcapsule core and to the continuous phase. The components diffuse through the shell in the same manner as the actives, but upon meeting, they precipitate to form solid particles within the shell; this significantly reduces leakage through the shell of the microcapsules. We show that the reduction in the leakage of actives is due to the blockage of channels or pores that exist in the shell of the capsules by the solid precipitates.
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Times Cited: 3
Zhao, Y. ; Shum, H. C. ; Chen, H. ; Adams, L. L. A. ; Gu, Z. ; Weitz, D. A. Microfluidic generation of multifunctional quantum dot barcode particles. Journal of the American Chemical Society 2011, 133, 8790-8793.Abstract
We develop a new strategy to prepare quantum dot (QD) barcode particles by polymerizing double-emulsion droplets prepared in capillary microfluidic devices. The resultant barcode particles are composed of stable QD-tagged core particles surrounded by hydrogel shells. These particles exhibit uniform spectral characteristics and excellent coding capability, as confirmed by photoluminescence analyses. By using double-emulsion droplets with two inner droplets of distinct phases as templates, we have also fabricated anisotropic magnetic barcode particles with two separate cores or with a Janus core. These particles enable optical encoding and magnetic separation, thus making them excellent functional barcode particles in biomedical applications.
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Times Cited: 43
Wyss, H. M. ; Henderson, J. M. ; Byfield, F. J. ; Bruggeman, L. A. ; Ding, Y. ; Huang, C. ; Suh, J. H. ; Franke, T. ; Mele, E. ; Pollak, M. R. ; et al. Biophysical properties of normal and diseased renal glomeruli. American Journal of Physiology-Cell Physiology 2011, 300, C397-C405.Abstract
Wyss HM, Henderson JM, Byfield FJ, Bruggeman LA, Ding Y, Huang C, Suh JH, Franke T, Mele E, Pollak MR, Miner JH, Janmey PA, Weitz DA, Miller RT. Biophysical properties of normal and diseased renal glomeruli. Am J Physiol Cell Physiol 300: C397-C405, 2011. First published December 1, 2010; doi:10.1152/ajpcell.00438.2010.-The mechanical properties of tissues and cells including renal glomeruli are important determinants of their differentiated state, function, and responses to injury but are not well characterized or understood. Understanding glomerular mechanics is important for understanding renal diseases attributable to abnormal expression or assembly of structural proteins and abnormal hemodynamics. We use atomic force microscopy (AFM) and a new technique, capillary micromechanics, to measure the elastic properties of rat glomeruli. The Young's modulus of glomeruli was 2,500 Pa, and it was reduced to 1,100 Pa by cytochalasin and latunculin, and to 1,400 Pa by blebbistatin. Cytochalasin or latrunculin reduced the F/G actin ratios of glomeruli but did not disrupt their architecture. To assess glomerular biomechanics in disease, we measured the Young's moduli of glomeruli from two mouse models of primary glomerular disease, Col4a3 (-/-) mice (Alport model) and Tg26(HIV/nl) mice (HIV-associated nephropathy model), at stages where glomerular injury was minimal by histopathology. Col4a3(-/-) mice express abnormal glomerular basement membrane proteins, and Tg26HIV/nl mouse podocytes have multiple abnormalities in morphology, adhesion, and cytoskeletal structure. In both models, the Young's modulus of the glomeruli was reduced by 30%. We find that glomeruli have specific and quantifiable biomechanical properties that are dependent on the state of the actin cytoskeleton and nonmuscle myosins. These properties may be altered early in disease and represent an important early component of disease. This increased deformability of glomeruli could directly contribute to disease by permitting increased distension with hemodynamic force or represent a mechanically inhospitable environment for glomerular cells.
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Times Cited: 15
Yao, N. Y. ; Becker, D. J. ; Broedersz, C. P. ; Depken, M. ; MacKintosh, F. C. ; Pollak, M. R. ; Weitz, D. A. Nonlinear viscoelasticity of actin transiently cross-linked with mutant alpha-actinin-4. Journal of Molecular Biology 2011, 411, 1062-1071.Abstract
Filamentous actin and associated actin binding proteins play an essential role in governing the mechanical properties of eukaryotic cells. They can also play a critical role in disease; for example, mutations in alpha-actinin-4 (Actn4), a dynamic actin cross-linking protein, cause proteinuric disease in humans and mice. Amino acid substitutions strongly affect the binding affinity and protein structure of Actn4. To study the physical impact of such substitutions on the underlying cytoskeletal network, we examine the bulk mechanical behavior of in vitro actin networks cross-linked with wild-type and mutant Actn4. These networks exhibit a complex viscoelastic response and are characterized by fluid-like behavior at the longest timescales, a feature that can be quantitatively accounted for through a model governed by dynamic cross-linking. The elastic behavior of the network is highly nonlinear, becoming much stiffer with applied stress. This nonlinear elastic response is also highly sensitive to the mutations of Actn4. In particular, we observe that actin networks cross-linked with Actn4 bearing the disease-causing K255E mutation are more brittle, with a lower breaking stress in comparison to networks cross-linked with wild-type Actn4. Furthermore, a mutation that ablates the first actin binding site (ABS1) in Actn4 abrogates the network's ability to stress-stiffen is standard nomenclature. These changes in the mechanical properties of actin networks cross-linked with mutant Actn4 may represent physical determinants of the underlying disease mechanism in inherited focal segmental glomerulosclerosis. (C) 2011 Elsevier Ltd. All rights reserved.
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Times Cited: 4
Wilking, J. N. ; Angelini, T. E. ; Seminara, A. ; Brenner, M. P. ; Weitz, D. A. Biofilms as complex fluids. Mrs Bulletin 2011, 36, 385-391.Abstract
Bacterial biofilms are interface-associated colonies of bacteria embedded in an extracellular matrix that is composed primarily of polymers and proteins. They can be viewed in the context of soft matter physics: the rigid bacteria are analogous to colloids, and the extracellular matrix is a cross-linked polymer gel. This perspective is beneficial for understanding the structure, mechanics, and dynamics of the biofilm. Bacteria regulate the water content of the biofilm by controlling the composition of the extracellular matrix, and thereby controlling the mechanical properties. The mechanics of well-defined soft materials can provide insight into the mechanics of biofilms and, in particular, the viscoelasticity. Furthermore, spatial heterogeneities in gene expression create heterogeneities in polymer and surfactant production. The resulting concentration gradients generate forces within the biofilm that are relevant for biofilm spreading and survival.
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Times Cited: 18
Windbergs, M. ; Weitz, D. A. Drug dissolution chip (DDC): A microfluidic approach for drug release. Small 2011, 7 3011-3015. [PDF]
Times Cited: 3
Weitz, D. A. Colloidal glasses; 2011; Vol. 61, pp. 25-39.Abstract
Classes and granular materials share many features in common: Both can flow under some conditions but form disordered solids under other conditions. The similarity is captured within the jamming phase diagram, which considers how the solid-like state is fluidized with decreasing density, increasing shear stress, and increasing agitation, due to temperature in the case of molecular glasses and to shaking or some other form of agitation in the case of granular materials. Colloidal particles also undergo both jamming and glass transitions. They have the advantage that they are thermalized by temperature and that the particles themselves are large enough to be directly visualized. Thus, the study of the glass transition in colloids can provide an interesting comparison between molecular glasses and granular materials. This paper reviews the properties of colloidal suspensions near the colloidal glass transition, and explores both the glass-like properties and the jamming properties of these materials.
Times Cited: 0 Poincare Seminar on Glasses and Grains Nov 21, 2009 Inst Henri Poincare, Paris, FRANCE Commissariat Energie Atom, Div Sci Matiere; Daniel Iagolnitzer Fdn; Triangle Phys Fdn; Ecole Polytechn
Wang, W. ; Xie, R. ; Ju, X. - J. ; Luo, T. ; Liu, L. ; Weitz, D. A. ; Chu, L. - Y. Controllable microfluidic production of multicomponent multiple emulsions. Lab on a Chip 2011, 11, 1587-1592.Abstract
A hierarchical and scalable microfluidic device constructed from a combination of three building blocks enables highly controlled generation of multicomponent multiple emulsions. The number, ratio and size of droplets, each with distinct contents being independently co-encapsulated in the same level, can be precisely controlled. The building blocks are a drop maker, a connector and a liquid extractor; combinations of these enable the scale-up of the device to create higher-order multicomponent multiple emulsions with exceptionally diverse structures. These multicomponent multiple emulsions offer a versatile and promising platform for precise encapsulation of incompatible actives or chemicals, for synergistic delivery and biochemical and chemical reactions, and for engineering multicompartment materials with controlled internal phases.
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Times Cited: 46
Vemula, P. K. ; Boilard, E. ; Syed, A. ; Campbell, N. R. ; Muluneh, M. ; Weitz, D. A. ; Lee, D. M. ; Karp, J. M. On-demand drug delivery from self-assembled nanofibrous gels: A new approach for treatment of proteolytic disease. Journal of Biomedical Materials Research Part A 2011, 97A, 103-110.Abstract
Local delivery of drugs offers the potential for high local drug concentration while minimizing systemic toxicity, which is often observed with oral dosing. However, local depots are typically administered less frequently and include an initial burst followed by a continuous release. To maximize efficiency of therapy, it is critical to ensure that drug is only released when needed. One of the hallmarks of rheumatoid arthritis, for example, is its variable disease activity consisting of exacerbations of inflammation punctuated by periods of remission. This presents significant challenges for matching localized drug delivery with disease activity. An optimal system would be nontoxic and only release drugs during the period of exacerbation, self-titrating in response to the level of inflammation. We report the development of an injectable self-assembled nanofibrous hydrogel, from a generally recognized as safe material, which is capable of encapsulation and release of agents in response to specific enzymes that are significantly upregulated in a diseased state including matrix metalloproteinases (MMP-2 and MMP-9) and esterases. We show that these self-assembled nanofibrous gels can withstand shear forces that may be experienced in dynamic environments such as joints, can remain stable following injection into healthy joints of mice, and can disassemble in vitro to release encapsulated agents in response to synovial fluid from arthritic patients. This novel approach represents a next-generation therapeutic strategy for localized treatment of proteolytic diseases. (C) 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 97A: 103-110, 2011.
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Times Cited: 6
Tambe, D. T. ; Hardin, C. C. ; Angelini, T. E. ; Rajendran, K. ; Park, C. Y. ; Serra-Picamal, X. ; Zhou, E. H. ; Zaman, M. H. ; Butler, J. P. ; Weitz, D. A. ; et al. Collective cell guidance by cooperative intercellular forces. Nature Materials 2011, 10, 469-475.Abstract
Cells comprising a tissue migrate as part of a collective. How collective processes are coordinated over large multi-cellular assemblies has remained unclear, however, because mechanical stresses exerted at cell-cell junctions have not been accessible experimentally. We report here maps of these stresses within and between cells comprising a monolayer. Within the cell sheet there arise unanticipated fluctuations of mechanical stress that are severe, emerge spontaneously, and ripple across the monolayer. Within that stress landscape, local cellular migrations follow local orientations of maximal principal stress. Migrations of both endothelial and epithelial monolayers conform to this behaviour, as do breast cancer cell lines before but not after the epithelial-mesenchymal transition. Collective migration in these diverse systems is seen to be governed by a simple but unifying physiological principle: neighbouring cells join forces to transmit appreciable normal stress across the cell-cell junction, but migrate along orientations of minimal intercellular shear stress.
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Times Cited: 81
Thiele, J. ; Windbergs, M. ; Abate, A. R. ; Trebbin, M. ; Shum, H. C. ; Foerster, S. ; Weitz, D. A. Early development drug formulation on a chip: Fabrication of nanoparticles using a microfluidic spray dryer. Lab on a Chip 2011, 11, 2362-2368.Abstract
Early development drug formulation is exacerbated by increasingly poor bioavailability of potential candidates. Prevention of attrition due to formulation problems necessitates physicochemical analysis and formulation studies at a very early stage during development, where the availability of a new substance is limited to small quantities, thus impeding extensive experiments. Miniaturization of common formulation processes is a strategy to overcome those limitations. We present a versatile technique for fabricating drug nanoformulations using a microfluidic spray dryer. Nanoparticles are formed by evaporative precipitation of the drug-loaded spray in air at room temperature. Using danazol as a model drug, amorphous nanoparticles of 20-60 nm in diameter are prepared with a narrow size distribution. We design the device with a geometry that allows the injection of two separate solvent streams, thus enabling co-spray drying of two substances for the production of drug co-precipitates with tailor-made composition for optimization of therapeutic efficiency.
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Times Cited: 8
Sinha, N. N. ; Weitz, D. A. Cocktail physics. Physics World 2011, 24, 25-28. [PDF]
Times Cited: 1
Sprakel, J. ; Lindstroem, S. B. ; Kodger, T. E. ; Weitz, D. A. Stress enhancement in the delayed yielding of colloidal gels. Physical Review Letters 2011, 106.Abstract
Networks of aggregated colloidal particles are solidlike and can sustain an applied shear stress while exhibiting little or no creep; however, ultimately they will catastrophically fail. We show that the time delay for this yielding decreases in two distinct exponential regimes with applied stress. This behavior is universal and found for a variety of colloidal gel systems. We present a bond-rupture model that quantitatively describes this behavior and highlights the role of mesoscopic structures. Our result gives new insight into the nature of yielding in these soft solid materials.
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Times Cited: 8
Studart, A. R. ; Studer, J. ; Xu, L. ; Yoon, K. ; Shum, H. C. ; Weitz, D. A. Hierarchical porous materials made by drying complex suspensions. Langmuir 2011, 27, 955-964.Abstract
Porous structures containing pores at different length scales are often encountered in nature and are important in many applications. While several processing routes have been demonstrated to create such hierarchical porous materials, most methods either require chemical gelation reactions or do not allow for the desired control of pore sizes over multiple length scales. We describe a versatile and simple approach to produce tailor-made hierarchical porous materials that relies solely on the process of drying. Our results show that simple drying of a complex suspension can lead to the self-assembly of droplets, colloidal particles and molecular species into unique 3D hierarchical porous structures. Using a microfluidic device to produce monodisperse templating droplets of tunable size, we prepared materials with up to three levels of hierarchy exhibiting monodisperse pores ranging from 10 nm to 800 mu m. While the size of macropores obtained after drying is determined by the size of initial droplets, the interconnectivity between macropores is strongly affected by the type of droplet stabilizer (surfactants or particles). This simple route can be used to prepare porous materials of many chemical compositions and has great potential for creating artificial porous structures that capture some of the exquisite hierarchical features of porous biological materials.
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Times Cited: 14
Steinhilber, D. ; Seiffert, S. ; Heyman, J. A. ; Paulus, F. ; Weitz, D. A. ; Haag, R. Hyperbranched polyglycerols on the nanometer and micrometer scale. Biomaterials 2011, 32, 1311-1316.Abstract
We report the preparation of polyglycerol particles on different length scales by extending the size of hyperbranched polyglycerols (3 nm) to nanogels (32 nm) and microgels (140 and 220 mu m). We use miniemulsion templating for the preparation of nanogels and microfluidic templating for the preparation of microgels, which we obtain through a free-radical polymerization of hyperbranched polyglycerol decaacrylate and polyethylene glycol-diacrylate. The use of mild polymerization conditions allows yeast cells to be encapsulated into the resultant microgels with cell viabilities of approximately 30%. (C) 2010 Elsevier Ltd. All rights reserved.
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Times Cited: 29

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