Publications

2015
Akartuna, I. ; Aubrecht, D. M. ; Kodger, T. E. ; Weitz, D. A. Chemically induced coalescence in droplet-based microfluidics. Lab Chip 2015, 15, 1140-1144. Publisher's VersionAbstract

We present a new microfluidic method to coalesce pairs of surfactant-stabilized water-in-fluorocarbon oil droplets. We achieve this through the local addition of a poor solvent for the surfactant{,} perfluorobutanol{,} which induces cohesion between droplet interfaces causing them to merge. The efficiency of this technique is comparable to existing techniques providing an alternative method to coalesce pairs of droplets.

akartuna2015.pdf
Shimanovich, U. ; Efimov, I. ; Mason, T. O. ; Flagmeier, P. ; Buell, A. K. ; Gedanken, A. ; Linse, S. ; Åkerfeldt, K. S. ; Dobson, C. M. ; Weitz, D. A. ; et al. Protein Microgels from Amyloid Fibril Networks. ACS Nano 2015, 9 43–51. Publisher's VersionAbstract

Nanofibrillar forms of proteins were initially recognized in the context of pathology, but more recently have been discovered in a range of functional roles in nature, including as active catalytic scaffolds and bacterial coatings. Here we show that protein nanofibrils can be used to form the basis of monodisperse microgels and gel shells composed of naturally occurring proteins. We explore the potential of these protein microgels to act as drug carrier agents, and demonstrate the controlled release of four different encapsulated drug-like small molecules, as well as the component proteins themselves. Furthermore, we show that protein nanofibril self-assembly can continue after the initial formation of the microgel particles, and that this process results in active materials with network densities that can be modulated in situ. We demonstrate that these materials are nontoxic to human cells and that they can be used to enhance the efficacy of antibiotics relative to delivery in homogeneous solution. Because of the biocompatibility and biodegradability of natural proteins used in the fabrication of the microgels, as well as their ability to control the release of small molecules and biopolymers, protein nanofibril microgels represent a promising class of functional artificial multiscale materials generated from natural building blocks.

shimanovich2015.pdf
2014
Fan, J. ; Li, Y. ; Bisoyi, H. K. ; Zola, R. S. ; Yang, Deng-ke, B. T. J. W. D. A. L. Q. Light-Directing Omnidirectional Circularly Polarized Reflection from Liquid-Crystal Droplets. Angewandte Chemie International Edition 2014, 54, 2160-2164. Publisher's VersionAbstract

Constructing and tuning self‐organized three‐dimensional (3D) superstructures with tailored functionality is crucial in the nanofabrication of smart molecular devices. Herein we fabricate a self‐organized, phototunable 3D photonic superstructure from monodisperse droplets of one‐dimensional cholesteric liquid crystal (CLC) containing a photosensitive chiral molecular switch with high helical twisting power. The droplets are obtained by a glass capillary microfluidic technique by dispersing into PVA solution that facilitates planar anchoring of the liquid‐crystal molecules at the droplet surface, as confirmed by the observation of normal incidence selective circular polarized reflection in all directions from the core of individual droplet. Photoirradiation of the droplets furnishes dynamic reflection colors without thermal relaxation, whose wavelength can be tuned reversibly by variation of the irradiation time. The results provided clear evidence on the phototunable reflection in all directions.

2014_angew_fan.pdf
Kim, S. - H. ; Park, J. - G. ; Choi, T. M. ; Manoharan, V. N. ; Weitz, D. A. Osmotic-pressure-controlled concentration of colloidal particles in thin-shelled capsules. Nature communications 2014, 5 3068. Publisher's VersionAbstract

Colloidal crystals are promising structures for photonic applications requiring dynamic control over optical properties. However, for ease of processing and reconfigurability, the crystals should be encapsulated to form ‘ink’ capsules rather than confined in a thin film. Here we demonstrate a class of encapsulated colloidal photonic structures whose optical properties can be controlled through osmotic pressure. The ordering and separation of the particles within the microfluidically created capsules can be tuned by changing the colloidal concentration through osmotic pressure-induced control of the size of the individual capsules, modulating photonic stop band. The rubber capsules exhibit a reversible change in the diffracted colour, depending on osmotic pressure, a property we call osmochromaticity. The high encapsulation efficiency and capsule uniformity of this microfluidic approach, combined with the highly reconfigurable shapes and the broad control over photonic properties, make this class of structures particularly suitable for photonic applications such as electronic inks and reflective displays.

2014_natcomm_kim.pdf
Deng, N. - N. ; Wang, W. ; Ju, X. - J. ; Xie, R. ; Weitz, D. A. ; Chu, L. - Y. Reply to the ‘Comment on “Wetting-induced formation of controllable monodisperse multiple emulsions in microfluidics”’by J. Guzowski and P. Garstecki, Lab Chip, 2014, 14, DOI: 10.1039/C3LC51229K. Lab on a Chip 2014, 14, 1479–1480. Publisher's VersionAbstract

A graphical abstract is available for this content.

2014_loc_deng.pdf
Thon, J. N. ; Mazutis, L. ; Wu, S. ; Sylman, J. L. ; Ehrlicher, A. ; Machlus, K. R. ; Feng, Q. ; Lu, S. ; Lanza, R. ; Neeves, K. B. ; et al. Platelet bioreactor-on-a-chip. Blood 2014, 124, 1857–1867. Publisher's VersionAbstract

Jonathan N. Thon1,2,3, Linas Mazutis3,4,5, Stephen Wu1, Joanna L. Sylman6, Allen Ehrlicher4,7, Kellie R. Machlus1,2, Qiang Feng8, Shijiang Lu8, Robert Lanza8, Keith B. Neeves6,9, David A. Weitz4, and Joseph E. Italiano Jr1,2,3,101Department of Medicine, Brigham and Women’s Hospital, Boston, MA; 2Harvard Medical School, Boston, MA; 3Platelet BioGenesis, Chestnut Hill, MA; 4School of Engineering and Applied Sciences, Harvard University, Cambridge, MA; 5Institute of Biotechnology, Vilnius University, Vilnius, Lithuania; 6Department of Chemical and Biological Engineering, Colorado School of Mines, Golden, CO; 7Department of Bioengineering, McGill University, Montreal, Canada; 8Advanced Cell Technologies, Marlborough, MA; 9Department of Pediatrics, University of Colorado, Denver, Aurora, CO; and 10Department of Surgery, Vascular Biology Program, Boston Children’s Hospital, Boston, MAKey PointsWe have developed a biomimetic microfluidic platelet bioreactor that recapitulates bone marrow and blood vessel microenvironments.Application of shear stress in this bioreactor triggers physiological proplatelet production, and platelet release.AbstractPlatelet transfusions total >2.17 million apheresis-equivalent units per year in the United States and are derived entirely from human donors, despite clinically significant immunogenicity, associated risk of sepsis, and inventory shortages due to high demand and 5-day shelf life. To take advantage of known physiological drivers of thrombopoiesis, we have developed a microfluidic human platelet bioreactor that recapitulates bone marrow stiffness, extracellular matrix composition, micro-channel size, hemodynamic vascular shear stress, and endothelial cell contacts, and it supports high-resolution live-cell microscopy and quantification of platelet production. Physiological shear stresses triggered proplatelet initiation, reproduced ex vivo bone marrow proplatelet production, and generated functional platelets. Modeling human bone marrow composition and hemodynamics in vitro obviates risks associated with platelet procurement and storage to help meet growing transfusion needs.Submitted May 9, 2014.Accepted July 8, 2014.© 2014 by The American Society of Hematology

thon2014.pdf
Schmid, L. ; Weitz, D. A. ; Franke, T. Sorting drops and cells with acoustics: acoustic microfluidic fluorescence-activated cell sorter. Lab Chip 2014, 14, 3710-3718. Publisher's VersionAbstract

We describe a versatile microfluidic fluorescence-activated cell sorter that uses acoustic actuation to sort cells or drops at ultra-high rates. Our acoustic sorter combines the advantages of traditional fluorescence-activated cell (FACS) and droplet sorting (FADS) and is applicable for a multitude of objects. We sort aqueous droplets{,} at rates as high as several kHz{,} into two or even more outlet channels. We can also sort cells directly from the medium without prior encapsulation into drops; we demonstrate this by sorting fluorescently labeled mouse melanoma cells in a single phase fluid. Our acoustic microfluidic FACS is compatible with standard cell sorting cytometers{,} yet{,} at the same time{,} enables a rich variety of more sophisticated applications.

schmid2014.pdf
Lin, T. ; Rubinstein, S. M. ; Korchev, A. ; Weitz, D. A. Pattern Formation of Charged Particles in an Electric Field. Langmuir 2014, 30, 12119-12123. Publisher's VersionAbstract

The application of an electric field to a suspension of charged particles can lead to the formation of patterns due to electrohydrodynamic instabilities which remain poorly understood. We elucidate this behavior by visualizing the dynamics of charged carbon black particles suspended in a nonpolar solvent in response to an electric field. As the particles are transported across a microfluidic channel, an instability occurs in which the initially uniform, rapidly advancing particle front develops fingers. Furthermore, when the direction of the applied field is repeatedly switched, the particles localize into a remarkably well-defined periodic pattern which reflects an interplay between the fingering instability and particle diffusion.

lin2014.pdf
Polenz, I. ; Datta, S. S. ; Weitz, D. A. Controlling the Morphology of Polyurea Microcapsules Using Microfluidics. Langmuir 2014, 30, 13405–13410. Publisher's VersionAbstract

We use microfluidics to continuously produce monodisperse polyurea microcapsules (PUMCs) having either aqueous or nonaqueous cores. The microcapsule shells are formed by the reaction between an isocyanate, dissolved in oil, and an amine, dissolved in water, at the surface of oil-in-water or water-in-oil drops immediately as they are formed. Different microcapsule morphologies can be generated using our approach. The thickness of the microcapsule shell increases with an increase in the amine solubility in the oil; this finding provides a simple mechanism by which the PUMC shell thickness can be controlled.

polenz2014.pdf
Rowat, A. C. ; Sinha, N. N. ; Sörensen, P. M. ; Campàs, O. ; Castells, P. ; Rosenberg, D. ; Brenner, M. P. ; Weitz, D. A. The kitchen as a physics classroom. Physics Education 2014, 49, 512. Publisher's VersionAbstract

Cooking is a tangible, familiar, and delicious tool for teaching physics, which is easy to implement in a university setting. Through our courses at Harvard and UCLA, each year we are engaging hundreds of undergraduate students, primarily non-science majors, in science concepts and the scientific research process. We find that weekly lectures by chefs and professors, paired with edible lab experiments, generate enthusiasm and provide strong motivation for students to learn physics. By the end of the course, students are able to conduct independent scientific research and present their results in a final science fair. Given the considerable broad appeal of food and cooking, the topic could be adapted to other post-secondary as well as secondary-level courses.

rowat2014.pdf
Duncanson, W. J. ; Arriaga, L. R. ; Ung, W. L. ; Kopechek, J. ; Porter, T. ; Weitz, D. A. Microfluidic Fabrication of Perfluorohexane-Shelled Double Emulsions for Controlled Loading and Acoustic-Triggered Release of Hydrophilic Agents. Langmuir 2014, 30, 13765–13770. Publisher's VersionAbstract

The ability of low boiling point liquid perfluorocarbons (PFCs) to undergo a phase change from a liquid to a gas upon ultrasound irradiation makes PFC-based emulsions promising vehicles for triggered delivery of payloads. However, loading hydrophilic agents into PFC-based emulsions is difficult due to their insolubility in PFC. Here, we address this challenge by taking advantage of microfluidic technologies to fabricate double emulsions consisting of large aqueous cores and a perfluorohexane (PFH) shell, thus yielding high loading capacities for hydrophilic agents. Using this technology, we efficiently encapsulate a model hydrophilic agent within the emulsions and study its response to ultrasound irradiation. Using a combination of optical and acoustic imaging methods, we observe payload release upon acoustic vaporization of PFH. Our work demonstrates the utility of microfluidic techniques for controllably loading hydrophilic agents into PFH-based emulsions, which have great potential for acoustically triggered release.

duncanson2014.pdf
Jensen, K. E. ; Weitz, D. A. ; Spaepen, F. Local shear transformations in deformed and quiescent hard-sphere colloidal glasses. Physical Review E 2014, 90, 042305. Publisher's VersionAbstract
We perform a series of deformation experiments on a monodisperse, hard-sphere colloidal glass while simultaneously following the three-dimensional trajectories of roughly 50000 individual particles with a confocal microscope. In each experiment, we deform the glass in pure shear at a constant strain rate [(1–5)×10−5 s−1] to maximum macroscopic strains (5%–10%) and then reverse the deformation at the same rate to return to zero macroscopic strain. We also measure three-dimensional particle trajectories in an identically prepared quiescent glass in which the macroscopic strain is always zero. We find that shear transformation zones exist and are active in both sheared and quiescent colloidal glasses, revealed by a distinctive fourfold signature in spatial autocorrelations of the local shear strain. With increasing shear, the population of local shear transformations develops more quickly than in a quiescent glass and many of these transformations are irreversible. When the macroscopic strain is reversed, we observe partial elastic recovery, followed by plastic deformation of the opposite sign, required to compensate for the irreversibly transformed regions. The average diameter of the shear transformation zones in both strained and quiescent glasses is slightly more than two particle diameters.
jensen2014.pdf
Zaburdaev, V. ; Biais, N. ; Schmiedeberg, M. ; Eriksson, J. ; Jonsson, A. - B. ; Sheetz, M.  P. ; Weitz, D.  A. Uncovering the Mechanism of Trapping and Cell Orientation during Neisseria gonorrhoeae Twitching Motility. 2014, 107, 1523 - 1531. Publisher's VersionAbstract

AbstractNeisseria gonorrheae bacteria are the causative agent of the second most common sexually transmitted infection in the world. The bacteria move on a surface by means of twitching motility. Their movement is mediated by multiple long and flexible filaments, called type IV pili, that extend from the cell body, attach to the surface, and retract, thus generating a pulling force. Moving cells also use pili to aggregate and form microcolonies. However, the mechanism by which the pili surrounding the cell body work together to propel bacteria remains unclear. Understanding this process will help describe the motility of N. gonorrheae bacteria, and thus the dissemination of the disease which they cause. In this article we track individual twitching cells and observe that their trajectories consist of alternating moving and pausing intervals, while the cell body is preferably oriented with its wide side toward the direction of motion. Based on these data, we propose a model for the collective pili operation of N. gonorrheae bacteria that explains the experimentally observed behavior. Individual pili function independently but can lead to coordinated motion or pausing via the force balance. The geometry of the cell defines its orientation during motion. We show that by changing pili substrate interactions, the motility pattern can be altered in a predictable way. Although the model proposed is tangibly simple, it still has sufficient robustness to incorporate further advanced pili features and various cell geometries to describe other bacteria that employ pili to move on surfaces.

zaburdaev2014.pdf
Larsen, R. J. ; Kim, J. - W. ; Zukoski, C. F. ; Weitz, D. A. Fluctuations in flow produced by competition between apparent wall slip and dilatancy. Rheologica Acta 2014, 53, 333-347. Publisher's VersionAbstract

Dense suspensions can exhibit a dramatic stress-induced transition from liquid-like to solid-like behavior. In many materials, the solid-like flow state is characterized by large flow fluctuations and instabilities. Although various experiments have been performed to characterize flow fluctuations, the mechanisms that govern the flow instabilities remain poorly understood. To elucidate these mechanisms, we characterize a system that rapidly fluctuates between two flow states. One of the flow states is dominated by apparent wall slip, and the other is dominated by dilatancy. The dilatant regime occurs at elevated stresses and is associated with reduced wall slip, whereas the wall slip-dominated regime occurs at lower stresses. At stresses that are intermediate between these two regimes, the material fluctuates between the two regimes in a semi-regular fashion. Our analysis of the fluctuations at millisecond timescales shows that fluctuations occur because neither regime is capable of supporting a constant stress in a stable manner. We rationalize our results in terms of the differences in the shear-induced particle pressure between regions that are particle-rich and regions of slip that are particle-depleted.

larsen2014.pdf
Jarosz, D.  F. ; Brown, J.  C. S. ; Walker, G.  A. ; Datta, M.  S. ; Ung, W.  L. ; Lancaster, A.  K. ; Rotem, A. ; Chang, A. ; Newby, G.  A. ; Weitz, D.  A. ; et al. Cross-Kingdom Chemical Communication Drives a Heritable, Mutually Beneficial Prion-Based Transformation of Metabolism. Cell 2014, 158, 1083 - 1093. Publisher's VersionAbstract

Summary In experimental science, organisms are usually studied in isolation, but in the wild, they compete and cooperate in complex communities. We report a system for cross-kingdom communication by which bacteria heritably transform yeast metabolism. An ancient biological circuit blocks yeast from using other carbon sources in the presence of glucose. [GAR+], a protein-based epigenetic element, allows yeast to circumvent this “glucose repression” and use multiple carbon sources in the presence of glucose. Some bacteria secrete a chemical factor that induces [GAR+]. [GAR+] is advantageous to bacteria because yeast cells make less ethanol and is advantageous to yeast because their growth and long-term viability is improved in complex carbon sources. This cross-kingdom communication is broadly conserved, providing a compelling argument for its adaptive value. By heritably transforming growth and survival strategies in response to the selective pressures of life in a biological community, [GAR+] presents a unique example of Lamarckian inheritance.

jarosz2014.pdf
Wang, B. L. ; Ghaderi, A. ; Zhou, H. ; Agresti, J. ; Weitz, D. A. ; Fink, G. R. ; Stephanopoulos, G. Microfluidic high-throughput culturing of single cells for selection based on extracellular metabolite production or consumption. Nat Biotech 2014, 32, 473 - 478. Publisher's VersionAbstract

Phenotyping single cells based on the products they secrete or consume is a key bottleneck in many biotechnology applications, such as combinatorial metabolic engineering for the overproduction of secreted metabolites. Here we present a flexible high-throughput approach that uses microfluidics to compartmentalize individual cells for growth and analysis in monodisperse nanoliter aqueous droplets surrounded by an immiscible fluorinated oil phase. We use this system to identify xylose-overconsuming Saccharomyces cerevisiae cells from a population containing one such cell per 104 cells and to screen a genomic library to identify multiple copies of the xylose isomerase gene as a genomic change contributing to high xylose consumption, a trait important for lignocellulosic feedstock utilization. We also enriched L-lactate-producing Escherichia coli clones 5,800[times] from a population containing one L-lactate producer per 104D-lactate producers. Our approach has broad applications for single-cell analyses, such as in strain selection for the overproduction of fuels, chemicals and pharmaceuticals.

wang2014.pdf
Pessi, J. ; Santos, H. A. ; Miroshnyk, I. ; JoukoYliruusi, ; Weitz, D. A. ; Mirza, S. Microfluidics-assisted engineering of polymeric microcapsules with high encapsulation efficiency for protein drug delivery. International Journal of Pharmaceutics 2014, 472, 82 - 87. Publisher's VersionAbstract

Abstract In this study, microfluidic technology was employed to develop protein formulations. The microcapsules were produced with a biphasic flow to create water–oil–water (W/O/W) double emulsion droplets with ultrathin shells. Optimized microcapsule formulations containing 1% (w/w) bovine serum albumin (BSA) in the inner phase were prepared with poly(vinyl alcohol), polycaprolactone and polyethylene glycol. All the particles were found to be intact and with a particle size of 23–47 μm. Furthermore, the particles were monodisperse, non-porous and stable up to 4 weeks. The encapsulation efficiency of \{BSA\} in the microcapsules was 84%. The microcapsules released 30% of their content within 168 h. This study demonstrates that microfluidics is a powerful technique for engineering formulations for therapeutic proteins.

2014_intjpharm_pessi.pdf
Guo, M. ; Ehrlicher, A.  J. ; Jensen, M.  H. ; Renz, M. ; Moore, J.  R. ; Goldman, R.  D. ; Lippincott-Schwartz, J. ; Mackintosh, F.  C. ; Weitz, D.  A. Probing the Stochastic, Motor-Driven Properties of the Cytoplasm Using Force Spectrum Microscopy. Cell 2014, 158, 822 - 832. Publisher's VersionAbstract

Molecular motors in cells typically produce highly directed motion; however, the aggregate, incoherent effect of all active processes also creates randomly fluctuating forces, which drive diffusive-like, nonthermal motion. Here, we introduce force-spectrum-microscopy (FSM) to directly quantify random forces within the cytoplasm of cells and thereby probe stochastic motor activity. This technique combines measurements of the random motion of probe particles with independent micromechanical measurements of the cytoplasm to quantify the spectrum of force fluctuations. Using FSM, we show that force fluctuations substantially enhance intracellular movement of small and large components. The fluctuations are three times larger in malignant cells than in their benign counterparts. We further demonstrate that vimentin acts globally to anchor organelles against randomly fluctuating forces in the cytoplasm, with no effect on their magnitude. Thus, FSM has broad applications for understanding the cytoplasm and its intracellular processes in relation to cell physiology in healthy and diseased states.

2014_cell_guo.pdf
Datta, S. S. ; Abbaspourrad, A. ; Weitz, D. A. Expansion and rupture of charged microcapsules. Mater. Horiz. 2014, 1 92-95. Publisher's VersionAbstract

We study the deformations of pH-responsive spherical microcapsules - micrometer-scale liquid drops surrounded by thin{,} solid shells - under the influence of electrostatic forces. When exposed to a large concentration of NaOH{,} the microcapsules become highly charged{,} and expand isotropically. We find that the extent of this expansion can be understood by coupling electrostatics with shell theory; moreover{,} the expansion dynamics is well described by Darcy{'}s law for fluid flow through the microcapsule shell. Unexpectedly{,} however{,} below a threshold NaOH concentration{,} the microcapsules begin to disintegrate{,} and eventually rupture; they then expand non-uniformly{,} ultimately forming large{,} jellyfish-like structures. Our results highlight the fascinating range of behaviors exhibited by pH-responsive microcapsules{,} driven by the interplay between electrostatic and mechanical forces.

2014_materials_horizons_datta.pdf
Carroll, N. J. ; Jensen, K. H. ; Parsa, S. ; Holbrook, M. N. ; Weitz, D. A. Measurement of Flow Velocity and Inference of Liquid Viscosity in a Microfluidic Channel by Fluorescence Photobleaching. Langmuir 2014, 30, 4868-4874. Publisher's VersionAbstract

We present a simple, noninvasive method for simultaneous measurement of flow velocity and inference of liquid viscosity in a microfluidic channel. We track the dynamics of a sharp front of photobleached fluorescent dye using a confocal microscope and measure the intensity at a single point downstream of the initial front position. We fit an exact solution of the advection diffusion equation to the fluorescence intensity recovery curve to determine the average flow velocity and the diffusion coefficient of the tracer dye. The dye diffusivity is correlated to solute concentration to infer rheological properties of the liquid. This technique provides a simple method for simultaneous elucidation of flow velocity and liquid viscosity in microchannels.

carroll2014.pdf

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