Sindy Tang

All Publications

• Fluorinated Pickering Emulsions with Nonadsorbing Interfaces for Droplet-based Enzymatic Assays ANALYTICAL CHEMISTRY Pan, M., Lyu, F., Tang, S. K. 2015; 87 (15): 7938-7943

  Abstract

  This work describes the use of fluorinated Pickering emulsions with nonadsorbing interfaces in droplet-based enzymatic assays. State-of-the-art droplet assays have relied on one type of surfactants consisting of perfluorinated polyether and polyethylene glycol (PFPE-PEG). These surfactants are known to have limitations including the tedious synthesis and interdrop molecular transport which leads to the cross-contamination of droplet contents. Previously we have shown that replacing surfactants with nanoparticles as droplet stabilizers mitigate interdrop transport of small molecules. The nonspecific adsorption of enzymes on nanoparticle surface, however, could cause structural changes in enzymes and consequently the loss of enzymatic activity. To overcome such challenge, we render nanoparticle surface nonadsorbing to enzymes by in situ adsorption of polyethylene glycol (PEG) on particle surfaces. We show that enzyme activities are preserved in droplets stabilized by PEG-adsorbed nanoparticles, and are comparable with those in drops stabilized by PFPE-PEG surfactants. In addition, our nonadsorbing Pickering emulsions successfully prevent interdrop molecular transport, thereby maintaining the accuracy of droplet assays. The particles are also simple and economical to synthesize. The PEG-adsorbed nanoparticles described in this work are thus a competitive alternative to the current surfactant system, and can potentially enable new droplet-based biochemical assays.

  View details for DOI 10.1021/acs.analchem.5b01753

  View details for Web of Science ID 000359277900062

  View details for PubMedID 26153615

• Actuating Fluid-Fluid Interfaces for the Reconfiguration of Light IEEE JOURNAL OF SELECTED TOPICS IN QUANTUM ELECTRONICS Pan, M., Kim, M., Kuiper, S., Tang, S. K. 2015; 21 (4)

  View details for DOI 10.1109/JSTQE.2015.2392075

  View details for Web of Science ID 000357383500001

• Quantitative detection of cells expressing BlaC using droplet-based microfluidics for use in the diagnosis of tuberculosis BIOMICROFLUIDICS Lyu, F., Xu, M., Cheng, Y., Xie, J., Rao, J., Tang, S. K. 2015; 9 (4)

  View details for DOI 10.1063/1.4928879

  View details for Web of Science ID 000360311900022

• Optofluidic ultrahigh-throughput detection of fluorescent drops LAB ON A CHIP Kim, M., Pan, M., Gai, Y., Pang, S., Han, C., Yang, C., Tang, S. K. 2015; 15 (6): 1417-1423

  Abstract

  This paper describes an optofluidic droplet interrogation device capable of counting fluorescent drops at a throughput of 254 000 drops per second. To our knowledge, this rate is the highest interrogation rate published thus far. Our device consists of 16 parallel microfluidic channels bonded directly to a filter-coated two-dimensional Complementary Metal-Oxide-Semiconductor (CMOS) sensor array. Fluorescence signals emitted from the drops are collected by the sensor that forms the bottom of the channel. The proximity of the drops to the sensor facilitates efficient collection of fluorescence emission from the drops, and overcomes the trade-off between light collection efficiency and field of view in conventional microscopy. The interrogation rate of our device is currently limited by the acquisition speed of CMOS sensor, and is expected to increase further as high-speed sensors become increasingly available.

  View details for DOI 10.1039/c4lc01465k

  View details for Web of Science ID 000350543500003

  View details for PubMedID 25588522

• Fluorinated Pickering Emulsions Impede Interfacial Transport and Form Rigid Interface for the Growth of Anchorage-Dependent Cells ACS APPLIED MATERIALS & INTERFACES Pan, M., Rosenfeld, L., Kim, M., Xu, M., Lin, E., Derda, R., Tang, S. K. 2014; 6 (23): 21446-21453

  Abstract

  This study describes the design and synthesis of amphiphilic silica nanoparticles for the stabilization of aqueous drops in fluorinated oils for applications in droplet microfluidics. The success of droplet microfluidics has thus far relied on one type of surfactant for the stabilization of drops. However, surfactants are known to have two key limitations: (1) interdrop molecular transport leads to cross-contamination of droplet contents, and (2) the incompatibility with the growth of adherent mammalian cells as the liquid-liquid interface is too soft for cell adhesion. The use of nanoparticles as emulsifiers overcomes these two limitations. Particles are effective in mitigating undesirable interdrop molecular transport as they are irreversibly adsorbed to the liquid-liquid interface. They do not form micelles as surfactants do, and thus, a major pathway for interdrop transport is eliminated. In addition, particles at the droplet interface provide a rigid solid-like interface to which cells could adhere and spread, and are thus compatible with the proliferation of adherent mammalian cells such as fibroblasts and breast cancer cells. The particles described in this work can enable new applications for high-fidelity assays and for the culture of anchorage-dependent cells in droplet microfluidics, and they have the potential to become a competitive alternative to current surfactant systems for the stabilization of drops critical for the success of the technology.

  View details for DOI 10.1021/am506443e

  View details for Web of Science ID 000346326600103

  View details for PubMedID 25347285

• Review and analysis of performance metrics of droplet microfluidics systems MICROFLUIDICS AND NANOFLUIDICS Rosenfeld, L., Lin, T., Derda, R., Tang, S. K. 2014; 16 (5): 921-939

  View details for DOI 10.1007/s10404-013-1310-x

  View details for Web of Science ID 000335457600015

• Prospective identification of parasitic sequences in phage display screens. Nucleic acids research Matochko, W. L., Cory Li, S., Tang, S. K., Derda, R. 2014; 42 (3): 1784-1798

  Abstract

  Phage display empowered the development of proteins with new function and ligands for clinically relevant targets. In this report, we use next-generation sequencing to analyze phage-displayed libraries and uncover a strong bias induced by amplification preferences of phage in bacteria. This bias favors fast-growing sequences that collectively constitute <0.01% of the available diversity. Specifically, a library of 10(9) random 7-mer peptides (Ph.D.-7) includes a few thousand sequences that grow quickly (the 'parasites'), which are the sequences that are typically identified in phage display screens published to date. A similar collapse was observed in other libraries. Using Illumina and Ion Torrent sequencing and multiple biological replicates of amplification of Ph.D.-7 library, we identified a focused population of 770 'parasites'. In all, 197 sequences from this population have been identified in literature reports that used Ph.D.-7 library. Many of these enriched sequences have confirmed function (e.g. target binding capacity). The bias in the literature, thus, can be viewed as a selection with two different selection pressures: (i) target-binding selection, and (ii) amplification-induced selection. Enrichment of parasitic sequences could be minimized if amplification bias is removed. Here, we demonstrate that emulsion amplification in libraries of ∼10(6) diverse clones prevents the biased selection of parasitic clones.

  View details for DOI 10.1093/nar/gkt1104

  View details for PubMedID 24217917

• Break-up of droplets in a concentrated emulsion flowing through a narrow constriction SOFT MATTER Rosenfeld, L., Fan, L., Chen, Y., Swoboda, R., Tang, S. K. 2014; 10 (3): 421-430

  View details for DOI 10.1039/c3sm51843d

  View details for Web of Science ID 000328886500002

• Break-up of droplets in a concentrated emulsion flowing through a narrow constriction Soft Matter Rosenfeld, L., Fan, L., Chen, Y., Swoboda, R., Tang, Sindy, K.Y. 2014; 10: 421-430
• Time capsule: an autonomous sensor and recorder based on diffusion-reaction LAB ON A CHIP Gerber, L. C., Rosenfeld, L., Chen, Y., Tang, S. K. 2014; 14 (22): 4324-4328

  View details for DOI 10.1039/c4lc00640b

  View details for Web of Science ID 000343920200003

• Filter-based assay for Escherichia coli in aqueous samples using bacteriophage-based amplification. Analytical chemistry Derda, R., Lockett, M. R., Tang, S. K., Fuller, R. C., Maxwell, E. J., Breiten, B., Cuddemi, C. A., Ozdogan, A., Whitesides, G. M. 2013; 85 (15): 7213-7220

  Abstract

  This paper describes a method to detect the presence of bacteria in aqueous samples, based on the capture of bacteria on a syringe filter, and the infection of targeted bacterial species with a bacteriophage (phage). The use of phage as a reagent provides two opportunities for signal amplification: (i) the replication of phage inside a live bacterial host and (ii) the delivery and expression of the complementing gene that turns on enzymatic activity and produces a colored or fluorescent product. Here we demonstrate a phage-based amplification scheme with an M13KE phage that delivers a small peptide motif to an F(+), α-complementing strain of Escherichia coli K12, which expresses the ω-domain of β-galactosidase (β-gal). The result of this complementation-an active form of β-gal-was detected colorimetrically, and the high level of expression of the ω-domain of β-gal in the model K12 strains allowed us to detect, on average, five colony-forming units (CFUs) of this strain in 1 L of water with an overnight culture-based assay. We also detected 50 CFUs of the model K12 strain in 1 L of water (or 10 mL of orange juice, or 10 mL of skim milk) in less than 4 h with a solution-based assay with visual readout. The solution-based assay does not require specialized equipment or access to a laboratory, and is more rapid than existing tests that are suitable for use at the point of access. This method could potentially be extended to detect many different bacteria with bacteriophages that deliver genes encoding a full-length enzyme that is not natively expressed in the target bacteria.

  View details for DOI 10.1021/ac400961b

  View details for PubMedID 23848541

• Prospective identification of parasitic sequences in phage-display screens Nucleic Acids Research Matochko, W., Li, C., Tang, Sindy, K.Y., Derda, R. 2013

  View details for DOI 10.1093/nar/gkt1104, 2013.

• Single particle detection in CMOS compatible photonic crystal nanobeam cavities Optics Express Quan, Q., Floyd, Daniel, L., Burgess, Ian, B., Deotare, Parag, B., Frank, Ian, W., Tang, Sindy, K.Y. 2013; 21: 32225-32233
• Uniform amplification of phage display libraries in monodisperse emulsions METHODS Matochko, W. L., Ng, S., Jafari, M. R., Romaniuk, J., Tang, S. K., Derda, R. 2012; 58 (1): 18-27

  Abstract

  In this paper, we describe a complete experimental setup for the uniform amplification of libraries of phage. Uniform amplification, which multiplies every phage clone by the same amount irrespective of the growth rate of the clone is essential for phage-display screening. Amplification of phage libraries in a common solution is often non-uniform: it favors fast-growing clones and eliminates those that grow slower. This competition leads to elimination of many useful binding clones, and it is a major barrier to identification of ligands for targets with multiple binding sites such as cells, tissues, or mixtures of proteins. Uniform amplification is achieved by encapsulating individual phage clones into isolated compartments (droplets) of identical volume. Each droplet contains culture medium and an excess of host (Escherichia coli). Here, we describe microfluidics devices that generate mono-disperse droplet-based compartments, and optimal conditions for amplification of libraries of different size. We also describe the detailed synthesis of a perfluoro surfactant, which gives droplets exceptional stability. Droplets stabilized by this compound do not coalesce after many hours in shaking culture. We identified a commercially available compound (Krytox), which destabilizes these droplets to recover the amplified libraries. Overall, uniform amplification is a sequence of three simple steps: (1) encapsulation of mixture of phage and bacteria in droplets using microfluidics; (2) incubation of droplets in a shaking culture; (3) destabilization of droplets to harvest the amplified phage. We anticipate that this procedure can be easily adapted in any academic or industrial laboratory that uses phage display.

  View details for DOI 10.1016/j.ymeth.2012.07.012

  View details for Web of Science ID 000311526000004

  View details for PubMedID 22819853

• Characterization of sensitivity and specificity in leaky droplet-based assays LAB ON A CHIP Chen, Y., Gani, A. W., Tang, S. K. 2012; 12 (23): 5093-5103

  View details for DOI 10.1039/c2lc40624a

  View details for Web of Science ID 000310916500022

• High-Q, Low Index-Contrast Polymeric Photonic Crystal Nanobeam Cavities 2012 CONFERENCE ON LASERS AND ELECTRO-OPTICS (CLEO) Quan, Q., Burgess, I. B., Tang, S. K., Floyd, D. L., Loncar, M. 2012

  View details for Web of Science ID 000310362402402

• High-Q, low index-contrast polymeric photonic crystal nanobeam cavities OPTICS EXPRESS Quan, Q., Burgess, I. B., Tang, S. K., Floyd, D. L., Loncar, M. 2011; 19 (22): 22191-22197

  Abstract

  We present the design, fabrication and characterization of high-Q (Q=36,000) polymeric photonic crystal nanobeam cavities made of two polymers that have an ultra-low index contrast (ratio=1.15) and observed thermo-optical bistability at hundred microwatt power level. Due to the extended evanescent field and small mode volumes, polymeric nanobeam cavities are ideal platform for ultra-sensitive biochemical sensing. We demonstrate that these sensors have figures of merit (FOM=9190) two orders of magnitude greater than surface plasmon resonance based sensors, and outperform the commercial Biacore(TM) sensors. The demonstration of high-Q cavity in low-index-contrast polymers can open up versatile applications using a broad range of functional and flexible polymeric materials.

  View details for Web of Science ID 000296568100099

  View details for PubMedID 22109061

• Bioinspired self-repairing slippery surfaces with pressure-stable omniphobicity NATURE Wong, T., Kang, S. H., Tang, S. K., Smythe, E. J., Hatton, B. D., Grinthal, A., Aizenberg, J. 2011; 477 (7365): 443-447

  Abstract

  Creating a robust synthetic surface that repels various liquids would have broad technological implications for areas ranging from biomedical devices and fuel transport to architecture but has proved extremely challenging. Inspirations from natural nonwetting structures, particularly the leaves of the lotus, have led to the development of liquid-repellent microtextured surfaces that rely on the formation of a stable air-liquid interface. Despite over a decade of intense research, these surfaces are, however, still plagued with problems that restrict their practical applications: limited oleophobicity with high contact angle hysteresis, failure under pressure and upon physical damage, inability to self-heal and high production cost. To address these challenges, here we report a strategy to create self-healing, slippery liquid-infused porous surface(s) (SLIPS) with exceptional liquid- and ice-repellency, pressure stability and enhanced optical transparency. Our approach-inspired by Nepenthes pitcher plants-is conceptually different from the lotus effect, because we use nano/microstructured substrates to lock in place the infused lubricating fluid. We define the requirements for which the lubricant forms a stable, defect-free and inert 'slippery' interface. This surface outperforms its natural counterparts and state-of-the-art synthetic liquid-repellent surfaces in its capability to repel various simple and complex liquids (water, hydrocarbons, crude oil and blood), maintain low contact angle hysteresis (<2.5°), quickly restore liquid-repellency after physical damage (within 0.1-1 s), resist ice adhesion, and function at high pressures (up to about 680 atm). We show that these properties are insensitive to the precise geometry of the underlying substrate, making our approach applicable to various inexpensive, low-surface-energy structured materials (such as porous Teflon membrane). We envision that these slippery surfaces will be useful in fluid handling and transportation, optical sensing, medicine, and as self-cleaning and anti-fouling materials operating in extreme environments.

  View details for DOI 10.1038/nature10447

  View details for Web of Science ID 000295080500036

  View details for PubMedID 21938066

• Denaturation of Proteins by SDS and Tetraalkylammonium Dodecyl Sulfates LANGMUIR Lee, A., Tang, S. K., Mace, C. R., Whitesides, G. M. 2011; 27 (18): 11560-11574

  Abstract

  This article describes the use of capillary electrophoresis (CE) to examine the influence of different cations (C(+); C(+) = Na(+) and tetra-n-alkylammonium, NR(4)(+), where R = Me, Et, Pr, and Bu) on the rates of denaturation of bovine carbonic anhydrase II (BCA) in the presence of anionic surfactant dodecylsulfate (DS(-)). An analysis of the denaturation of BCA in solutions of Na(+)DS(-) and NR(4)(+)DS(-) (in Tris-Gly buffer) indicated that the rates of formation of complexes of denatured BCA with DS(-) (BCA(D)-DS(-)(n,sat)) are indistinguishable and independent of the cation below the critical micellar concentration (cmc) and independent of the total concentration of DS(-) above the cmc. At concentrations of C(+)DS(-) above the cmc, BCA denatured at rates that depended on the cation; the rates decreased by a factor >10(4) in the order of Na(+) ? NMe(4)(+) > NEt(4)(+) > NPr(4)(+) > NBu(4)(+), which is the same order as the values of the cmc (which decrease from 4.0 mM for Na(+)DS(-) to 0.9 mM for NBu(4)(+)DS(-) in Tris-Gly buffer). The relationship between the cmc values and the rates of formation of BCA(D)-DS(-)(n,sat()) suggested that the kinetics of denaturation of BCA involve the association of this protein with monomeric DS(-) rather than with micelles of (C(+)DS(-))(n). A less-detailed survey of seven other proteins (?-lactalbumin, ?-lactoglobulin A, ?-lactoglobulin B, carboxypeptidase B, creatine phosphokinase, myoglobin, and ubiquitin) showed that the difference between Na(+)DS(-) and NR(4)(+)DS(-) observed with BCA was not general. Instead, the influence of NR(4)(+) on the association of DS(-) with these proteins depended on the protein. The selection of the cation contributed to the properties (including the composition, electrophoretic mobility, and partitioning behavior in aqueous two-phase systems) of aggregates of denatured protein and DS(-). These results suggest that the variation in the behavior of NR(4)(+)DS(-) with changes in R may be exploited in methods used to analyze and separate mixtures of proteins.

  View details for DOI 10.1021/la201832d

  View details for Web of Science ID 000294790500037

  View details for PubMedID 21834533

• Reconfigurable Self-Assembly of Mesoscale Optical Components at a Liquid-Liquid Interface ADVANCED MATERIALS Tang, S. K., Derda, R., Mazzeo, A. D., Whitesides, G. M. 2011; 23 (21): 2413-?

  View details for DOI 10.1002/adma.201100067

  View details for Web of Science ID 000291732000002

  View details for PubMedID 21491514

• Multizone Paper Platform for 3D Cell Cultures PLOS ONE Derda, R., Tang, S. K., Laromaine, A., Mosadegh, B., Hong, E., Mwangi, M., Mammoto, A., Ingber, D. E., Whitesides, G. M. 2011; 6 (5)

  Abstract

  In vitro 3D culture is an important model for tissues in vivo. Cells in different locations of 3D tissues are physiologically different, because they are exposed to different concentrations of oxygen, nutrients, and signaling molecules, and to other environmental factors (temperature, mechanical stress, etc). The majority of high-throughput assays based on 3D cultures, however, can only detect the average behavior of cells in the whole 3D construct. Isolation of cells from specific regions of 3D cultures is possible, but relies on low-throughput techniques such as tissue sectioning and micromanipulation. Based on a procedure reported previously ("cells-in-gels-in-paper" or CiGiP), this paper describes a simple method for culture of arrays of thin planar sections of tissues, either alone or stacked to create more complex 3D tissue structures. This procedure starts with sheets of paper patterned with hydrophobic regions that form 96 hydrophilic zones. Serial spotting of cells suspended in extracellular matrix (ECM) gel onto the patterned paper creates an array of 200 micron-thick slabs of ECM gel (supported mechanically by cellulose fibers) containing cells. Stacking the sheets with zones aligned on top of one another assembles 96 3D multilayer constructs. De-stacking the layers of the 3D culture, by peeling apart the sheets of paper, "sections" all 96 cultures at once. It is, thus, simple to isolate 200-micron-thick cell-containing slabs from each 3D culture in the 96-zone array. Because the 3D cultures are assembled from multiple layers, the number of cells plated initially in each layer determines the spatial distribution of cells in the stacked 3D cultures. This capability made it possible to compare the growth of 3D tumor models of different spatial composition, and to examine the migration of cells in these structures.

  View details for DOI 10.1371/journal.pone.0018940

  View details for Web of Science ID 000290305600010

  View details for PubMedID 21573103

• Externally Applied Electric Fields up to 1.6 x 10(5) V/m Do Not Affect the Homogeneous Nucleation of Ice in Supercooled Water JOURNAL OF PHYSICAL CHEMISTRY B Stan, C. A., Tang, S. K., Bishop, K. J., Whitesides, G. M. 2011; 115 (5): 1089-1097

  Abstract

  The freezing of water can initiate at electrically conducting electrodes kept at a high electric potential or at charged electrically insulating surfaces. The microscopic mechanisms of these phenomena are unknown, but they must involve interactions between water molecules and electric fields. This paper investigates the effect of uniform electric fields on the homogeneous nucleation of ice in supercooled water. Electric fields were applied across drops of water immersed in a perfluorinated liquid using a parallel-plate capacitor; the drops traveled in a microchannel and were supercooled until they froze due to the homogeneous nucleation of ice. The distribution of freezing temperatures of drops depended on the rate of nucleation of ice, and the sensitivity of measurements allowed detection of changes by a factor of 1.5 in the rate of nucleation. Sinusoidal alternation of the electric field at frequencies from 3 to 100 kHz prevented free ions present in water from screening the electric field in the bulk of drops. Uniform electric fields in water with amplitudes up to (1.6 ± 0.4) × 10(5) V/m neither enhanced nor suppressed the homogeneous nucleation of ice. Estimations based on thermodynamic models suggest that fields in the range of 10(7)-10(8) V/m might cause an observable increase in the rate of nucleation.

  View details for DOI 10.1021/jp110437x

  View details for Web of Science ID 000286797700038

  View details for PubMedID 21174462

• Diversity of Phage-Displayed Libraries of Peptides during Panning and Amplification MOLECULES Derda, R., Tang, S. K., Li, S. C., Ng, S., Matochko, W., Jafari, M. R. 2011; 16 (2): 1776-1803

  Abstract

  The amplification of phage-displayed libraries is an essential step in the selection of ligands from these libraries. The amplification of libraries, however, decreases their diversity and limits the number of binding clones that a screen can identify. While this decrease might not be a problem for screens against targets with a single binding site (e.g., proteins), it can severely hinder the identification of useful ligands for targets with multiple binding sites (e.g., cells). This review aims to characterize the loss in the diversity of libraries during amplification. Analysis of the peptide sequences obtained in several hundred screens of peptide libraries shows explicitly that there is a significant decrease in library diversity that occurs during the amplification of phage in bacteria. This loss during amplification is not unique to specific libraries: it is observed in many of the phage display systems we have surveyed. The loss in library diversity originates from competition among phage clones in a common pool of bacteria. Based on growth data from the literature and models of phage growth, we show that this competition originates from growth rate differences of only a few percent for different phage clones. We summarize the findings using a simple two-dimensional "phage phase diagram", which describes how the collapse of libraries, due to panning and amplification, leads to the identification of only a subset of the available ligands. This review also highlights techniques that allow elimination of amplification-induced losses of diversity, and how these techniques can be used to improve phage-display selection and enable the identification of novel ligands.

  View details for DOI 10.3390/molecules16021776

  View details for Web of Science ID 000287745400051

  View details for PubMedID 21339712

• Continuously tunable microdroplet-laser in a microfluidic channel OPTICS EXPRESS Tang, S. K., Derda, R., Quan, Q., Loncar, M., Whitesides, G. M. 2011; 19 (3): 2204-2215

  Abstract

  This paper describes the generation and optical characterization of a series of dye-doped droplet-based optical microcavities with continuously decreasing radius in a microfluidic channel. A flow-focusing nozzle generated the droplets (~21 ?m in radius) using benzyl alcohol as the disperse phase and water as the continuous phase. As these drops moved down the channel, they dissolved, and their size decreased. The emission characteristics from the drops could be matched to the whispering gallery modes from spherical micro-cavities. The wavelength of emission from the drops changed from 700 to 620 nm as the radius of the drops decreased from 21 ?m to 7 ?m. This range of tunability in wavelengths was larger than that reported in previous work on droplet-based cavities.

  View details for Web of Science ID 000286807100058

  View details for PubMedID 21369038

• Cytoplasmic self-organization of internal membranes, microtubule- and actin-cytoskeleton inside microfluidics generated droplets Tang, S., Renz, M., Driscoll, M., REBER, S., Nguyen, A., Daniels, B., Field, C., Lippincott-Schwartz, J. AMER SOC CELL BIOLOGY. 2011

  View details for Web of Science ID 000305505500248

• Slippery surfaces with omniphobicity, self-repair, high-pressure stability and optical transparency Nature Wong, T., Kang, S. H., Tang, Sindy, K.Y., Smythe, E., Hatton, B., Grinthal, A. 2011; 447: 443
• Monte Carlo simulation of centrosomal self-centering due to pushing by microtubules in large cells. Tang, S. K., Castle, B. T., Odde, D. J. AMER SOC CELL BIOLOGY. 2011

  View details for Web of Science ID 000305505504158

• Cofabrication: A Strategy for Building Multicomponent Microsystems ACCOUNTS OF CHEMICAL RESEARCH Siegel, A. C., Tang, S. K., Nijhuis, C. A., Hashimoto, M., Phillips, S. T., Dickey, M. D., Whitesides, G. M. 2010; 43 (4): 518-528

  Abstract

  This Account describes a strategy for fabricating multicomponent microsystems in which the structures of essentially all of the components are formed in a single step of micromolding. This strategy, which we call "cofabrication", is an alternative to multilayer microfabrication, in which multiple layers of components are sequentially aligned ("registered") and deposited on a substrate by photolithography. Cofabrication has several characteristics that make it an especially useful approach for building multicomponent microsystems. It rapidly and inexpensively generates correctly aligned components (for example, wires, heaters, magnetic field generators, optical waveguides, and microfluidic channels) over very large surface areas. By avoiding registration, the technique does not impose on substrates the size limitations of common registrations tools, such as steppers and contact aligners. We have demonstrated multicomponent microsystems with surface areas exceeding 100 cm(2), but in principle, device size is only limited by the requirements of generating the original master. In addition, cofabrication can serve as a low-cost strategy for building microsystems. The technique is amenable to a variety of laboratory settings and uses fabrication tools that are less expensive than those used for multistep microfabrication. Moreover, the process requires only small amounts of solvent and photoresist, a costly chemical required for photolithography; in cofabrication, photoresist is applied and developed only once to produce a master, which is then used to produce multiple copies of molds containing the microfluidic channels. From a broad perspective, cofabrication represents a new processing paradigm in which the exterior (or shell) of the desired structures are produced before the interior (or core). This approach, generating the insulation or packaging structure first and injecting materials that provide function in channels in liquid phase, makes it possible to design and build microsystems with component materials that cannot be easily manipulated conventionally (such as solid materials with low melting points, liquid metals, liquid crystals, fused salts, foams, emulsions, gases, polymers, biomaterials, and fragile organics). Moreover, materials can be altered, removed, or replaced after the manufacturing stage. For example, cofabrication allows one to build devices in which a liquid flows through the device during use, or is replaced after use. Metal wires can be melted and reset by heating (in principle, repairing a break). This method leads to certain kinds of structures, such as integrated metallic wires with large cross-sectional areas or optical waveguides aligned in the same plane as microfluidic channels, that would be difficult or impossible to make with techniques such as sputter deposition or evaporation. This Account outlines the strategy of cofabrication and describes several applications. Specifically, we highlight cofabricated systems that combine microfluidics with (i) electrical wires for microheaters, electromagnets, and organic electrodes, (ii) fluidic optical components, such as optical waveguides, lenses, and light sources, (iii) gels for biological cell cultures, and (iv) droplets for compartmentalized chemical reactions, such as protein crystallization.

  View details for DOI 10.1021/ar900178k

  View details for Web of Science ID 000277006400004

  View details for PubMedID 20088528

• Uniform Amplification of Phage with Different Growth Characteristics in Individual Compartments Consisting of Monodisperse Droplets ANGEWANDTE CHEMIE-INTERNATIONAL EDITION Derda, R., Tang, S. K., Whitesides, G. M. 2010; 49 (31): 5301-5304

  View details for DOI 10.1002/anie.201001143

  View details for Web of Science ID 000280464200012

  View details for PubMedID 20583018

• Paper-supported 3D cell culture for tissue-based bioassays PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Derda, R., Laromaine, A., Mammoto, A., Tang, S. K., Mammoto, T., Ingber, D. E., Whitesides, G. M. 2009; 106 (44): 18457-18462

  Abstract

  Fundamental investigations of human biology, and the development of therapeutics, commonly rely on 2D cell-culture systems that do not accurately recapitulate the structure, function, or physiology of living tissues. Systems for 3D cultures exist but do not replicate the spatial distributions of oxygen, metabolites, and signaling molecules found in tissues. Microfabrication can create architecturally complex scaffolds for 3D cell cultures that circumvent some of these limitations; unfortunately, these approaches require instrumentation not commonly available in biology laboratories. Here we report that stacking and destacking layers of paper impregnated with suspensions of cells in extracellular matrix hydrogel makes it possible to control oxygen and nutrient gradients in 3D and to analyze molecular and genetic responses. Stacking assembles the "tissue", whereas destacking disassembles it, and allows its analysis. Breast cancer cells cultured within stacks of layered paper recapitulate behaviors observed both in 3D tumor spheroids in vitro and in tumors in vivo: Proliferating cells in the stacks localize in an outer layer a few hundreds of microns thick, and growth-arrested, apoptotic, and necrotic cells concentrate in the hypoxic core where hypoxia-sensitive genes are overexpressed. Altering gas permeability at the ends of stacks controlled the gradient in the concentration of the O(2) and was sufficient by itself to determine the distribution of viable cells in 3D. Cell cultures in stacked, paper-supported gels offer a uniquely flexible approach to study cell responses to 3D molecular gradients and to mimic tissue- and organ-level functions.

  View details for DOI 10.1073/pnas.0910666106

  View details for Web of Science ID 000271429800011

  View details for PubMedID 19846768

• Independent Control of Drop Size and Velocity in Microfluidic Flow-Focusing Generators Using Variable Temperature and Flow Rate ANALYTICAL CHEMISTRY Stan, C. A., Tang, S. K., Whitesides, G. M. 2009; 81 (6): 2399-2402

  Abstract

  This paper describes a method to control the volume and the velocity of drops generated in a flow-focusing device dynamically and independently. This method involves simultaneous tuning of the temperature of the nozzle of the device and of the flow rate of the continuous phase; the method requires a continuous phase liquid that has a viscosity that varies steeply with temperature. Increasing the temperature of the flow-focusing nozzle from 0 to 80 degrees C increased the volume of the drops by almost 2 orders of magnitude. Tuning both the temperature and the flow rate controlled the drop volume and the drop velocity independently; this feature is not possible in a basic flow-focusing device. This paper also demonstrates a procedure for identifying the range of possible drop volumes and drop velocities for a given flow-focusing device and shows how to generate drops with a specified volume and velocity within this range. This method is easy to implement in on-chip applications where thermal management is already incorporated in the system, such as DNA amplification using the polymerase chain reaction and nanoparticle synthesis.

  View details for DOI 10.1021/ac8026542

  View details for Web of Science ID 000264142000049

  View details for PubMedID 19209912

• A multi-color fast-switching microfluidic droplet dye laser LAB ON A CHIP Tang, S. K., Li, Z., Abate, A. R., Agresti, J. J., Weitz, D. A., Psaltis, D., Whitesides, G. M. 2009; 9 (19): 2767-2771

  Abstract

  We describe a multi-color microfluidic dye laser operating in whispering gallery mode based on a train of alternating droplets containing solutions of different dyes; this laser is capable of switching the wavelength of its emission between 580 nm and 680 nm at frequencies up to 3.6 kHz-the fastest among all dye lasers reported; it has potential applications in on-chip spectroscopy and flow cytometry.

  View details for DOI 10.1039/b914066b

  View details for Web of Science ID 000269799800004

  View details for PubMedID 19967111

• Basic Microfluidic and Soft Lithographic Techniques Optofluidics: Fundamentals, Devices, and Applications Tang, Sindy, K.Y., Whitesides, George, M. McGraw-Hill. 2009
• Optical Components Based on Dynamic Liquid-liquid Interfaces Optofluidics: Fundamentals, Devices, and Applications Tang, Sindy, K.Y., Whitesides, George, M. McGraw-Hill. 2009
• Dynamically reconfigurable liquid-core liquid-cladding lens in a microfluidic channel LAB ON A CHIP Tang, S. K., Stan, C. A., Whitesides, G. M. 2008; 8 (3): 395-401

  Abstract

  This paper describes the design and operation of a liquid-core liquid-cladding (L(2)) lens formed by the laminar flow of three streams of liquids in a microchannel whose width expands laterally in the region where the lens forms. Two streams of liquid with a lower refractive index (the cladding) sandwich a stream of liquid with a higher refractive index (the core). As the core stream enters the expansion chamber, it widens and becomes biconvex in shape, for some rates of flow. This biconvex fluidic element focuses light. Manipulating the relative rates of flow of the streams reconfigures the shape, and therefore the focal distance, of the L(2) lens. This paper also describes a technique for beam tracing, and for characterization of a lens in an enclosed micro-scale optical system. The use of a cladding liquid with refractive index matched to that of the material used in the fabrication of the microfluidic system (here, poly(dimethylsiloxane)) improves the quality of the focused beam.

  View details for DOI 10.1039/b717037h

  View details for Web of Science ID 000254424300005

  View details for PubMedID 18305856

• Optical waveguiding using thermal gradients across homogeneous liquids in microfluidic channels APPLIED PHYSICS LETTERS Tang, S. K., Mayers, B. T., Vezenov, D. V., Whitesides, G. M. 2006; 88 (6)

  View details for DOI 10.1063/1.2170435

  View details for Web of Science ID 000235252800012

• Optical waveguiding using thermal gradients across homogeneous liquids in microfluidic channels Applied Physics Letters Tang, Sindy, K.Y., Mayers, Brian, T., Vezenov, Dmitri, V., Whitesides, George, M. 2006; 6 (88): 061112