The Micro/Nano/Molecular Biotechnology Lab

Kojima, T.; Takayama, S. "Microscale Determination of Aqueous Two Phase System Binodals by Droplet Dehydration in Oil." Analytical Chemistry. 2013. DOI: 10.1021/ac400628b.
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This paper analyzes the use of a dehydrating oil system to determine binodal curves of aqueous two phase system (ATPS). Aqueous droplets containing phase-forming polymers are dehydrated at the interface between two immiscible oils. Comparison of the droplet diameter at this phase separation point and at the beginning allows facile calculation of the concentration of polymers that determine the binodal curve. The miniaturized droplet dehydration-based binodals obtained in this manner matched the binodals determined by the conventional diluting method but using several orders of magnitude less sample amounts.

Kojima, T.; Takayama, S. "Patchy surfaces stabilize DEX-PEG aqueous two phase system liquid patterns." Langmuir. 2013. DOI: 10.1021/la400580q.
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This paper analyzes surface chemistry effects to stably pattern aqueous two phase system (ATPS) droplets on chemically modified poly(dimethylsiloxane) (PDMS). PDMS surface modifications studied include primary amine groups, carboxylic acid groups, and neutral polymer surfaces. While homogeneous surfaces of different functional groups affect DEX droplet pinning somewhat, the most stable patterns were realized using surfaces with chemical heterogeneity. Arbitrary DEX solution patterning was achieved on a chemically patchy surface.

Frampton, J. P.; Shi, H.; Kao, A.; Parent, J.M.; Takayama, S. "Delivery of Proteases in Aqueous Two-Phase Systems Enables Direct Purification of Stem Cell Colonies from Feeder Cell Co-Cultures for Differentiation into Functional Cardiomyocytes." Advanced Healthcare Materials. 2013. DOI: 10.1002/adhm.201300049.
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Feeder cell co-culture is used by most stem cell biologist because it maintains stem cell viability and phenotype, is relatively cost effective, and produces consistent results across ESC and IPSC lines. However, for many applications, stem cells need to be purified from the surrounding feeder cells. We developed a method that uses ATPSs for high resolution delivery of enzymes directly to stem cell colonies to remove them from feeder cultures. This technique uses the smallest user-controlled ATPS droplets yet reported and will be useful for high-resolution protein patterning on a variety of other cell types.

Frampton, J. P.; White, J. B.; Abraham, A. T.; Takayama, S. "Cell Co-culture Patterning Using Aqueous Two-phase Systems." J. Vis. Exp. 2013. DOI: 10.3791/50304.
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In this video tutorial we describe how to use ATPSs for patterning cells. We demonstrate patterning of islands, exclusion zones, and co-cultures so that users can adapt this technology to study cell migration and cell-cell interactions of their cells of interest. This technique can be performed using only pipettes, without the need for any specialized equipment.

Lee, D; Bolton, O.; Kim, B-C.; Youk, J. H.; Takayama, S.; Kim, J. "Room Temperature Phosphorescence of Metal-free Organic Materials in Amorphous Polymer Matrices." JACS. 2013. DOI: 10.1021/ja401769g.
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Bright room temperature phosphorescence by embedding a purely organic phosphor into an amorphous glassy polymer matrix. It implies that the reduced beta (beta)-relaxation of isotactic PMMA most efficiently suppresses vibrational triplet decay and allows the embedded organic phosphors to achieve a bright 7.5% phosphorescence quantum yield. It was applied to a microfluidic device integrated with a novel temperature sensor based on the metal-free purely organic phosphors in the temperature-sensitive polymer matrix.

Kim, S-J.; Paczesny, S.; Takayama, S.; Kurabayashi, K. "Preprogrammed capillarity to passively control system-level sequential and parallel microfluidic flows." Lab Chip. 2013. DOI: 10.1039/C3LC50187F.
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The small length scales of microfluidic systems enable capillary flow but few efforts have been made to harness this passive flow for controlled an tunable operations. This paper demonstrates a microfluidic chip capable of controlling flow and sequence passively, without the need for valves or pumps.

Kang, E.; Ryoo, J.; Jeong, G.S.; Choi, Y.Y; Jeong, S.M.; Ju, J.; Chung, S.; Takayama, S.; Lee, S-H. "Large-Scale, Ultrapliable, and Free-Standing Nanomembranes." Advanced Materials. 2013. DOI: 10.1002/adma.201204619.
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We outline and characterize a strategy for generating PDMS membranes as thin as 50 nm. The ultra-thin membranes allow for a simplified treatment of cell monolayer mechanics and we apply them to study stretch-induced injury in epithelia.

Baac, Hyoung Won; Frampton, J.P.; Ok, Jong G.; Takayama, S.; Guo, L. Jay. "Localized micro-scale disruption of cells using laser-generated focused ultrasound." J. Biophotonics. 2013. DOI: 10.1002/jbio.201200247.
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Laser-generated focused ultrasound (LGFU) was used to disrupt single cells. The LGFU technique uses a carbon nanotube-coated optoacoustic lens to convert laser pulses into focused ultrasound. The sharp focus and high peak pressure of the ultrasound produces microscale disturbances such as micro-jets and secondary shock-waves arising from micro-bubble collapse that can activate single cells for cell harvesting from culture substrates or biomolecule delivery.

Frampton, J.P.; Fan, Z.; Simon, A.; Chen, D.; Deng, C.X.; Takayama, S. "Aqueous Two-Phase System Patterning of Microbubbles: Localized Induction of Apoptosis in Sonoporated Cells." Adv Func Mat.. 2013. DOI: 10.1002/adfm.201203321.
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This new method for studying apoptosis adapts bubbles commonly used for ultrasound imaging to open pores in cell membranes when ultrasound is applied. The most innovative aspect of this new method is our ability to pattern the microbubbles directly on cells. Normally this is very difficult to achieve because microbubbles float in the liquid covering the cells. We overcame this issue by confining the microbubbles in polymer solutions composed of polyethylene glycol and dextran. There are forces associated with the boundary between these two polymer liquids that prevent the microbubbles from escaping. By patterning the microbubbles we can design experiments that test many ultrasound, microbubble or even drug combinations in a single experiment. This will enable high throughput studies of cell death.

Kim, S-J; Yokokawa, R.; Takayama, S. "Microfluidic oscillators with widely tunable periods." Lab Chip.. 2013. DOI: 10.1039/C3LC41415A.
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We present a widely tunable period, constant flow-driven microfluidic oscillator. With the use of tunable external membrane capacitors, the oscillation period spans 4 orders of magnitude from 0.3 s to 4.1 h. We also show that relatively larger external capacitance than internal capacitance of the microfluidic valve is a critical requirement for oscillation.

Byun, C.K.; Hwang, H.; Choi, W.S.; Yaguchi, T.; Park, J.; Kim, D.; Mitchell, R.J.; Kim, T.; Cho, Y-K; Takayama, S. "Productive chemical interaction between a bacterial microcolony couple is enhanced by periodic relocation." J. Am. Chem. Soc.. 2013. DOI: 10.1021/ja3094923.
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Aqueous two phase systems (ATPS) allow for spatio-temporal control of bacterial colonies in chemically unrestricted culture. A PEG-Dex ATPS supplemented with magnetic-bead conjugated Dex is used to efficiently relocate Dex-contained bacterial colonies. ATPS-enabled colony relocation increased quorum-sensing markers by moving colonies from a resource-depleted microenvironment to a resource-rich one without disturbing chemical signaling. Computer simulations confirm these observations.

Cheng, M.-C.; Leske, A.T.; Matsuoka, T.; Kim, B. C.; Lee, J.; Burns, M. A.; Takayama, S; Biteen, J.S. "Super-Resolution Imaging of PDMS Nanochannels by Single-Molecule Micelle-Assisted Blink Microscopy." J. Phys. Chem. B. 2013. DOI: 10.1021/jp307635v.
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Micelle-assisted blink (MAB) microscopy overcomes the difficulty of conventional imaging techniques to measure the nanostrucutre inside devices. This super-resolution imaging technique helps to characterize nanochannel widths, to reveal heterogeneity along channel lengths and between different channels in the same device and to prove biologically relevant information about the nanoenvironment, such as solvent accessibility.

Kim, S.J.; Yokokawa, R.; Takayama, S. "Analyzing threshold pressure limitations in microfluidic transistors for sel-regulated microfluidic circuits." Applied Physics Letters. 2012. DOI: 10.1063/1.4769985.
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Although electric/electronic circuit analogy is prevalent in microfluidic systems, we report that a hydraulic microfluidic membrane-valve is different from electronic transistors: (1) the valve has two significantly different opening and closing threshold pressures, and (2) its opening threshold pressure depends on external parameters like inflow rates and resistances.

Matsuoka, T.; Kim, B.C.; Huang, J.; Douville, N.J.; Thouless, M.D.; Takayama, S. "Nanoscale Squeezing in Elastomeric Nanochannels for Single Chromatin Linearization." Nano Letters. 2012. DOI: 10.1021/nl304063f.
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This nanoscale squeezing procedure generates hydrodynamic flows while also confining the biopolymers into smaller and smaller volumes. The unique features of this technique enable full linearization then trapping of biopolymers such as DNA. The versatility of the method is also demonstrated by analysis of chromatin stretchability and mapping of histone states using single strands of chromatin.

Lesher-Perez, S.C.; Frampton, J.P.; Takayama, S. "Microfluidic systems: A new toolbox for pluripotenet stem cells." Biotechnology Journal. 2012. DOI: 10.1002/biot.201200206.
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This review provides a comprehensive insight into the implications of microfluidics on pluripotent stem cell research, by describing ways in which microfluidic systems can help minimize the gap between conventional in vitro cell culture environments and the in vivo stem cell niche. Our goal was to encompass detailed and specific work applied to pluripotent stem cells cultured in microfluidic environments, and the benefits of using microfluidics as a culturing platform and analysis tool. Additionally, the review touches on existing microfluidic tool sets that have not been applied to pluripotent stem cells, but have potential to enter into this area of research and application, providing more insightful systems and robust techniques.

Kim, S.-J.; Lai, D.; Park, J.Y.; Yokokawa, R.; Takayama, S. "Microfluidic Automation Using Elastomeric Valves and Droplets: Reducing Reliance on External Controllers." Small. 2012. DOI: 10.1002/smll.201200456.
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In recent microfluidic chips, demands for high-throughput analysis with minimal reliance on off-chip controllers are increasing. In this context, we overview elastomeric valve- and droplet-based microfluidic systems: their working principles, limitations of representative components, and the relevant biochemical applications are discussed.

Lai, D.; Smith, G.D.; Takayama, S. "Lab-on-a-chip biophotonics: its application to assisted reproductive technologies." J. Biophotoincs. 2012. DOI: 10.1002/jbio.201200041.
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The integration of biophotonics into microfluidics for lab-on-a-chip (LOC) assisted reproductive technology (ART) is currently a useful tool for non-invasive gamete and embryo quality assessment beyond just simple morphological assessment. As we integrate more advanced biophotonics into LOC devices, the future will bring highly accurate quality assessment and strong predictive power from biophotonics combined with the sensitivity and automation of microlfuidics.

Mehta, G.; Hsiao, A.Y.; Ingram, M.; Luker, G.D.; Takayama, S. "Opportunities and challenges for use of tumor spheroids as models to test drug delivery efficacy." J. Controlled Release. 2012 DOI: 10.1016/j.jconrel.2012.04.045.
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Spheroids offer a physiologically relevant platform for in vitro drug delivery experiments. This review assesses key advantages and challenges, describes experimental techniques, and provides relevant examples of the use of spheroids in drug delivery testing.

Park, J.Y; Ahn, D.; Choi, Y.Y; Hwang, C.M.; Takayama, S.; Lee, S.H.; Lee, S.-H. "Surface chemistry modification of PDMS elastomers with boiling water improves cellular adhesion." J. Sensors and Actuators B. 2012 DOI: 10.1016/j.snb.2012.06.096.
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Although ubiquitous in microfluidics applications, PDMS lacks suitable cell adhesion motifs and therefore requires modification before being used in cell culture assays, typically with ECM proteins. Herein, we describe a simple method for improve the cell adhesion properties of native PDMS using boiling water to generate surface hydroxyl groups. This technique represents a mild, convenient and cheap method for inducing cell adhesion to PDMS microdevices.

Yaguchi, T.; Dwidar, M.; Byun, C.K.; Leung, B.; Lee, S.; Cho, Y.-K.; Mitchell, R.J.; Takayama, S. "Aqueous two-phase system-derived biofilms for bacterial interaction studies." BioMacromolecules. 2012 DOI: 10.1021/bm300500y.
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APTS can be used to selectively pattern bacterial colonies which, over time, form spatially distinct biofilms. Since ATPS printing restricts the diffusion of the bacteria, but not smaller molecules, individual populations are able to communicate with each other. To demonstrate this phenomenon, we show that a B-lactamase producing biofilm can confer ampicillin resistance to neighboring, nonresistant planktonic cells.

Wang, J.D.; Douville, N.J.; Takayama, S.; El-Sayed, M. "Quantitative Analysis of Molecular Absorption into PDMS Microfluidic Channels." Annals of Biomedical Engineering. 2012 DOI: 10.1007/s10439-012-0562-z.
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Many molecules common to cell culture experiments are know to be absorbed by PDMS microchannels during cell culture experiments. We quantify that absorption as a function of the log of a solutes partition coefficient, P. For log(P) < 2.47, absorption was minimal. TiO2 and SiO2 coating was shown to reduce absorption for molecules with log(P) > 2.62.

Heo, Y.S.; Cabrera, L.M.; Bormann, C.L.; Smith, G.D.; Takayama, S. "Real time culture and analysis of embryo metabolism using a microfluidic device with deformation based actuation." Lab Chip. 2012 DOI: 10.1039/C2LC21050A.
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Using a Braille valving and pumping system, we report a microfluidic device for automated, real-time analysis of embryo metabolism. We show simultaneous time-dependent measurements for live mouse blastocyst-stage embryos with pmol/hour sensitivity.

Fang, Y.; Frampton, J.P.; Raghavan, S.; Savahi-Kaviani, R.; Luker, G.; Deng, C.X.; Takayama, S. "Rapid Generation fo Multiplexed Cell Cocultures Using Acousitc Droplet Ejection Followed by Aqueous Two-Phase Exclusion Patterning." Tiss. Eng. C. 2012. DOI: 10.1089/ten.tec.2011.0709.
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Acoustic droplet ejection was used with aqueous two-phase systems to exclusion pattern co-cultures of cells. We used this system to study the chemokinetic responses of cancer cells to surrounding cells. This system will also be useful for patterning other types of cells to study their interactions.

Zamankhan, P.; Helenbrook, B.T.; Takayama, S.; Grotberg, J.B. "Steady motion of Bingham liquid plugs in two-dimensional channels." J Fluid Mech. 2012. DOI: 10.1017/jfm.2011.43.
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Using numerical analysis, we model non-Newtonian (Bingham) fluid plug behavior in 2D channels. This research has implications for various lung pathologies.

Hsiao, A.Y.; Tung, Y.-C.; Qu, X.; Patel, L.R.; Pienta, K.J.; Takayama, S. "384 hanging drop arrays give excellent z-factors and allow versatile formation of co-culture spheroids." Biotechnology and Bioengineering 2012. DOI: 10.1002/bit.24399.
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A previously reported 384 hanging droplet spheroid culture platform was shown to perform well in fluorescence and colorimetric-based assays. We also demonstrate spheroid transfer and retrieval, as well as sequential addition of cell types for concentric, co-culture applications.

Ray; P.; Lewin, S.A.; Mihalko, L.A.; Lesher-Perez, S.C.; Takayama, S.; Luker, K.E.; Luker, G.D. "Secreted CXCL12 (SDF-1) Forms Dimers under Physiologic Conditions." Biochem. J. 2012. DOI: 10.1042/BJ20111341.
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This paper showed that CXCL12 was secreted from cells both in monomer and dimer forms, and that in three-dimensional culture systems homodimerization occurred as well, a characteristic not achieved within the two-dimensional cultures. Furthermore this paper demonstrated that the monomer and dimer CXCL12 populations preferentially activated different CXCR4 signalling pathways and produced differential migratory responses, while CXCL12 monomer was only significantly sequestered by CXCR7.

Moraes, C.; Mehta, G.; Lesher-Perez, S.C.; Takayama, S. "Organs-on-a-Chip: A Focus on Compartmentalized Microdevices." Annals of Biomedical Engineering 2012.. DOI: 10.1007/s10439-011-0455-6.
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Microengineering techniques have yield significant advances in the biomedical sciences. Designing micro-scale systems to simulate entire organs would be a powerful experimental tool, increasing relevance while decreasing costs and complexity. This article surveys and discusses recently reported organ-on-a-chip systems.

Hsiao, A.Y.; Tung, Y-C; Kuo, C-H, Mosadegh, B.; Bedenis, R.; Pienta, K.J.; Takayama, S. "Micro-ring structures stabilize microdroplets to enable long term spheroid culture in 384 hanging drop array plates." Biomed. Microdev. 2012. DOI: 10.1007/s10544-011-9608-5.
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Micro-ring structures were used to enhance the stability of 384 well hanging drop assay plate. This new design was shown to be more resistant against mechanical perturbations than previous methods and reliably enabled sustained cell culture for over three weeks.

Smith, G.D.; Takayama, S.; Swain, J.E. "Rethinking In Vitro Embryo Culture: New Developments in Culture Platforms and Potential to Improve Assisted Reproductive Technologies." Biol. Reprod. 2012.. DOI:10.1095/biolreprod.111.095778.
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Research on in vitro embryo development has focused on traditionally focused on soluble factors. This review considers how other factors (such as temporal or mechanical cues) may influence embryo development.

Kim,S.-J.; Yokokawa, R.; Lesher-Perez, S.C.; Takayama, S. "Constant flow-driven microfluidic oscillator for different duty cycles." Anal Chem 2011. DOI: 10.1021/ac202866b.
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We designed a normally closed 3-terminal valve constant flow-driven oscillator, building on our previous 4-valve design, this switch to a more electronic circuit analogous design, allowed us to achieve different duty cycles within our device. This paper further characterized the necessary pressures to produce oscillatory behavior within our devices, as well as demonstrated this system to be capable of periodic stimulation/treatment of cultured cells.

White, J.B.; Takayama, S. "Receptor differential activation and cooperativity better explain cellular preference for different chemoattractant gradient shapes in an EGFR system." Integr. Biol. 2011. DOI:10.1039/C1IB00040C.
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This paper describes a model that explains how cells can fine-tune their migratory response to chemokines. Receptors, especially EGFR, have much different signaling characteristics depending on their degree of oligomerization. We demonstrate how receptor cooperativity and oligomerization can change a cell's migration abilities in vitro which could have implications in how we study cancer metastasis and autoimmunity in vitro.

Lai, D.; Frampton, J.P.; Sriram, H.; Takayama, S. "Rounded multi-level microchannels with orifices made in one exposure enable aqueous two-phase system droplet microfluidics." Lab Chip 2011. DOI:10.1039/C1LC20560A.
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A one-step exposure to fabricate multi-layer channels for Aqueous Two-Phase System droplets with the lowest interfacial tension to date.

Mosadegh, B.; Bersano-Begey, T.; Park, J.Y.; Burns, M.A.; Takayama, S. "Next-generation integrated microfluidic circuits." Lab Chip 2011. DOI: 10.1039/C1LC20387H.
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This paper provides a brief overview of microfluidic devices that allow for increased on-chip control of fluid flow through embedded elastomer valves. Parallel instruction, serial instruction, and embedded instruction control schemes are specifically addressed.

Frampton, J.P.; Lai, D.; Sriram, H.; Takayama, S. "Precisely targeted delivery of cells and biomolecules within microchannels using aqueous two-phase systems." Biomedical Microdevices 2011. DOI: 10.1007/s10544-011-9574-y.
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Small molecule delivery in microfluidic channels has previously been limited by diffusion of the molecules across liquid-liquid interfaces. Aqueous two-phase technology is a biocompatible method that allows for improved spatial resolution when delivering cells, proteins, or small molecules.

Park, J.Y.; White, J.B.; Walker, N.; Kuo, C.H.; Cha, W.; Meyerhoff, M.E.; Takayama, S. "Response of endothelial cells to extremely slow flows." Biomicrofluidics 2011. DOI: 10.1063/1.3576932.
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This paper describes the effects of extremely slow fluid flow on endothelial cells. Traditional flow studies examine the effects of flow with shear greater than 0.1 dyne/cm2, we utilize an osmotic pump to achieve 10-1000 times smaller shear which can have implications in angiogenesis and developmental biology.

Douville, N.J.; Li, Z.; Takayama, S.; Thouless, M.D. "Fracture of metal coated elastomers." Soft Matter 2011. DOI: 10.1039/C1SM05140G.
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Strain-induced cracks in gold-coated elastomeric PDMS slabs were examined. These cracks were orders of magnitude deeper than the gold film. We suggest that cracking of the PDMS substrate occurs to release residual energy from failure of the gold film.

Tavana, H.; Kaylan, K.; Bersano-Begley, T.: Luker, K.E.; Luker, G.D.; Takayama, S. "Rehydration of polymeric, aqueous, biphasic system facilitates high throughput cell exclusion patterning for cell migration studies." Advanced Functional Materials 2011. DOI: 10.1002/adfm.201002559.
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Using aqueous two-phase systems for non-contact cell exclusion printing, we design a novel, high-throughput method for cell migration studies. We validate our "gap migration" platform using known cytoskeletal inhibitors.

Jovic, A.; Wade, S.M.; Miyawaki, A.; Neubig, R.R.; Linderman, J.J.; Takayama, S. "Hi-Fi transmission of periodic signals amid cell-to-cell variability." Molecular BioSystems 2011. DOI: 10.1039/c1mb05031a.
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This paper combines experimental and theoretical approaches to high fidelity develop techniques for monitoring changes in intracellular calcium oscillations due to extracellular signals (such as G-protein coupled receptor activation).

Tavana, H.; Mosadegh, B.; Zamankhan, P.; Grotberg, J.B.; Takayama, S. "Microprinted Feeder cells guide embryonic stem cell fate." Biotechnology and Bioengineering 2011. DOI: 10.1002/bit.23190.
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A non-contact, microprinting technique allows for controlled patterning of feeder cell arrays of different sizes on a gel substrate. We demonstrate that feeder cell type can direct fate of overlaid mouse embryonic stem cells.

Thouless, M.D.; Li, Z.; Douville, N.J.; Takayama, S. "Periodic cracking of films supported on compliant substrates." J. Mechanics and Physics of Solids 2011. DOI:10.1016/j.jmps.2011.04.009.
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Strain can cause patterns of parallel cracks to form in rigid films and their soft substrates. This paper modifies a linear-elastic fracture model to explain this phenomenon.

Tavana, H.; Zamankhan, P.; Christensen, P.J.; Grotberg, J.B.; Takayama, S. "Epithelium damage and protection during reopening of occluded airway in a physiologic microfluidic pulmonary airway model." Biomed. Microdev. 2011. DOI: 10.1007/s10544-011-9543-5.
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Using a microfluidic device, we study the response of lung airway epithelial cells to stresses generated from repeated exposure to liquid plugs. Addition of surfactant rescues cells from plug-induced cell damage and death. Mathematical modeling confirms the experimental observations.

Didwania, M.; Didwania, A.; Mehta, G.; Basak, G.W; Yasukawa, S.; Takayama, S.; de Necochea-Campion, R.; Srivastava, A.; Carrier, E. "Artificial Hematopoietic Stem Cell Niche: Bioscaffolds to Microfluids to Mathematical Simulations." Curr. Top. Med. Chem 2011.
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Two recreate an artificial, in vivo-like niche for hematopoietic stem cells, it is necessary to consider the scaffold, the cells themselves, and soluble factors. We describe the states of the art for these three areas and include a mathematical model to aid in design and optimization of an artificial bioreactor.

Tavana, H.; Takayama, S. "Aqueous biphasic microprinting approach to tissue engineering." Biomicrofluidics 2011, 5. DOI: 10.10631/1.3516658.
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Recent developments have shown aqueous two-phase printing (ATPS) to be a valuable tool for non-contact printing of biomaterials. Since both parts of an ATPS are completely aqueous, yet immiscible, this technique is ideal for spatially patterning delicate molecules or cells without compromising substrate integrity or cell viability.

Chantiwas, R.; Park, S.; Soper, S. A.; Kim, B.C.; Takayama, S.; Sunkara, V.; Hwang, H.; Cho, Y.-K. "Flexible Fabrication and Applications of Polymer Nanochannels and Nanoslits." Chem. Soc. Rev. 2011. DOI: 10.1039/C0CS00138D.
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This critical review provides an overview of recent advances in polymer-based nanofluidics.

Torisawa, Y; Mosadegh, B.; Cavnar, S. P.; Ho, M.; Takayama, S. "Transwells with Microstamped Membranes Produce Micropatterned 2D and 3D Co-cultures" Tissue Eng Part C 2011, 17, 61-67.
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Hydrodynamic forces created by a microcontact printed PDMS layer are used to guide cell patterns on the underside of a Transwell co-culture insert. Through co-culture experiments, this paper shows that HepG2 cells inhibit mouse embryonic fibroblast Sox17 formation via direct cell-cell contact and cellular signaling mechanisms.

Douville, N. J.; Zamankhan, P.; Tung, Y.-C.; Li, R.; Vaughan, B. L.; White, J.; Grotberg, J. B.; Takayama, S. "Combination Fluid and Solid Mechanical Stresses Contribute to Cell Death and Detachment in a Microfluidic Alveolar Model" Lab Chip 2011 11, 609-619.
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This paper describes the importance of mechanical stretch and fluid mechanical stresses in lung injury. In diseased lungs, edematous liquid can fill the airways and impart injurious shear and pressure on alveolar cells; we developed a device to investigate the under-studied contribution of these stresses to alveolar cell death and delamitation.

Mosadegh, B.; Tavana, H.; Lesher-Perez, S.C.; Takayama, S. "Patterned deactivation of oxidized polydimethylsiloxane surface for high-density fabrication of normally-closed microfluidic valves" Lab Chip 2011, 11, 734-742. DOI: 10.1142/S0219519410003617.
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Plasma oxidation of PDMS is ubiquitous in microfluidic research. Plasma-induced changes in surface chemistry can be reversed in a spatially-controlled manner by microcontact printing with a second PDMS stamp. Applications in valving and "open microfluidics" are demonstrated.

Tung, Y.-C.; Hsiao, A.Y.; Allen, S.; Torisawa, Y.; Ho, M.; Takayama, S. "High-throughput spheroid formation, culture, and anti-cancer drug testing using a 384 hanging drop array." Analyst 2011, 136, 473-478. DOI:10.1039/C0AN00609B.
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This paper describes a 384-well format hanging drop cell culture plate that allows for 3D spheroid formation and culture using existing high-throughput screening instruments. Using this platform, we demonstrated anti-cancer drug testing and found differential response of cells cultured in 2D versus 3D for drugs with different modes of action. This user-friendly 3D culture plate provides a simple way to obtain biological insights that are often lost in 2D monolayer cultures.