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Cells in a pinch

Figure

Researchers at the University of California, Los Angeles have developed a method to rapidly quantify the mechanical properties of single cells at high resolution using hydrodynamic and inertial fluid focusing. 

Cells undergo structural changes during disease states, particularly in certain cancer cell lines. For example, tumor cells with increased invasive potential exhibit increased deformability, which aids them during their migration into surrounding tissues1. Measuring the mechanical properties of single cells as a biomarker of cell health using conventional Atomic Force Microscopy (AFM) or micropipette aspiration is time-consuming and requires extensive sample prep, limiting the analysis to a few cells. Dino Di Carlo’s group and collaborators developed a way to apply fluids to stretch single cells along two axes using hydrodynamic flow and perpendicular cross-flows without waiting for cells to stop within the channel. This method, termed ‘hydropipetting’, is compatible with inline microfluidic rinsing, capable of processing 65000 cells/sec, and utilizes automatic image processing to rapidly derive the mechanical phenotype of cell populations. 

Hydropipetting starts with inertial fluid focusing of cells to position them precisely in a flow channel by balancing lift forces and secondary flows by fine control over the Reynolds number of the fluid. Cell-free liquid is then excluded and cells are deformed both parallel and perpendicular to the main channel flow. Automated image data analysis then extracts metrics of cell strain, viscosity, diameter and deformability from high speed observation during cell deformation. 

Di Carlo and his group demonstrated the hydropipetting technique on two cancer cell lines (HeLa and Jurkat cells) and observed increases in cell deformability upon drug treatment to increase invasiveness, metastatic potential, and when disrupting structural cellular filaments. 

References:
[1] S. E. Cross, Y. Jin, J. Rao and J. K. Gimzewski, Nature Nanotechnology, 2007, 2, 780-783. 

Pinched-flow hydrodynamic stretching of single-cells
Jaideep S. Dudani, Daniel R. Gossett, Henry T. K. Tse and Dino Di Carlo. Lab Chip, 2013, 13, 3728-3734.
DOI: 10.1039/C3LC50649E

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Simplifying Microfluidic Flow Control

New research shows that it is possible to carry out flow switching in microfluidic devices via a single active hardware element: a tunable frequency periodic pressure source.

A common hindrance to the design of microfluidic systems is the large amount of unwieldy and expensive hardware (valves, actuators, etc.) required to control fluid flow rates in different parts of the chip. A team of engineers and chemists from UC Santa Barbara, the University of Virginia, and the University of Southampton has devised a method to address this problem. In the new method, a single variable-frequency pressure source communicates with the microfluidic chip via tubes connected to deformable films (“capacitors”) on the chip. The length of each tube is chosen such that the tubes will have well-separated resonance frequencies. Then, the frequency of the actuator is tuned to drive fluid flow in the desired channel only.

As demonstrated in their recent paper, the authors produced three separate devices with clearly differentiated excitation frequencies (see figure below). In addition, they demonstrated a single device with two separate flow channels that could be switched between by modulation of the driving frequency.

Fluid flow in the chip (left, from Figure 1E) is controlled by a periodic pressure source connected to a deformable film by a tube. By using tubes of different lengths, one can selectively drive fluid flow in a channel by tuning the pressure source to that channel’s resonant frequency (right, from Figure 2A).

Fluid flow in the chip (left, from Figure 1E) is controlled by a periodic pressure source connected to a deformable film by a tube. By using tubes of different lengths, one can selectively drive fluid flow in a channel by tuning the pressure source to that channel’s resonant frequency (right, from Figure 2A).

The authors state that by utilizing a large range of excitation frequencies it should be possible to independently control up to 10 flow channels on a single chip using their technique. They also project that it should be possible to control multiple channels simultaneously by employing an excitation signal incorporating multiple frequencies. Thus, this new flow control technique has the potential to be an elegant and low-cost solution for many types of diagnostic applications.

Read this article in Lab on a Chip today:

Flow switching in microfluidic networks using passive features and frequency tuning
Rachel R. Collino, Neil Reilly-Shapiro, Bryant Foresman, Kerui Xu, Marcel Utz, James P. Landers, and Matthew R. Begley
DOI: 10.1039/c3lc50481f

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Reprogrammable microfluidic chips

A microfluidic chip with channels that can be programmed then reset and reconfigured has been developed by scientists from France and Japan.

Water is dispensed into chip reservoirs. By selectively switching on electrodes, water is manipulated to carve out the channels

Water is dispensed into chip reservoirs. By selectively switching on electrodes, water is manipulated to carve out the channels

In recent years, scientists from across of the globe have developed a plethora of microfluidic chips to perform a variety of tasks, from PCR to cell sorting. However, a serious drawback of microfluidic technologies is that each application requires a unique arrangement of inlets, outlets and microchannels, so microfluidic chips are usually specific to one particular purpose. This, combined with the time-consuming and costly manufacturing processes required to construct microfluidic devices, makes the idea of a reprogrammable chip very attractive.

Read the full article here at Chemistry World.

Programmable and reconfigurable microfluidic chip
Raphaël Renaudot, et al.
Lab Chip, 2013, Accepted Manuscript
DOI: 10.1039/C3LC50850A, Paper

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Free to access HOT articles!

These HOT articles have been recommended by our referees and are free to access for 4 weeks*

Multiplexed single molecule immunoassays
David M. Rissin, Cheuk W. Kan, Linan Song, Andrew J. Rivnak, Matthew W. Fishburn, Qichao Shao, Tomasz Piech, Evan P. Ferrell, Raymond E. Meyer, Todd G. Campbell, David R. Fournier and David C. Duffy  
DOI: 10.1039/C3LC50416F

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Rapid fabrication of pressure-driven open-channel microfluidic devices in omniphobic RF paper
Ana C. Glavan, Ramses V. Martinez, E. Jane Maxwell, Anand Bala Subramaniam, Rui M. D. Nunes, Siowling Soh and George M. Whitesides  
DOI: 10.1039/C3LC50371B

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A simple three-dimensional-focusing, continuous-flow mixer for the study of fast protein dynamics
Kelly S. Burke, Dzmitry Parul, Michael J. Reddish and R. Brian Dyer
DOI: 10.1039/C3LC50497B

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Assessment of pathogenic bacteria using periodic actuation
Sorin David, Cristina Polonschii, Mihaela Gheorghiu, Dumitru Bratu, Alin Dobre and Eugen Gheorghiu  
DOI: 10.1039/C3LC50411E

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Microfluidic heart on a chip for higher throughput pharmacological studies
Ashutosh Agarwal, Josue Adrian Goss, Alexander Cho, Megan Laura McCain and Kevin Kit Parker 
DOI: 10.1039/C3LC50350J

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Low-cost fabrication of centimetre-scale periodic arrays of single plasmid DNA molecules
Brett Kirkland, Zhibin Wang, Peipei Zhang, Shin-ichiro Takebayashi, Steven Lenhert, David M. Gilbert and Jingjiao Guan   
DOI: 10.1039/C3LC50562F

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A novel microfluidic technology for the preparation of gas-in-oil-in-water emulsions
Lu Yang, Kai Wang, Sy Mak, Yankai Li and Guangsheng Luo  
DOI: 10.1039/C3LC50652E

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A microfluidic approach for protein structure determination at room temperature via on-chip anomalous diffraction
Sarah L. Perry, Sudipto Guha, Ashtamurthy S. Pawate, Amrit Bhaskarla, Vinayak Agarwal, Satish K. Nair and Paul J. A. Kenis
DOI: 10.1039/C3LC50276G

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Steam-on-a-chip for oil recovery: the role of alkaline additives in steam assisted gravity drainage
Thomas W. de Haas, Hossein Fadaei, Uriel Guerrero and David Sinton  
DOI: 10.1039/C3LC50612F

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Out of the cleanroom, self-assembled magnetic artificial cilia
Ye Wang, Yang Gao, Hans Wyss, Patrick Anderson and Jaap den Toonder 
DOI: 10.1039/C3LC50458A

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Flow switching in microfluidic networks using passive features and frequency tuning
Rachel R. Collino, Neil Reilly-Shapiro, Bryant Foresman, Kerui Xu, Marcel Utz, James P. Landers and Matthew R. Begley  
DOI: 10.1039/C3LC50481F

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Single vesicle biochips for ultra-miniaturized nanoscale fluidics and single molecule bioscience
Andreas L. Christensen, Christina Lohr, Sune M. Christensen and Dimitrios Stamou  
DOI: 10.1039/C3LC50492A

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Pinched-flow hydrodynamic stretching of single-cells
Jaideep S. Dudani, Daniel R. Gossett, Henry T. K. Tse and Dino Di Carlo  
DOI: 10.1039/C3LC50649E

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An acoustofluidic micromixer based on oscillating sidewall sharp-edges
Po-Hsun Huang, Yuliang Xie, Daniel Ahmed, Joseph Rufo, Nitesh Nama, Yuchao Chen, Chung Yu Chan and Tony Jun Huang  
DOI: 10.1039/C3LC50568E

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Thermal migration of molecular lipid films as a contactless fabrication strategy for lipid nanotube networks
Irep Gözen, Mehrnaz Shaali, Alar Ainla, Bahanur Örtmen, Inga Põldsalu, Kiryl Kustanovich, Gavin D. M. Jeffries, Zoran Konkoli, Paul Dommersnes and Aldo Jesorka  
DOI: 10.1039/C3LC50391G

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On-chip microbial culture for the specific detection of very low levels of bacteria
Sihem Bouguelia, Yoann Roupioz, Sami Slimani, Laure Mondani, Maria G. Casabona, Claire Durmort, Thierry Vernet, Roberto Calemczuk and Thierry Livache
DOI: 10.1039/C3LC50473E

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Gas/liquid sensing via chemotaxis of Euglena cells confined in an isolated micro-aquarium
Kazunari Ozasa, Jeesoo Lee, Simon Song, Masahiko Hara and Mizuo Maeda
DOI: 10.1039/C3LC50696G

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Smart-phone based computational microscopy using multi-frame contact imaging on a fiber-optic array
Isa Navruz, Ahmet F. Coskun, Justin Wong, Saqib Mohammad, Derek Tseng, Richie Nagi, Stephen Phillips and Aydogan Ozcan
DOI: 10.1039/C3LC50589H

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Protein–DNA force assay in a microfluidic format
Marcus Otten, Philip Wolf and Hermann E. Gaub  
DOI: 10.1039/C3LC50830G

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Ultrasensitive microfluidic solid-phase ELISA using an actuatable microwell-patterned PDMS chip
Tanyu Wang, Mohan Zhang, Dakota D. Dreher and Yong Zeng  
DOI: 10.1039/C3LC50783A

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Detection of real-time dynamics of drug–target interactions by ultralong nanowalls
Andreas Menzel, Raphael J. Gübeli, Firat Güder, Wilfried Weber and Margit Zacharias  
DOI: 10.1039/C3LC50694K

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Capillarics: pre-programmed, self-powered microfluidic circuits built from capillary elements
Roozbeh Safavieh and David Juncker  
DOI: 10.1039/C3LC50691F

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A portable explosive detector based on fluorescence quenching of pyrene deposited on coloured wax-printed μPADs
Regina Verena Taudte, Alison Beavis, Linzi Wilson-Wilde, Claude Roux, Philip Doble and Lucas Blanes  
DOI: 10.1039/C3LC50609F

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Electrokinetic tweezing: three-dimensional manipulation of microparticles by real-time imaging and flow control
Zachary Cummins, Roland Probst and Benjamin Shapiro
DOI: 10.1039/C3LC50674F

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Albumin testing in urine using a smart-phone
Ahmet F. Coskun, Richie Nagi, Kayvon Sadeghi, Stephen Phillips and Aydogan Ozcan 
DOI: 10.1039/C3LC50785H

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Look Mum, no pumps!

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Richard Crooks and colleagues, researchers at the University of Texas, Austin developed a way to locally concentrate and move analytes using internal bipolar electrodes (bypassing the need for an outside driver of fluid flow). Electrodes printed on the bottom of the microfluidic channels create controllable gates which balance the convective and electrokinetic forces acting on charged sample molecules. A single DC power supply and controller box is needed to open/close these gates to deliver analytes to different regions of the chip.­­

Crooks and his group have extensively investigated bipolar electrochemistry theory and in this paper demonstrate the use of bipolar electrodes to separate, enrich, and transport ­­­­­bands of analytes in microfluidic channels. Electric potentials applied across a channel induce an electric field within the buffer whilst conductive substrates present on the floor of the microchannel also adopt a potential between their two poles. H+ ions within the buffer are partially neutralized by electrogenerated OH- and thus regions of ion depletion appear. These depletion zones attract charged analytes from the solution to maintain the charge gradient induced by the electric field (the speed of electromigration of analytes to the depletion zone is proportional to the electric field). Bipolar electrodes on the channel bottom contain their own local field and so analytes concentrate in these areas, leading to enrichment near the electrodes.

In this work, Crooks and his team demonstrate separation and enrichment of two common fluorescent dyes:  BODIPY2- and MPTS3-. The two dye bands are then directed to two separate reservoirs. In previous papers, the group focused on optimizing enrichment and achieved enrichment rates of up to 0.57 BODIPY2 1, . The current extension and integration of online separation and enrichment achieves comparable rates of enrichment, 0.11 and 0.31 fold/second for BODIPY and MPTS, respectively, while also enabling control over separating analytes of different electromobility (μep) and transporting these bands to designated areas of the device.

To create the devices presented, the group used conventional photolithography techniques to pattern gold bipolar passive electrodes (BPEs) on glass and bonded PDMS channels on top of the regions. This method can be easily multiplexed as additional BPEs can be activated to guide separated and enriched analytes to different areas of the chip.

 References:

1 R. K. Anand, E. Sheridan, D. Hlushkou, U. Tallarek and R. M. Crooks, Lab on a Chip, 2011, 11, 518-527.

Electrochemically-gated delivery of analyte bands in microfluidic devices using bipolar electrodes
Karen Scida, Eoin Sheridan and Richard M. Crooks, Lab Chip, 2013, 13, 2292-2299.
DOI: 10.1039/c3lc50321f

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Engineering the ‘microHuman’

Research based on the use of organs-on-chips is rapidly expanding and developing. These microengineered devices are microfluidic physiological models of tissues and organs. All sorts of organs-on-chips have been reported, including lung-on-a-chip, heart-on-a-chip and even blood-brain barrier-on-a-chip. See http://dx.doi.org/10.1039/C2LC40089H for a Frontier article by Ingber et. al., which focuses on advances in these microengineered organs.

The models have great potential in the field of pharmacology and toxicology, where they can be used to chart the effects of candidate drugs. But what if we could connect all these organs-on-chips together, and create an actual ‘human-on-a-chip’? Could such a model be used to replace the popular animal models? Could we soon be testing our drug candidates not on mouse or rat, but on the microHuman?

What would a microHuman look like? The answer is tiny. It would be a million times lighter than a regular human, giving it a mass of merely 70 mg. At such an incredible size, would the microHuman be functional, like you or I?

In a Critical Review by John Wikswo and colleagues (http://dx.doi.org/10.1039/C3LC50243K), the scaling requirements of a microHuman are discussed. It is concluded that a simple scaling system is not enough; a microhuman would be completely dysfunctional if we applied basic scaling laws to it. For example, its breathing rate would be approximately 10 breaths per second. In addition, its capillaries would be so small that any naturally-occurring blood cell would be too large to traverse them.

In response to these barriers, Wikswo and colleagues provide detailed discussion of scaling in a number of organ systems in the microHuman. Additionally, they give an overview of structural and functional parameters to guide the scaling of organs-on-chips in a microHuman, which are based upon human and animal data.

Interestingly, whilst the potential of a microengineered human-on-a-chip is huge, Wikswo et. al. point out that, like any model system, the microHuman will never be perfect: “It is important to realize that [these] systems reside in a niche of abstraction that will improve constantly with technology but will never exactly recreate a full human, which represents approx. 109 years of evolutionary engineering”.

Organs-on-chips, and their potential for the development into humans-on-chips, are currently an incredibly hot topic area. If you want to find out more, in addition to Wikswo’s excellent review you can read more about this exciting field in a paper by Shuichi Takayama and colleagues, published recently in the RSC Journal Integrative Biology (http://dx.doi.org/10.1039/C3IB40040A).

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New YouTube videos

View the new videos on the Lab on a Chip YouTube site using the links below:

 

Aqueous two-phase microdroplets with reversible phase transitions

 

Passive Droplet Sorting using Viscoelastic Flow Focusing 

 

Formation of polymersomes with double bilayers templated by quadruple emulsions

 

A doubly cross-linked nano-adhesive for the reliable sealing of flexible microfluidic devices

 

Ultrafast cell switching for recording cell surface transitions: new insights into epidermal growth factor receptor signalling

Flow-switching allows independently programmable, extremely stable, high-throughput diffusion-based gradients

Highly reproducible chronoamperometric analysis in microdroplets

Disaggregation of microparticle clusters by induced magnetic dipole–dipole repulsion near a surface

Exploring a direct injection method for microfluidic generation of polymer microgels

Droplet morphometry and velocimetry (DMV): a video processing software for time-resolved, label-free tracking of droplet parameters

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Circulating cancer cells spiral towards separation

Repeated biopsies of tumours can be a painful and distressing procedure for cancer patients. A new biochip developed by researchers in Singapore can isolate tumour cells from blood samples, and may one day be an alternative to more invasive methods for tracking later stage cancers. 

Operating principle of circulating tumour cell enrichment by a spiral channel with trapezoid cross-section

Operating principle of circulating tumour cell enrichment by a spiral channel with trapezoid cross-section

Deaths from cancer generally occur after the cancer has spread. Cells detach from the primary tumour and travel through the blood, subsequently forming new tumours. Being able to isolate and characterise these circulating tumour cells (CTCs) can provide information about the original tumour. However, CTCs exist in very low numbers in the blood stream and hence require enrichment and separation before analysis. 

Read the full article in Chemistry World 

Slanted spiral microfluidics for the ultra-fast, label-free isolation of circulating tumor cells
E W Majid et al, Lab Chip, 2013, Accepted manuscript, Paper
DOI: 10.1039/C3LC50617G

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New Youtube videos

View the new videos on the Lab on a Chip YouTube site using the links below:

 

Microfluidic Synthesis of Atto-liter Scale Double Emulsions toward Ultrafine Hollow Silica Spheres with Hierarchical Pore Networks

  

Droplet sorting based on the number of encapsulated particles using a solenoid valve

 

Temperature-driven self-actuated microchamber sealing system for highly integrated microfluidic devices

 

Vector separation of particles and cells using an array of slanted open cavities

A simple route to functionalize polyacrylamide hydrogels for the independent tuning of mechanotransduction cues

Microfluidic chemostat for measuring single cell dynamics in bacteria

Electrostatic charging and control of droplets in microfluidic devices 

Dynamic pH mapping in microfluidic devices by integrating adaptive coatings based on polyaniline with colorimetric imaging techniques

 An integrated microfluidic cell culture system for high-throughput perfusion three-dimensional cell culture-based assays: effect of cell culture model on the results of chemosensitivity assays

Rapid generation and manipulation of microfluidic vortex flows induced by AC electrokinetics with optical illumination

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New YouTube videos

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A phaseguided passive batch microfluidic mixing chamber for isothermal amplification

 

Vacuum-assisted cell loading enables shear-free mammalian microfluidic culture

 

Configuration change of liquid crystal microdroplets coated with a novel polyacrylic acid block liquid crystalline polymer by protein adsorption

 

Formation and optogenetic control of engineered 3D skeletal muscle bioactuators

 

Self-priming compartmentalization digital LAMP for point-of-care

 Reactive deposition of nano-films in deep polymeric microcavities

RhoA mediates flow-induced endothelial sprouting in a 3-D tissue analogue of angiogenesis

Optical microplates for high-throughput screening of photosynthesis in lipid-producing algae

Optoelectronic reconfigurable microchannels

Blood plasma separation in a long two-phase plug flowing through disposable tubing

DropletMicroarray: facile formation of arrays of microdroplets and hydrogel micropads for cell screening applications

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