Archive for ‘Rapid Disease’

Microfluidic Chip Uses Sound to Rapidly Sort Cells

Microfluidic Chip Uses Sound to Rapidly Sort Cells

Microfluidic Chip Uses Sound to Rapidly Sort Cells

UNIVERSITY PARK, Pa. — A technique that uses acoustic waves to sort cells on a chip may create miniature medical analytic devices that could make Star Trek’s tricorder seem a bit bulky in comparison, according to a team of researchers.

The device uses two beams of acoustic — or sound — waves to act as acoustic tweezers and sort a continuous flow of cells on a dime-sized chip, said Tony Jun Huang, associate professor of engineering science and mechanics, Penn State. By changing the frequency of the acoustic waves, researchers can easily alter the paths of the cells.

Huang said that since the device can sort cells into five or more channels, it will allow more cell types to be analyzed simultaneously, which paves the way for smaller, more efficient and less expensive analytic devices.

“Eventually, you could do analysis on a device about the size of a cell phone,” said Huang. “It’s very doable and we’re making in-roads to that right now.”

Biological, genetic and medical labs could use the device for various types of analysis, including blood and genetic testing, Huang said.

Most current cell-sorting devices allow the cells to be sorted into only two channels in one step, according to Huang. He said that another drawback of current cell-sorting devices is that cells must be encapsulated into droplets, which complicates further analysis.

“Today, cell sorting is done on bulky and very expensive devices,” said Huang. “We want to minimize them so they are portable, inexpensive and can be powered by batteries.”

Using sound waves for cell sorting is less likely to damage cells than current techniques, Huang added.

In addition to the inefficiency and the lack of controllability, current methods produce aerosols, gases that require extra safety precautions to handle.

The researchers, who released their findings in the current edition of Lab on a Chip, created the acoustic wave cell-sorting chip using a layer of silicone — polydimethylsiloxane. According to Huang, two parallel transducers, which convert alternating current into acoustic waves, were placed at the sides of the chip. As the acoustic waves interfere with each other, they form pressure nodes on the chip. As cells cross the chip, they are channeled toward these pressure nodes.

The transducers are tunable, which allows researchers to adjust the frequencies and create pressure nodes on the chip.

The researchers first tested the device by sorting a stream of fluorescent polystyrene beads into three channels. Prior to turning on the transducer, the particles flowed across the chip unimpeded. Once the transducer produced the acoustic waves, the particles were separated into the channels.

Following this experiment, the researchers sorted human white blood cells that were affected by leukemia. The leukemia cells were first focused into the main channel and then separated into five channels.

The device is not limited to five channels, according to Huang.

“We can do more,” Huang said. “We could do 10 channels if we want, we just used five because we thought it was impressive enough to show that the concept worked.”

Huang worked with Xiaoyun Ding, graduate student, Sz-Chin Steven Lin, postdoctoral research scholar, Michael Ian Lapsley, graduate student, Xiang Guo, undergraduate student, Chung Yu Keith Chan, doctoral student, Sixing Li, doctoral student, all of the Department of Engineering Science and Mechanics at Penn State; Lin Wang, Ascent BioNano Technologies; and J. Philip McCoy, National Heart, Lung and Blood Institute, National Institutes of Health.

The National Institutes of Health Director’s New Innovator Award, the National Science Foundation, Graduate Research Fellowship and the Penn State Center for Nanoscale Science supported this work.

Researchers from Penn State, Ascent BioNano Technologies, and National Institutes of Health have collaborated to develop a cell sorting device that uses acoustic waves to do its job. Two acoustic wavefronts are used to create pressure nodes on the chip for each individual cell, helping to guide it down one of five channels. More channels could be added to a future version of the device, increasing the variety of cell types that can be analyzed at the same time.

The team believes that the technology can be miniaturized to the point that “could make Star Trek’s tricorder seem a bit bulky in comparison.”

Most current cell-sorting devices allow the cells to be sorted into only two channels in one step, according to Huang. He said that another drawback of current cell-sorting devices is that cells must be encapsulated into droplets, which complicates further analysis.

“Today, cell sorting is done on bulky and very expensive devices,” said Huang. “We want to minimize them so they are portable, inexpensive and can be powered by batteries.”

Using sound waves for cell sorting is less likely to damage cells than current techniques, Huang added.

In addition to the inefficiency and the lack of controllability, current methods produce aerosols, gases that require extra safety precautions to handle.

Source : http://live.psu.edu/story/61681

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Microfluidic Device Rapidly Studies Biochemical Interactions

Microfluidic Device Rapidly Studies Biochemical Interactions

Microfluidic Device Rapidly Studies Biochemical Interactions

Quantitative biology requires quantitative data. No high-throughput technologies exist capable of obtaining several hundred independent kinetic binding measurements in a single experiment. We present an integrated microfluidic device (k-MITOMI) for the simultaneous kinetic characterization of 768 biomolecular interactions. We applied k-MITOMI to the kinetic analysis of transcription factor (TF)—DNA interactions, measuring the detailed kinetic landscapes of the mouse TF Zif268, and the yeast TFs Tye7p, Yox1p, and Tbf1p. We demonstrated the integrated nature of k-MITOMI by expressing, purifying, and characterizing 27 additional yeast transcription factors in parallel on a single device. Overall, we obtained 2,388 association and dissociation curves of 223 unique molecular interactions with equilibrium dissociation constants ranging from 2 × 10-6 M to 2 × 10-9 M, and dissociation rate constants of approximately 6 s-1 to 8.5 × 10-3 s-1. Association rate constants were uniform across 3 TF families, ranging from 3.7 × 106 M-1 s-1 to 9.6 × 107 M-1 s-1, and are well below the diffusion limit. We expect that k-MITOMI will contribute to our quantitative understanding of biological systems and accelerate the development and characterization of engineered systems.

Inside our cells, molecules are constantly binding and separating from one another. It’s this game of constant flux that drives gene expression asides essentially every other biological process.

Understanding the specific details of how these interactions take place is thus crucial to our overall understanding of the fundamental mechanisms of living organisms. There are millions of possible combinations of molecules, however; determining all of them would be a Herculean task. Various tools have been developed to measure the degree of affinity between a strand of DNA and its transcription factor. They provide an indication of the strength of the affinity between them.

“Commercial” devices, however, have one main drawback: many preliminary manipulations are necessary before an experiment can be carried out, and even then, the experiment can only focus on a dozen interactions at a time.

Microns-wide channels

As part of his doctoral research at the California Institute of Technology (Caltech), Sebastian Maerkl designed a device that he named “MITOMI” – a small device containing hundreds of microfluidic channels equipped with pneumatic valves. This week Maerkl, who is now an assistant professor in EPFL’s Bioengineering Institute, is publishing an article describing the next step in the evolution of the device in Proceedings of the National Academy of Sciences (PNAS). The new version, “k-MITOMI,” was developed in the context of the SystemsX.ch RTD DynamiX in cooperation with the University of Geneva.

This microfluidic device has 768 chambers, each one with a valve that allows DNA and transcription factors to interact in a very carefully controlled manner. “In traditional methods, we generally manage to determine if an interaction takes place or not, and then we restart the experiment with another gene or another transcription factor,” Maerkl explains. “Our device goes much further, because it allows us to measure the affinity and kinetics of the interaction.”

The strength of the device lies in a sort of “push-button” in its microreactors. A protein substrate is immobilized on the device; above it circulates a solution containing DNA moelcules. The push-button is activated at regular intervals of a few milliseconds, trapping protein-DNA complexes that form on the surface of the device. “Then we close the lid, and fluorescence reveals the exact number of bound molecules,” explains Maerkl. “We can also observe how long these molecules remain bound.”

In addition to providing quantitative kinetic information, the k-MITOMI device can work in a “massively parallel” manner. Each of the 768 independent chambers can simultaneously analyze different molecule pairs. It can also be used to synthesize proteins in vitro, with a massive reduction in time and number of manipulations compared to the traditional method, which involves producing proteins inside a living organism such as a bacterium, purifying, and putting them in contact with the genes to be studied.

“The number of protein-protein and protein-DNA interactions that remain to be characterized is phenomenal. Our device not only allows us to accelerate the acquisition of this information, which is crucial to our understanding of living organisms, but it also meets a need for the production of specific proteins,” adds Maerkl.

This research has been conducted with support of a SystemsX.ch research, technology and development grant (DynamiX). SystemsX.ch is a Swiss initiative with the goal of stimulating research and education in key sectors of Systems Biology.

A new device developed at California Institute of Technology and Ecole Polytechnique Federale de Lausanne in Switzerland may help research conduct large scale studies of biomolecular interactions at a rapid rate.

Known as k-MITOMI, the current version of the microfluidic device features 768 chambers within which DNA strings and transcription factors that can stick onto them are carefully brought together. While this is happening, the k-MITOMI is able to measure the attraction between the compounds and the kinetics involved.

Some details from Ecole Polytechnique Federale de Lausanne:

This microfluidic device has 768 chambers, each one with a valve that allows DNA and transcription factors to interact in a very carefully controlled manner. “In traditional methods, we generally manage to determine if an interaction takes place or not, and then we restart the experiment with another gene or another transcription factor,” Maerkl explains. “Our device goes much further, because it allows us to measure the affinity and kinetics of the interaction.”

The strength of the device lies in a sort of “push-button” in its microreactors. A protein substrate is immobilized on the device; above it circulates a solution containing DNA moelcules. The push-button is activated at regular intervals of a few milliseconds, trapping protein-DNA complexes that form on the surface of the device. “Then we close the lid, and fluorescence reveals the exact number of bound molecules,” explains Maerkl. “We can also observe how long these molecules remain bound.”

In addition to providing quantitative kinetic information, the k-MITOMI device can work in a “massively parallel” manner. Each of the 768 independent chambers can simultaneously analyze different molecule pairs. It can also be used to synthesize proteins in vitro, with a massive reduction in time and number of manipulations compared to the traditional method, which involves producing proteins inside a living organism such as a bacterium, purifying, and putting them in contact with the genes to be studied.

“The number of protein-protein and protein-DNA interactions that remain to be characterized is phenomenal. Our device not only allows us to accelerate the acquisition of this information, which is crucial to our understanding of living organisms, but it also meets a need for the production of specific proteins,” adds Maerkl.

Source : http://actu.epfl.ch/news/hundreds-of-biochemical-analyses-on-a-single-devic/

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Lab-on-a-Bead Technology for Rapid Disease Detection

Lab-on-a-Bead Technology for Rapid Disease Detection

Lab-on-a-Bead Technology for Rapid Disease Detection

If you throw a ball underwater, you’ll find that the smaller it is, the faster it moves: A larger cross-section greatly increases the water’s resistance. Now, a team of MIT researchers has figured out a way to use this basic principle, on a microscopic scale, to carry out biomedical tests that could eventually lead to fast, compact and versatile medical-testing devices.

The results, based on work by graduate student Elizabeth Rapoport and assistant professor Geoffrey Beach, of MIT’s Department of Materials Science and Engineering (DMSE), are described in a paper published in the journal Lab on a Chip. MIT graduate student Daniel Montana ’11 also contributed to the research as an undergraduate.

The balls used here are microscopic magnetic beads that can be “decorated” with biomolecules such as antibodies that cause them to bind to specific proteins or cells; such beads are widely used in biomedical research. The key to this new work was finding a way to capture individual beads and set them oscillating by applying a variable magnetic field. The rate of their oscillation can then be measured to assess the size of the beads.

When these beads are placed in a biological sample, biomolecules attach to their surfaces, making the beads larger — a change that can then be detected through the biomolecules effect on the beads’ oscillation. This would provide a way to detect exactly how much of a target biomolecule is present in a sample, and provide a way to give a virtually instantaneous electronic readout of that information.

This new technique, for the first time, allows these beads — each about one micrometer, or millionth of a meter, in diameter — to be used for precise measurements of tiny quantities of materials. This could, for example, lead to tests for disease agents that would need just a tiny droplet of blood and could deliver results instantly, instead of requiring laboratory analysis.

In a paper published earlier this year in the journal Applied Physics Letters, the same MIT researchers described their development of a technique for creating magnetic tracks on a microchip surface, and rapidly transporting beads along those tracks. (The technology required is similar to that used to read and write magnetic data on a computer’s hard disk.) An operational device using this new approach would consist of a small reservoir above the tracks, where the liquid containing the magnetic beads and the biological sample would be placed.

Rather than pumping the fluid and the particles through channels, as in today’s microfluidic devices, the particles would be controlled entirely through changes in applied magnetic fields. By controlling the directions of magnetic fields in closely spaced adjacent regions, the researchers create tiny areas with extremely strong magnetic fields, called magnetic domain walls, whose position can be shifted along the track. “We can use the magnetic domain walls to capture and transport the beads along the tracks,” Beach says.

In the researchers’ most recent paper, Rapoport explains, they have now shown that once a bead is captured, a magnetic field can be used to shake it back and forth. Then, the researchers measure how fast the bead moves as they change the frequency of the oscillation. “The resonant frequency is a function of the bead size,” she says — and could be used to reveal whether the bead has grown in size through attachment to a target biomolecule.

Besides being potentially quicker and requiring a far smaller biological sample to produce a result, such a device would be more flexible than existing chip-based biomedical tests, the researchers say. While most such devices are specifically designed to detect one particular kind of protein or disease agent, this new device could be used for a wide variety of different tests, simply by inserting a fresh batch of fluid containing beads coated with the appropriate reactant. After the test, the material could be flushed out, and the same chip used for a completely different test by inserting a different type of magnetic beads. “You’d just use it, wash it off, and use it again,” Rapoport says.

There are dozens of types of magnetic beads commercially available now, which can be coated to react with many different biological materials, Beach explains, so such a test device could have enormous flexibility.

The MIT team has not yet used the system to detect biological molecules. Rather, they used magnetic beads of different sizes to demonstrate that their system is capable of detecting size differences corresponding to those between particles that are bound to biological molecules and those that are not. Having succeeded in this proof of concept, the researchers’ next step will be to repeat the experiment using biological samples.

“We now have all the elements required to make a sensing device,” Beach says. The next step is to combine the pieces in an operational device and demonstrate its performance.

R. Sooryakumar, a professor of physics at Ohio State University who was not involved in this research, calls this an “innovative approach.”

“It is very interesting how the researchers combine technologies that are well understood for applications in computing and data storage, and apply them to something completely different,” Sooryakumar says. He adds, “These magnetic devices are potentially valuable tools that could go well beyond how one may normally expect them to be used. The ramifications, for example in food safety and health care, such as pathogen or cancer detection, are indeed exciting.”

An integrated platform for the capture, transport, and detection of individual superparamagnetic microbeads is described for lab-on-a-chip biomedical applications. Magnetic domain walls in magnetic tracks have previously been shown to be capable of capturing and transporting individual beads through a fluid at high speeds. Here it is shown that the strong magnetostatic interaction between a bead and a domain wall leads to a distinct magneto-mechanical resonance that reflects the susceptibility and hydrodynamic size of the trapped bead. Numerical and analytical modeling is used to quantitatively explain this resonance, and the magneto-mechanical resonant response under sinusoidal drive is experimentally characterized both optically and electrically. The observed bead resonance presents a new mechanism for microbead sensing and metrology. The dual functionality of domain walls as both bead carriers and sensors is a promising platform for the development of lab-on-a-bead technologies.

Researchers at MIT have developed a new way to measure the mass of individual particles using tiny superparamagnetic beads, a technology that will hopefully lead to cheap and portable point-of-care diagnostic devices. The trick relies on using an oscillating magnetic field to make individual beads resonate . The frequency of the field that makes a bead resonate the most is proportional to the mass of the bead.

The team used magnetic walls within magnetic tracks to resonate the beads. By attaching antibodies to the beads that attract specific pathogens, they can measure the difference between the resonant frequency of the bead with and without the new particle and therefore derive its mass.

From MIT’s news room:

An operational device using this new approach would consist of a small reservoir above the tracks, where the liquid containing the magnetic beads and the biological sample would be placed.

Rather than pumping the fluid and the particles through channels, as in today’s microfluidic devices, the particles would be controlled entirely through changes in applied magnetic fields. By controlling the directions of magnetic fields in closely spaced adjacent regions, the researchers create tiny areas with extremely strong magnetic fields, called magnetic domain walls, whose position can be shifted along the track.

Besides being potentially quicker and requiring a far smaller biological sample to produce a result, such a device would be more flexible than existing chip-based biomedical tests, the researchers say. While most such devices are specifically designed to detect one particular kind of protein or disease agent, this new device could be used for a wide variety of different tests, simply by inserting a fresh batch of fluid containing beads coated with the appropriate reactant. After the test, the material could be flushed out, and the same chip used for a completely different test by inserting a different type of magnetic beads.

Source : http://web.mit.edu/newsoffice/2012/magnetic-beads-lab-on-a-chip-0925.html

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