Watching fluid flow at nanometer scales | MIT News

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Imicrofluidics_03magine if you could drink a glass of water just by inserting a solid wire into it and sucking on it as though it were a soda straw. It turns out that if you were tiny enough, that method would work just fine — and wouldn’t even require the suction to start.

New research carried out at MIT and elsewhere has demonstrated for the first time that when inserted into a pool of liquid, nanowires — wires that are only hundreds of nanometers (billionths of a meter) across — naturally draw the liquid upward in a thin film that coats the surface of the wire. The finding could have applications in microfluidic devices, biomedical research and inkjet printers.

The phenomenon had been predicted by theorists, but never observed because the process is too small to be seen by optical microscopes; electron microscopes need to operate in a vacuum, which would cause most liquids to evaporate almost instantly. To overcome this, the MIT team used an ionic liquid called DMPI-TFSI, which remains stable even in a powerful vacuum. Though the observations used this specific liquid, the results are believed to apply to most liquids, including water.

The results are published in the journal Nature Nanotechnology by a team of researchers led by Ju Li, an MIT professor of nuclear science and engineering and materials science and engineering, along with researchers at Sandia National Laboratories in New Mexico, the University of Pennsylvania, the University of Pittsburgh, and Zhejiang University in China.

While Li says this research intended to explore the basic science of liquid-solid interactions, it could lead to applications in inkjet printing, or for making a lab on a chip. “We’re really looking at fluid flow at an unprecedented small length scale,” Li says — so unexpected new phenomena could emerge as the research continues.

At molecular scale, Li says, “the liquid tries to cover the solid surface, and it gets sucked up by capillary action.” At the smallest scales, when the liquid forms a film less than 10 nanometers thick, it moves as a smooth layer (called a “precursor film”); as the film gets thicker, an instability (called a Rayleigh instability) sets in, causing droplets to form, but the droplets remain connected via the precursor film. In some cases, these droplets continue to move up the nanowire, while in other cases the droplets appear stationary even as the liquid within them flows upward.

The difference between the smooth precursor film and the beads, Li says, is that in the thinner film, each molecule of liquid is close enough to directly interact, through quantum-mechanical effects, with the molecules of the solid buried beneath it; this force suppresses the Rayleigh instability that would otherwise cause beading. But with or without beading, the upward flow of the liquid, defying the pull of gravity, is a continuous process that could be harnessed for small-scale liquid transport.

Although this upward pull is always present with wires at this tiny scale, the effect can be further enhanced in various ways: Adding an electric voltage on the wire increases the force, as does a slight change in the profile of the wire so that it tapers toward one end. The researchers used nanowires made of different materials — silicon, zinc oxide and tin oxide, as well as two-dimensional graphene — to demonstrate that this process applies to many different materials.

Nanowires are less than one-tenth the diameter of fluidic devices now used in biological and medical research, such as micropipettes, and one-thousandth the diameter of hypodermic needles. At these small scales, the researchers found, a solid nanowire is just as effective at holding and transferring liquids as a hollow tube. This smaller scale might pave the way for new kinds of microelectromechanical systems to carry out research on materials at a molecular level.

The methodology the researchers developed allows them to study the interactions between solids and liquid flow “at almost the smallest scale you could define a fluid volume, which is 5 to 10 nanometers across,” Li says. The team now plans to examine the behavior of different liquids, using a “sandwich” of transparent solid membranes to enclose a liquid, such as water, for examination in a transmission electron microscope. This will allow “more systematic studies of solid-liquid interactions,” Li says — interactions that are relevant to corrosion, electrodeposition and the operation of batteries.

Erich Stach, head of the Electron Microscopy Group at Brookhaven National Laboratory in New York, says, “The dynamic observations from Huang and colleagues provide fascinating insight into the mechanisms of fluid flow at the deep nanoscale, and demonstrate that it is possible to deliver controlled volumes of liquid for novel applications in nanotechnology.”

The research was supported by Sandia National Laboratories, the U.S. Department of Energy, and the National Science Foundation.


‘Micro-ants’: Tiny conveyor belts for the 21st century | MIT News

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micro-antsA new microscopic system devised by researchers in MIT’s Department of Materials Science and Engineering could provide a novel method for moving tiny objects inside a microfluidic chip, and could also provide new insights into how cells and other objects are transported within the body.

Inside organs such as the trachea and the intestines, tiny hair-like filaments called cilia are constantly in motion, beating in unison to create currents that sweep along cells, nutrients, or other tiny particles. The new research uses a self-assembling system to mimic that kind of motion, providing a simple way to move particles around in a precisely controlled way.

Alfredo Alexander-Katz, the Merton C. Flemings Assistant Professor of Materials Science and Engineering, his doctoral student Charles Sing, and researchers at Boston University and in Germany, devised a system that uses so-called superparamagnetic beads — tiny beads made of polymers with specks of magnetic material in them — suspended in liquid.

Due to the heavy magnetic material content, these beads sink to the bottom of the liquid. They placed the whole system inside two pairs of magnetic coils and used them to apply a rotating magnetic field, which caused the beads to spontaneously form short chains that began spinning. This motion created currents that could then carry along surrounding particles — even particles as much as 100 times larger than the beads themselves.

Alexander-Katz refers to the microscopic assembly of beads — each just a few microns (millionths of a meter) in size — as “micro-ants,” because of their ability to move along while “carrying” objects so much larger than themselves. A paper describing the research will appear the week of Dec. 14 in the Proceedings of the National Academy of Sciences.

He says the way the chains of beads moved is a bit like a person trying to do cartwheels while standing on an icy surface. “As they rotate, they slip a bit,” he says, “but overall, they keep moving,” and this imparts a directional flow to the surrounding fluid.

The new method could provide a simpler, less-expensive alternative to present microfluidic devices, a technology involving the precise control of tiny amounts of liquids flowing through microscopic channels on a chip in order to carry out chemical or biological analysis of tiny samples. Now, such devices require precisely made channels, valves and pumps created on a silicon chip using microchip manufacturing methods, in order to control the movement of fluids through them. But the new system could offer such precise control over the movement of liquids and the particles suspended in them that it may be possible to dispense with the channels and other plumbing altogether, controlling the movements entirely through variations in the applied magnetic field.

In short, software rather than hardware could control the chip’s properties, allowing it to be instantly reconfigured through changes in the controlling software — an approach Alexander-Katz refers to as “virtual microfluidics.” This could reduce the cost and increase the flexibility of the devices, which might be used for such things as biomedical screening, or the detection of trace elements for pollution monitoring or security screening. It might also provide even finer spatial control than can presently be achieved using conventional channels on chips.

Alexander-Katz says the work might also help scientists better understand the way cilia work, by providing a way to mimic their activity in the lab. “People are still trying to understand how you get hydrodynamic synchronization in the systems” of cilia in organisms — that is, having the individual cilia all working together in a pattern of motion that controls the flow of fluid over them. “This might be a way to test many of the theories.”

David Weitz, a physicist at Harvard University who studies colloidal physics and biological systems, says that “The work is a beautiful example of the use of colloidal particles to mimic the behavior of cilia, which are used by cells for propulsion.” The use of the beads in a magnetic field “actually causes the chains to move, and induces flow in the fluid. This effect is difficult to achieve by any means, and the method reported here is an elegant and simple means of accomplishing this.”

Weitz adds that in terms of applications, “The main utility of these observations is likely to be the understanding of the fundamental properties of these [cilia] structures. They could conceivably ultimately find use as miniature fluid pumps.” He adds that Alexander-Katz “is likely to have considerable impact with work like this.”

Such a system might someday even be developed to use in medical diagnostics, by allowing controlled delivery of particles inside the body to specifically targeted locations, for example while the patient is in a nuclear magnetic resonance (NMR) imaging system.

Although medical applications might take many years to develop because of the stringent requirements for safety testing, Alexander-Katz says, applications to creating a new kind of microfluidics chips could be achieved “within a year or so.” This would essentially just be a matter of scaling up from the simple, basic systems that were tested in this study to more complex assemblies.

Moving microfluidics from the lab bench to the factory floor | MIT News

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microfluidics_02As the United States seeks to reinvigorate its job market and move past economic recession, MIT News examines manufacturing’s role in the country’s economic future through this series on work at the Institute around manufacturing.

In the not-too-distant future, plastic chips the size of flash cards may quickly and accurately diagnose diseases such as AIDS and cancer, as well as detect toxins and pathogens in the environment. Such lab-on-a-chip technology — known as microfluidics — works by flowing fluid such as blood through microscopic channels etched into a polymer’s surface. Scientists have devised ways to manipulate the flow at micro- and nanoscales to detect certain molecules or markers that signal disease.

Microfluidic devices have the potential to be fast, cheap and portable diagnostic tools. But for the most part, the technology hasn’t yet made it to the marketplace. While scientists have made successful prototypes in the laboratory, microfluidic devices — particularly for clinical use — have yet to be manufactured on a wider scale.

MIT’s David Hardt is working to move microfluidics from the lab to the factory. Hardt heads the Center for Polymer Microfabrication — a multidisciplinary research group funded by the Singapore-MIT Alliance — which is designing manufacturing processes for microfluidics from the ground up. The group is analyzing the behavior of polymers under factory conditions, building new tools and machines to make polymer-based chips at production levels, and designing quality-control processes to check a chip’s integrity at submicron scales — all while minimizing the cost of manufacturing.

“These are devices that people want to make by the millions, for a few pennies each,” says Hardt, the Ralph E. and Eloise F. Cross Professor of Mechanical Engineering at MIT. “The material cost is close to zero, there’s not enough plastic here to send a bill for. So you have to get the manufacturing cost down.”


Hardt and his colleagues found that in making microfluidic chips, many research groups and startups have adopted equipment mainly from the semiconductor industry. Hardt says this equipment — such as nano-indenting and bonding machines — is incredibly expensive, and was never designed to work on polymer-based materials. Instead, Hardt’s team looked for ways to design cheaper equipment that’s better suited to work with polymers.

The group focused on an imprinting technique called microembossing, in which a polymer is heated, then stamped with a pattern of tiny channels. In experiments with existing machines, the researchers discovered a flaw in the embossing process: When they tried to disengage the stamping tool from the cooled chip, much of the plastic ripped out with it.

To prevent embossing failures in a manufacturing setting, the team studied the interactions between the cooling polymer and the embossing tool, measuring the mechanical forces between the two. The researchers then used the measurements to build embossing machines specifically designed to minimize polymer “stickiness.” In experiments, the group found that the machines fabricated chips quickly and accurately, “at very low cost,” Hardt says. “In many cases it makes sense to build your own equipment for the task at hand,” he adds.

In addition to building microfluidic equipment, Hardt and his team are coming up with innovative quality-control techniques. Unlike automobile parts on an assembly line that can be quickly inspected with the naked eye, microfluidic chips carry tiny features, some of which can only be seen with a high-resolution microscope. Checking every feature on even one chip is a time-intensive exercise.

Hardt and his colleagues came up with a fast and reliable way to gauge the “health” of a chip’s production process. Instead of checking whether every channel on a chip has been embossed, the group added an extra feature — a tiny X — to the chip pattern. They designed the feature to be more difficult to emboss than the rest of the chip. Hardt says how sharply the X is stamped is a good indication of whether the rest of the chip has been rendered accurately.

Jumpstarting an industry

The group’s ultimate goal is to change how manufacturing is done. Typically, an industry builds up its production processes gradually, making adjustments and improvements over time. Hardt says the semiconductor industry is a prime example of manufacturing’s iterative process.

“Now what they do in manufacturing is impossibly difficult, but it’s been a series of small incremental improvements over years,” Hardt says. “We’re trying to jumpstart that and not wait until industry identifies all these problems when they’re trying to make a product.”

The group is now investigating ways to design a “self-correcting factory” in which products are automatically tested. If the product doesn’t work, Hardt envisions the manufacturing process changing in response, adjusting settings on machines to correct the process. For example, the team is looking for ways to evaluate how fluid flows through a manufactured chip. The point at which two fluids mix within a chip should be exactly the same in every chip produced. If that mixing point drifts from chip to chip, Hardt and his colleagues have developed algorithms that adjust equipment to correct the drift.

Holger Becker, co-founder of Microfluidic ChipShop, a lab-on-a-chip production company in Jena, Germany, says the center’s research plays an important role in understanding the different processes involved in large-scale production of microfluidics.

“Most of the academic work in microfluidics concentrates on applications, and unfortunately only very few concentrate on the actual manufacturing technologies suited for industrialization,” Becker says. “David Hardt’s team takes a very holistic approach looking into all different process steps and the complete manufacturing process instead of individual technologies.”

“We’re at the stage where we’d like industry to know what we’re doing,” Hardt says. “We’ve been sort of laboring in the vineyard for years, and now we have this base, and it could get to the point where we’re ahead of the group.”


Tiny tools help advance medical discoveries | MIT News

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microfluidicsWith the recent launch of MIT’s Institute for Medical Engineering and Science, MIT News examines research with the potential to reshape medicine and health care through new scientific knowledge, novel treatments and products, better management of medical data, and improvements in health-care delivery.

To understand the progression of complex diseases such as cancer, scientists have had to tease out the interactions between cells at progressively finer scales — from the behavior of a single tumor cell in the body on down to the activity of that cell’s inner machinery.

To foster such discoveries, mechanical engineers at MIT are designing tools to image and analyze cellular dynamics at the micro- and nanoscale. Such tools, including microfluidics, membrane technology and metamaterials, may help scientists better characterize and develop therapies for cancer and other complex diseases.

New medical discoveries depend on engineering advances in real-time, multifunctional imaging and quantitative analysis, says Nicholas Fang, an associate professor of mechanical engineering.

“What we’ve learned so far is more or less the architecture of cells, and the next layer is the dynamics of cells,” says Fang, who is developing optical sensors to illuminate individual components within a cell. “Cells operate like a city, or a metropolitan area: You have traffic, flow of information, and logistics of materials, and responses related to different events. Medicine requires new modes of seeing these events with better precision in time and space.”

Materials beyond nature

Fang is developing new imaging tools from metamaterials — materials engineered to exhibit properties not normally found in nature. Such materials may be designed as “superlenses” that bend and refract light to image extremely small objects. For example, Fang says that today’s best imaging tools can capture signaling between individual neurons, which may appear as a fuzzy “plume” of neurotransmitters. A superlens, in contrast, would let scientists see individual neurotransmitter molecules at the scale of a few nanometers. Such acuity, he says, would allow scientists to identify certain chemical transmitters that are directly related to particular diseases.

Metamaterials may also help scientists manipulate cells at the microscale. Fang is exploring the use of metamaterials as optical antennae to improve a technique known as optogenetics. This technique, developed in 2005 (and pioneered by MIT’s Ed Boyden, the Benesse Career Development Associate Professor of Research in Education), involves genetically engineering proteins to respond to light. Using various colors of light, scientists may control the activity or expression of such proteins to study the progression of disease. However, researchers have found that the technique requires a large amount of light to prompt a response, risking overheating or damaging the proteins of interest.

To solve this problem, Fang and his colleagues are looking to metamaterials to design tiny optical receivers, similar to radio antennae. Such receivers would attach to a given protein, boosting its receptivity to light, and thereby requiring less light to activate the protein. The project is in its initial stages; Fang says his group is now seeking materials that are compatible with proteins and other biological tissues.

Sorting cells

MIT researchers are also developing tools to sort individual cells — part of an effort to provide simple, cost-effective diagnostic tools for certain diseases. Rohit Karnik, an associate professor of mechanical engineering, is approaching cell sorting from a variety of directions. His lab is fabricating microfluidic, or “lab-on-a-chip,” devices — chips as small as a dime that efficiently sort cells, separating out those of interest from a sample of blood or biological fluid.

Karnik’s group employs nanofabrication techniques to etch tiny, precisely patterned channels into small squares of polymer. The arrangement of the channels directs fluid, capturing cells of interest via “cell rolling,” a phenomenon by which cells roll to one side of a channel, attracted by a wall’s surface coating. The device is a relatively simple, passive cell-sorter that Karnik says may efficiently sort out material such as white blood cells — cells that may quickly be counted to identify conditions such as sepsis and inflammation.

Karnik is also developing small membranes punctured with microscopic pores. Each pore is a few nanometers wide, small enough to let individual DNA molecules through. By passing an electric current through the nanopore, the researchers can measure certain characteristics of a DNA molecule, such as its size and the presence of any additional proteins bound to it.

Such membrane technology may drastically simplify the process of sizing DNA molecules and mapping DNA modifications, which are critical for understanding gene regulation and the dynamics of cellular machinery — now a lengthy process that involves expensive bench-top instruments. Instead, Karnik says, nanopore membranes may be a faster, cheaper alternative that could work with single DNA molecules with no loss of information from DNA-amplification steps.

Cancer in a chip

Researchers are investigating microfluidics not only as a means to sort cells, but as a way of replicating whole biological environments at the microscale.

“We use microfluidics to develop more realistic models of organs and human physiology so that we can look at, for example, how a tumor cell interacts with other cells in the local environment,” says Roger Kamm, the Cecil and Ida Green Distinguished Professor of Biological and Mechanical Engineering.

Kamm and his colleagues have developed a microfluidic chip that contains tiny channels and reservoirs, in which they can seed various cell types. The group is using the device to study how cancer spreads through the body. Cancer becomes metastatic when tumor cells break off from a primary tumor and cross through a blood vessel wall and into the bloodstream. Kamm is using the group’s microfluidic designs to mimic the metastatic process and identify agents to prevent it.

To replicate the lining of a blood vessel, Kamm seeds one channel in the chip with endothelial cells. In a neighboring channel, he injects a gel, mimicking the body’s extracellular matrix. The group can introduce tumor cells into the gel, along with other chemical agents. In the controlled setup, they can monitor the behavior of tumor cells, and the conditions in which the cells penetrate the endothelial lining, in order to enter a blood vessel.

“This allows us to put cells in close proximity so they can signal with each other in a more realistic fashion,” Kamm says.

Compared with conventional cancer-screening techniques, the microfluidic technique more closely resembles natural processes in the body, Kamm says. For example, pharmaceutical companies tend to test potential drugs in large batches, injecting a drug into tiny, isolated wells containing tumor cells. That works well to test for drugs that kill the tumor, but not so well for identifying drugs that can prevent metastatic disease.

“What we’re finding is that cells behave completely differently when you have a realistic environment, with cells communicating with different cell types, and when a cell is in a three-dimensional matrix, as opposed to when you have a single cell type inside a well on a two-dimensional, rigid surface,” Kamm says. “High-throughput systems probably miss a lot of potentially good drugs, and they also identify drugs that fail at subsequent stages of testing.”

Karnik, who has collaborated with Kamm on a few lab-on-a-chip designs, sees such devices and other engineering tools as a key connection in pushing medical discoveries, and effective therapies, forward.

“A clinician might say, ‘I need to know whether the patient has this disease or that disease,’ and the biologist would say, ‘Oh, in order to do that, you need to measure molecules A, B and C,’ and it’s up to the engineers to figure out how to do it,” Karnik says. “That’s our key role, bridging in between.”


New particle-sorting method breaks speed records | MIT News

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Researchers compare the processing of biological fluid samples with searching for a needle in a haystack — only in this case, the haystack could be diagnostic samples, and the needle might be tumor cells present in just parts-per-million concentrations. Now, a new way of processing these samples could make such detections possible in real time, according to a team from MIT, Massachusetts General Hospital (MGH), and Harvard Medical School.

The team’s surprising discovery is described in a paper in the journal Nature Communications. The technique could allow cells to be sorted while hurtling through the channels of a microfluidic device at speeds faster than those of race cars, the authors say — at least 100 times faster than any existing system

Normally, fluid flowing through a narrow channel at such high velocity would break up into a chaotic, turbulent flow, making any sorting or identification of cells impossible. But the research team found ways of eliminating this turbulence and even focusing the flow, driving the particles into single file within the channel.

“If you’re trying to find a needle in a haystack, it’s a lot easier if the needle is right in the middle of the haystack,” says co-author Gareth McKinley, the School of Engineering Professor of Teaching Innovation in MIT’s Department of Mechanical Engineering. With this method, that’s essentially what you get: In a process the team calls “inertio-elastic flow focusing,” McKinley says, the flow itself helps concentrate the particles that are of interest. “The bigger particles go to the center first,” he says.

In searching for tumor cells in a large volume of fluid — for example, in a fluid sample drained from a patient’s lungs, or in peritoneal fluid — there may be millions of cells, including those from the tumor, in a volume of up to a few liters; these cells’ shapes, numbers, and biophysical characteristics could make them indicators of cancer.

The researchers showed that by adjusting the flow properties of the fluid sample, they could concentrate all of the larger particles at the center of the flow. They adapted a high-speed, pulsed-laser imaging system to take snapshots of the shapes, sizes, and orientations of the particles as they fly through the device.

Ultimately, the researchers say, the work might lead to a compact, bedside device that could take a blood sample from a patient and provide diagnostic information immediately, rather than requiring processing at a lab, which can take hours or even days.

The new technique might have other uses, the researchers say. The ability to separate tiny nanoscale particles according to size at high speed “could be extremely important for a broad range of clinical applications and biological applications,” says co-author Mehmet Toner of Harvard Medical School and MGH.

Toner explains that the basic concept of flow focusing in microchannels, at low-flow rates, is a very active research field, with at least 50 different groups around the world studying the basic physics of flow focusing and exploring a broad range of applications. This new use of the technique for extremely high-speed processing could unleash a similar surge of interest, he says.

In describing how a fluid moves through a channel, the key flow parameter is called the Reynolds number — a quantity that combines the speed of the flow, the size of the channel, and the viscosity of the liquid. Experimental observation shows that a fluid doesn’t flow smoothly at a Reynolds number greater than about 2,400, Toner says, before breaking up into turbulence.

But the team found that by adding a minuscule amount of hyaluronic acid — a biopolymer — to the fluid, flow rates could be increased to a Reynolds number of 10,000 without introducing turbulence. Indeed, adding the polymer changes the flow properties of the fluid itself, giving rise to fluid viscoelasticity. Measuring how important this effect is in a fluid requires a new parameter, called the Weissenberg number; by understanding the relative magnitude of these two key parameters, the researchers were able to examine flow patterns that had never been studied before.

Doing so required finding a new way of making the microfluidic channels; existing soft materials used for microfluidic devices would not have withstood the high pressures associated with such flow rates. “At that kind of pressure, they would just explode,” Toner says, “so we had to develop a rigid device that was still optically transparent.”

In the new system, liquid can hurtle through a microfluidic channel just 50 micrometers across — about half the width of a human hair — at peak speeds of more than 400 mph, without turbulence. By using flashes of laser light just 10 billionths of a second in duration, the team was able to image the size, shape, and orientation of cells as they moved through the device and were squeezed by the effects of the fluid additive.

Hyaluronic acid is a biological derivative — it acts as a lubricant in the knee — that is harmless to biological samples, Toner says. And it turns out that at great speed, the focusing mechanism grows even more effective. “We didn’t imagine that you could get focusing at such rates,” McKinley says. The new system can achieve flow speeds up to 100 times greater than in existing microfluidic systems.

While the team suggests numerous possible applications in diagnostics, water purification, or even industrial separation of materials, such as for biofuel production, all such possibilities remain speculative at this point, Toner says.

Howard Stone, a professor of mechanical and aerospace engineering at Princeton University who was not involved in this research, says the work “appears original and significant.” He adds, “The ability to control focusing of particles by … adding small amounts of hyaluronic acid seems flexible and very interesting. Moreover, the authors have demonstrated the effect at high Reynolds numbers and so at high speeds and flow rates. This work will be of interest to many people and is likely to find applications in several fields.”

The team also included MIT graduate students Eugene Lim and Thomas Ober and five others.