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Microfluidics offers new portals for discovery

Caroline Alexander and David Beebe

With five-year funding from the National Institutes of Health, Biomedical Engineering Professor David Beebe is taking PhD-level coursework in biology. With his mentor, Assistant Professor of Oncology Caroline Alexander, Beebe is studying the cellular mechanisms of breast cancer. (15K JPG)

After years of intensive technology development, the field of microfluidics has advanced to the point that it now could be applied widely in scientific fields ranging from materials development to basic biology, says Biomedical Engineering Professor David Beebe.

With former postdoctoral student Javier Atencia (now with the National Institute of Standards and Technology), Beebe co-authored a review of the ways in which microfluidics can offer researchers precise control over interfaces. The review appeared in the Sept. 29 issue of the journal Nature.

Exploiting small-scale physics

Tiny self-contained laboratories that easily can fit in the palm of a researcher's hand, microfluidic systems enable scientists to study the behavior of fluids on the microscale. At a few millionths of a meter, that's smaller than a single grain of sugar. Shrinking a research subject to this size means a huge increase in its surface area relative to its volume, making factors like surface tension, capillary forces and diffusion the dominant physical phenomena.

As a result of that large surface-area-to-volume ratio, interfaces, or common boundaries, play a key role in research conducted at this scale. Interfaces include not only the boundary layer that separates two distinct phases of matter, like liquid and gas or liquid and liquid, but also secondary boundaries — those Beebe calls “new” interfaces — like the interactions that exist between two cells that secrete “factors” to communicate. “It's not an interface that you can necessarily see easily, like you can air-liquid, but in fact it is an interface, because as an interface, it's certainly something a cell can identify through receptors on its surface,” says Beebe.

96-microchannel plate

Biomedical Engineering Professor David Beebe and his students are developing multi-microchannel plates, which they couple with a robot they program to do time-consuming pipetting. Although they have created plates with as many as 768 channels, this one has 96. (16K JPG)

48-channel plate

Using their microfluidic systems (in this case, a 48-channel plate), researchers in Beebe's lab stain the nuclei of cells to make it easier to count them. The stain makes the nuclei fluoresce in a certain color and the researchers use filters to see them. (11K JPG)

Microfluidic systems exploit surface tension, capillary forces and diffusion, giving scientists an entirely new mechanism for observing and manipulating the materials they study. They also provide an environment that is virtually free of external influences like air movement, temperature gradients, light variations and other factors. For example, trying to study cell behavior in a relatively large environment, like a Petri dish, is something like trying to read the newspaper outside on a very windy day. But place those same cells in one of Beebe's “no-flow” microfluidic channels, in which those outside influences don't exist, he says, and the factors they excrete radiate in predictable patterns.

Secretions from cells in the sealed channel form “spheres of influence,” says Beebe, which will enable scientists to quantifiably observe cell-cell interactions. “If you know that one cell is secreting a protein of 'X' size, you could predict from basic physical equations very precisely how long it will take that molecule to reach a neighboring cell,” he says. “So you know when that cell has been stimulated and then you can see when that cell responds to the stimulus. In the past, there was no way to quantify those sorts of events.”

Beyond biology, microfluidic systems already are commercially available for biomolecular separations and hold promise as tools for high-throughput discovery and screening studies in chemistry and materials science. “The interfaces may be useful, for example, in creating new types of materials by directing the growth of polymers,” says Beebe.

Applications in biology

In his own lab, Beebe and his students are exploiting biological interfaces to study what regulates adult progenitor/stem-cell growth in the mammary gland. Many scientists believe that most cancers are initiated in progenitor cells, or those that form only specific organs within the body. Using artificial in vitro microfluidic environments that they create to mimic the environment within the body, Beebe's group is investigating how neighboring cells influence mammary progenitor cells.

Ultimately, the group hopes to learn more about how breast cancer occurs — and potentially, to discover ways to treat it. “We hope to understand what causes the progenitor cells to start proliferating,” he says. “Those same pathways provide targets to develop drugs to inhibit proliferation, because those arguably would be the pathways that would go wrong.”

In Beebe's case, a carefully regulated, sealed microfluidic system will enable his research group to take cells out of an experimental animal and for short periods of time, “convince” them to behave as though they were still in the animal.

In addition, he and his students are automating the process, which means that they will be able to quickly gather more data from fewer animals. “With the cells from one mammary gland and one mouse, we're going to be able to get more data than we would have gotten with large numbers of mice before,” he says. “And that has the potential to transform the way people do cell biology. They're such complex systems that you need to be able to examine a lot of parameters.”

Improving on a familiar biologists' tool, the 96-well plate, the group has developed a multi-microchannel plate (up to 768 channels per plate) and coupled it with a robot they program to do the time-consuming pipetting biologists previously had to do themselves.

A truly interdisciplinary approach

As an engineer, Beebe was a self-proclaimed “widget-maker,” and among a handful of researchers who shaped the face of microfluidics technologies. Today, however, he's focused much more on the applications of his devices, particularly as they relate to biology. He recently completed the first year of a five-year National Institutes of Health retraining grant, which has enabled him to take PhD-level biology coursework and focus on breast-cancer-related problems under the mentorship of Assistant Professor of Oncology Caroline Alexander. As a result of the grant, Beebe was the subject of a profile in the Sept. 22 issue of Nature.

“I was always frustrated internally because I didn't know enough to contribute on the biology side,” says Beebe, “and yet I always had the sense that they didn't know enough about engineering to really take advantage of the technology like I thought it could be taken advantage of.”

Now his concern, he says, is in developing the knowledge and tools that can help make a difference in the world. “The payoff is getting biologists to use them to help people,” says Beebe.