A new microfluidic device isolates target cells (in pink) from the rest of the flow by getting them to stick weakly to the device’s ridges, then roll through trenches, and into a collection chamber. Image: Nicolle Rager Fuller
rolling is a common mechanism cells use to navigate through the body.
During inflammation, for example, the endothelial cells that line blood
vessels present certain molecules that attract white blood cells just
enough to divert them from the rest of the vessel’s cellular traffic.
White blood cells then roll along the vessel wall, slowing down to help
in the healing of inflamed areas.
at Massachusetts Institute of Technology and Brigham and Women’s Hospital have now designed a
cell-sorting microchip that takes advantage of this natural cell-rolling
mechanism. The device takes in mixtures of cells, which flow through
tiny channels coated with sticky molecules. Cells with specific
receptors bind weakly to these molecules, rolling away from the rest of
the flow, and out into a separate receptacle.
cell sorters, about the size of postage stamps, may be fabricated and
stacked one on top of another to sift out many cells at once—an
advantage for scientists who want to isolate large quantities of cells
quickly. The device doesn’t necessarily require an external pump to push
cells through the chip, which makes it a portable, affordable option
for use in laboratories or clinics, where cell samples may be taken and
sorted without specialized equipment.
working on a disposable device where you wouldn’t even need a syringe
pump to drive the separation,” says Rohit Karnik, the d’Arbeloff
Assistant Professor of Mechanical Engineering at MIT. “You could
potentially buy a $5 or $10 kit and get the cells sorted without needing
any kind of [additional] instrument.”
collaborated with postdoc Sung Young Choi of MIT and Jeffrey Karp,
co-director of the Center for Regenerative Therapeutics at Brigham and
Women’s. The team reported their findings in a paper posted online in
the journal Lab on a Chip.
current cell-sorting technologies separate large batches of cells
quickly and efficiently, they have several limitations.
Fluorescence-activated cell sorting, a widely used technique, requires
lasers and voltage to sort cells based on their electric charge—a
complex system requiring multiple parts. Researchers have also used
fluorescent markers and magnetic beads that bind to desired cells,
making them easy to spot and sift out. However, once collected, the
cells need to be separated from the beads and markers—an added step that
risks modifying the samples.
Going with the flow
team designed a compact cell sorter that requires no additional parts
or steps. The team built upon their 2007 work with MIT’s Robert Langer
and others, in which they first came up with the sorting-by-rolling
principle. Since then, the group has been turning principle into
practice, designing a working device to sort cells. The initial
proof-of-principle design was relatively simple: Cells were injected
into a single inlet, which gave way to a large chamber coated on one
side with sticky, roll-inducing molecules. The incoming cells flowed
through the chamber; the cells that bound to the molecules rolled to one
side, then out to a collection chamber.
the researchers found that in order to allow target cells to first
settle on the chamber’s surface, long channels were required, which
would make the device too large. Instead, Choi came up with a surface
pattern that causes cells to circulate within the chamber. The pattern
comprises 10 parallel channels with 50 ridges and trenches, each ridge
about 40 microns high. The researchers coated the ridges with
P-selectin, a well-known molecule that promotes cell rolling. They then
injected two kinds of leukemia cells: one with receptors for P-selectin,
the other without.
found that once injected, the cells entered the chamber and bounced
across the top of the ridges, exiting the chip through an outlet. The
cells with P-selectin receptors were “caught” by the sticky molecule and
flipped into trenches that led to a separate receptacle. Through their
experiments, the team successfully recovered the cells they intended to
sift out with 96 percent purity.
says the device may be replicated and stacked to sort large batches of
cells at relatively low cost. He and his colleagues are hoping to apply
the device to sort other blood cells, as well as certain types of cancer
cells for diagnostic applications and stem cells for therapeutic
applications. To do that, the team is investigating molecules similar to
P-selectin that bind weakly to such cells. In the future, Karnik
envisions tailor-made cell rolling, designing molecules and surfaces
that weakly adhere to any desired type of cell.
really the ability to design molecules to separate cells of interest
that will be powerful,” Karnik says. “There’s no reason to believe it
cannot be done, because nature has already done it.”
device is a “smart design,” says Milica Radisic, an associate professor
of biomedical engineering at the University of Toronto, who was not
involved in this research. Radisic says because the device relies on
hydrodynamics within the chamber, it doesn’t require external equipment.
design is probably good as it is for separation of leukemia cell
lines,” Radisic says. “The question is if it can be adopted for other