<http://www.berkeley.edu/>Berkeley
Microsized microscopes: UC Berkeley researchers develop microlens and
scanner that can provide views inside living cells
13 March 2002
By Sarah Yang, Media Relations
Berkeley - Imagine a future where doctors can view the DNA of tumor cells
inside a patient as cancer drugs are delivered, or where anti-terrorism
units can identify single molecules of a biowarfare agent on site with a
portable detector. With a significant development in miniaturized
microscopes at the University of California, Berkeley, scientists are
inching closer to such possibilities.
Luke Lee
Assistant Professor Luke Lee is developing a micro-lens smaller than the
period at the end of this sentence. Peg Skorpinski photo
micro-CIA
Shown is an image of a scanner of the micro confocal imaging array, or
micro-CIA, taken by a scanning electron microscope. The photopolymer
microlens in the center of the scanner is shaped by surface tension, not by
etching, and is therefore extremely smooth. Comb-drives on opposing sides
of the scanner power the side-to-side movements using electrostatic forces.
The "fingers" of the comb-drives are spaced 2-5 microns apart.
micro confocal imaging array
As seen in this schematic of a micro confocal imaging array, the staging
platform that holds the sample is on the bottom. Three scanners stacked
vertically above the platform scan each of the three axes (X, Y and Z) for
three-dimensional images. The fluorescent signal detector sits above the
scanners.
Luke P. Lee, assistant professor of bioengineering at UC Berkeley, and his
doctoral student Sunghoon Kwon have captured an image of a plant cell with
a microlens smaller than the period at the end of this sentence.
"It's shrinking a million dollar machine down to a size that can balance on
the tip of a ballpoint pen," said Lee, who presented the results at a
recent International Conference on Micro Electro Mechanical Systems. "The
microlens and scanner we've made is a crucial part of a microscope that is
500 to 1,000 times smaller than anything in its class."
In testing the accuracy of the microlens and scanner, Kwon placed a cell
sample taken from a flowering lily, Convallaria majalis, onto the platform
of a conventional confocal microscope. Without moving the sample, they
captured a cross-sectional image of the cell wall, first with the
traditional microscope, then with the microlens scanner. They found that
the two images matched, showing for the first time that his microscopic
lens could perform as well as a conventional one.
"Honestly, we were shocked," said Lee, who also is co-director of the
Berkeley Sensor & Actuator Center. "What we've finally shown is a proof of
concept. We have tested only 2-D images now, but it's just a matter of time
and manpower before we get the first 3-D image."
The microlens and scanner are part of a device Lee is developing called the
micro confocal imaging array, or micro-CIA. The micro-CIA belongs to a
group of devices known as Bio-Polymer-Opto-Electro-Mechanical-Systems, or
BioPOEMS. Invented by Lee, BioPOEMS marry the world of optics to that of
microelectromechanical systems, or MEMS, for use in biological applications.
The size and sensitivity of the micro-CIA would allow technicians to
quickly test even trace amounts of anthrax or smallpox in the field. It
could become a crucial part of a "lab-on-a-chip," where researchers can
study genes and proteins in ways unimagined decades ago. Lee is
particularly excited by the potential for advancements in medicine possible
with a miniaturized microscope.
"You could put this device on the tip of an endoscope that could be guided
inside a cancer patient," said Lee. "Doctors could then see how tumor cells
behave in vivo. It would also be feasible to deliver drugs directly to the
tumor cell, and then view how the cell responds to the drugs."
High-end confocal microscopes, which house several lasers, take up to a
meter of desk space, can cost more than $1 million and typically require
highly-trained operators to run them, said Lee. The high cost of owning and
running confocal microscopes limits the amount of research that can be done
with them, he said.
"My goal is to not only shrink the size of these microscopes, but to make
them as easy and as cheap to use as a digital camera," said Lee. It is with
a hint of populist sentiment that Lee began devising a teeny version of the
confocal microscope, the micro-CIA. He envisions a future where confocal
microscopy is as common as a Bunsen burner in academic and industry
research labs.
Unlike scanning electron microscopes, which construct 3-D topological
images of dead cells, confocal microscopes can capture images of nanoscale
activity inside living cells. Confocal microscopes also allow researchers
to focus on specific components inside the cell, such as DNA strands, or
mitochondria.
Cell parts marked with a fluorescent dye are "excited" by the laser and
emit light back at specific wavelengths. Mitochondria, for instance, emit a
fluorescent red color while nucleic acids emit a fluorescent blue,
depending upon the molecular labeling of each component in the cell. To
form 3-D images, 2-D slices are stacked together in a way similar to how an
MRI image is formed.
Equipped with a microlens about 300 microns in diameter, the microscopic
scanner Lee tested is a square of about 1 millimeter on each side and can
move a distance of 50 to 100 microns. Lee is also testing a nanolens as
small as 500 nanometers in diameter, or 200 times thinner than a strand of
human hair, and smaller than the average red blood cell.
Lee's design of the micro-CIA will include three scanners stacked
vertically above the staging platform where samples are studied. The
scanners will measure each of the three axes - X, Y and Z - in
three-dimensional space.
To make the scanner and lens, Lee employed technology similar to that used
to manufacture microchips. The lens is made of a tiny drop of polymer
shaped by surface tension and hardened by exposure to ultraviolet light. To
focus the lens, Lee and Kwon adjusted the distance between the lens and
sample. While it is also possible to focus by changing the shape of the
lens, Lee said doing so would likely increase the cost and complexity of
production, something he wants to avoid.
Comb-drives on each side of the microlens act as microactuators, tiny
engines powered by electrostatic forces that move the microlens back and
forth 4,500 times per second. Sensors then pick up fluorescent signals and
feed the data back to a computer where the image is displayed in real time.
Lee's work is part of UC Berkeley's Health Sciences Initiative, which
brings together scientists from disparate fields in the pursuit of major
advances in health and medicine.
The research is part of a three-year project funded by the Defense Advanced
Research Projects Agency.
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