The Caltech researchers’ new technique allows them to focus light deep inside biological tissue. In the experiment, the researchers shined green laser light into the tissue sample seen here in the center. Image: Caltech/Benjamin Judkewitz and Ying Min Wang
Imagine if doctors could perform surgery without ever
having to cut through your skin. Or if they could diagnose cancer by seeing
tumors inside the body with a procedure that is as simple as an ultrasound.
Thanks to a technique developed by engineers at the California Institute of
Technology (Caltech), all of that may be possible in the not-so-distant future.
The new method enables researchers to focus light
efficiently inside biological tissue. While the previous limit for how deep
light could be focused was only about one millimeter, the Caltech team is now
able to reach two and a half millimeters. And, in principle, their technique
could focus light as much as a few inches into tissue. The technique is used
much like a flashlight shining on the body’s interior, and may eventually
provide researchers and doctors with a host of possible biomedical applications,
such as a less invasive way of diagnosing and treating diseases.
If you crank up the power of light, you might even be
able to do away with a traditional scalpel. “It enables the possibilities
of doing incision-less surgery,” says Changhuei Yang, a professor of
electrical engineering and bioengineering at Caltech and a senior author on the
new study. “By generating a tight laser-focus spot deep in tissue, we can
potentially use that as a laser scalpel that leaves the skin unharmed.”
Ying Min Wang, a graduate student in electrical
engineering, and Benjamin Judkewitz, a postdoctoral scholar, are the lead
authors on the paper, which was published in Nature
The new work builds on a previous technique that Yang and
his colleagues developed to see through a layer of biological tissue, which is
opaque because it scatters light. In the previous work, the researchers shined
light through the tissue and then recorded the resulting scattered light on a
holographic plate. The recording contained all the information about how the
light beam scattered, zigzagging through the tissue. By playing the recording
in reverse, the researchers were able to essentially send the light back
through to the other side of the tissue, retracing its path to the original
source. In this way, they could send light through a layer of tissue without
the blurring effect of scattering.
But to make images of what is inside tissue—to get a picture of cells or molecules that
are embedded inside, say, a muscle—the researchers would have to be able to
focus a light beam into the tissue. “For biologists, it’s most important
to know what’s happening inside the tissue,” Wang says.
To focus light into tissue, the researchers expanded on
the recent work of Lihong Wang’s group at Washington University
in St. Louis (WUSTL); they had developed a method to focus light using the
high-frequency vibrations of ultrasound. The WUSTL group took advantage of two
properties of ultrasound. First, the high-frequency sound waves are not
scattered by tissue, which is why it is great for taking images of fetuses in utero. Second, ultrasonic vibrations
interact with light in such a way that they shift the light’s frequency ever so
slightly. As a result of this so-called acousto-optic effect, any light that
has interacted with ultrasound changes into a slightly different color.
How the technique works. Left: Light enters the tissue sample and is scattered (blue arrows). From above, ultrasound is focused into a small area inside the tissue. The ultrasound shifts the frequency of any light that passed through that area ever so slightly, changing its color. The color-shifted light (green) is then recorded. Right: The recorded light is sent back to retrace its steps to the small region where the ultrasound was focused—which means the light itself is focused on that area. Image: Caltech/Benjamin Judkewitz and Ying Min Wang
In both the WUSTL and Caltech experiments, the teams
focused ultrasound waves into a small region inside a tissue sample. They then
shined light into the sample, which, in turn, scattered the light. Because of
the acousto-optic effect, any of the scattered light that passes through the
region with the focused ultrasound will change to a slightly different color.
The researchers can pick out this color-shifted light and record it. By
employing the same playback technique as in the earlier Caltech work, they then
send the light back, having only the color-shifted bits retrace their path to
the small region where the ultrasound was focused—which means that the light
itself is focused on that area, allowing an image to be created. The
researchers can control where they want to focus the light simply by moving the
The WUSTL experiment was limited, however, because only a
very small amount of light could be focused. The Caltech engineers’ new method,
on the other hand, allows them to fire a beam of light with as much power as
they want—which is essential for potential applications.
The team demonstrated how the new method could be used
with fluorescence imaging—a powerful technique used in a wide range of
biological and biomedical research. The researchers embedded a patch of gel
with a fluorescent pattern that spelled out “CIT” inside a tissue
sample. Then, they scanned the sample with focused light beams. The focused
light hit and excited the fluorescent pattern, resulting in the glowing letters
“CIT” emanating from inside the tissue. The team also demonstrated
their technique by taking images of tumors tagged with fluorescent dyes.
“This demonstration that we can focus significant
optical power deep within tissues opens up significant possibilities in optical
imaging,” Yang says. By tagging cells or molecules that are markers for
disease with fluorescent dyes, doctors can use this technique to make diagnoses
noninvasively, much as if they were doing an ultrasound procedure.
Doctors might also use this process to treat cancer with
photodynamic therapy. In this procedure, a drug that contains light-sensitive,
cancer-killing compounds is injected into a patient. Cancer cells absorb those
compounds preferentially, so that the compounds kill the cells when light
shines on them. Photodynamic therapy is now only used at tissue surfaces,
because of the way light is easily scattered. The new technique should allow
doctors to reach cancer cells deeper inside tissue.
The team has been able to more than double the current
limit for how far light can be focused into tissue. With future improvements on
the optoelectronic hardware used to record and play back light, the engineers
say, they may be able to reach 10 cm (almost 4 in)—the depth limit of ultrasound—within
a few years.
Still, the researchers say, their
demonstration shows they have overcome the main conceptual hurdle for
effectively focusing light deep inside tissue. “This is a big
breakthrough, and we’re excited about the potential,” Judkewitz says. Adds
Caltech’s Wang, “It’s a very new way to image into tissue, which could
lead to a lot of promising applications.”