St. Louis, MO, USA. Scientists have figured out how to focus light deep under the skin, offering a steep improvement in biomedical imaging and light therapy.

Tissue is a light scattering medium. Maintaining the focus of light has been a basic goal since the beginning of biomedical optics. Existing technologies could not focus beyond the range of one millimeter (the approximate width of a human hair). Scientists now can focus on a desired target without taking any invasive measures.


The new method is called Time-reversed Ultrasonically Encoded (TRUE) Optical Focusing. TRUE adapts a proven astronomical technique that removes blur from ground-based telescopic images by compensating for atmospheric turbulence. Astronomers do this by creating a guide star of known properties that provides a basis for calibrating the instrument. The journal Nature Photonics has published a description and backstage interview.



Time Reversal Mirror (TRM). An application of Time Reversal Signal Processing (TRSP), the TRM typically uses arrays of transducers to focus waves.

The conventional mirror shown at the top of the image does not correct the wavefront distortion produced by the water-filled bottle.

A phase conjugating (or time reversal) mirror (shown, bottom) produces a wavefront that retraces the path of the light with precision.

At first glance, it seems like time moves in a backward direction.

The effect is to correct (reverse) distortions introduced by the water, producing a perfect image of the tiger.

Mathias Fink invented TRM at the École supérieure de physique et de chimie industrielles de la ville de Paris.

TRM exploits a feature of the reciprocity wave equation. That is, if one possesses a solution to the wave equation, then the time reversal that results from using a negative time of that solution is also a solution of the wave equation.

Finks' original paper, Acoustic time-reversal mirrors, paved the way toward managing acoustic phenomena.

The paper showed why it could be done and demonstrated the principle for multi-target pulse-echo detection in an iterative time-reversal mode within a reverberant medium.

The method has since been adapted to light and a variety of other wave phenomena.

Click Pic for DetailsThe new biomedical guide star is a beam of ultrasound that tags light as it passes through tissue. When the tagged light emerges, it combines with a reference beam to create a hologram.

The reading beam, when shown back through the hologram, acts as a time-reversal mirror. The resulting light waves follow their own paths backward through the tissue, coming to a focus at their virtual source, the spot where the ultrasound is focused. This allows the scientist to focus light to a controllable position within tissue.

Lihong Wang, PhD, the Gene K. Beare Distinguished Professor of Biomedical Engineering at Washington University in St. Louis, thinks TRUE will lead to more effective light imaging, sensing, manipulation and therapy. All of thse advances would accelerate and deepen medical research, diagnostics, and therapeutics.

For example, when using photothermal therapy scientists have trouble delivering enough photons to a tumor to heat and kill the cells. So, they either have to treat the tumor for a long time or use very strong light to get enough photons to the site. Wang says TRUE will allow them to focus light directly on the tumor, ideally without losing a single tagged photon to scattering.

The Problem

Light is in many ways the ideal form of electromagnetic radiation for imaging and treating biological tissues, but there is a critical drawback. Light photons ricochets off nonuniformities in tissue like a steel ball ricochets off the bumpers of an old-fashioned pinball machine.

This scattering prevents visibility at even the short distance through tissue; for example, you can't see the bones in your hand. Light of the correct color can penetrate several centimeters into biological tissue but even the best current technology cannot produce high-resolution images of objects more than a millimeter below the skin with light alone.

Ultrasound's advantages and drawbacks are in many ways complementary to those of light. Ultrasound scattering is a thousand times weaker than optical scattering. Ultrasound reveals a tissue's density and compressibility, which are often not very revealing. For example, the density of early-stage tumors doesn't differ that much from that of healthy tissue.

The TRUE technique overcomes these problems by combining for the first time two tricks of biomedical imaging science: ultrasound tagging and time reversal.

Ultrasound Tagging

Wang had experimented with ultrasound tagging of light in 1994 when he was working at the M.D. Anderson Cancer Center in Houston, Texas. In experiments using a tissue phantom (a model that mimics the opacity of tissue), he focused ultrasound into the phantom from above, and then probed the phantom with a laser beam from the side.

The laser light had only one frequency as it entered the tissue sample, but the ultrasound, which is a pressure wave, changed the tissue's density and the positions of its scattering centers. Light passing through the precise point where the ultrasound was focused acquired different frequency components, a change that "tagged" these photons for further manipulation.

By tuning a detector to these frequencies, it is possible to sort photons arriving from one spot (the ultrasound focus) within the tissue and to discard others that have bypassed the ultrasonic beam and carry no information about that spot. The tagged photons can then be used to paint an image of the tissue at the ultrasound focus.

Ultrasound modulation of light allowed Wang to make clearer images of objects in tissue phantoms than could be made with light alone. But this technology selects only photons that have traversed the ultrasound field and cannot focus light.

Time Reversal

While Wang worked on ultrasound modulation of optical light, Mathias Fink worked on time reversal of sound waves at his Langevin Institute lab in Paris. No law of physics is violated if waves run backward instead of forward. So for every burst of sound (or light) that diverges from a source, there is in theory a set of waves that could precisely retrace the path of the sound back to the source.

To make this happen, however, you need a time-reversal mirror, a device to send the waves backward along exactly the same path by which they arrived. In Fink's experiments, the mirror consisted of a line of transducers that detected arriving sound and fed the signal to a computer. Each transducer then played back its sound in reverse — in synchrony with the other transducers. This created what is called the conjugate of the original wave, a copy of the wave that traveled backward rather than forward and refocused on the original point source.

The idea of time reversal is so remote from everyday experience it is difficult to grasp, but as Scientific American reported at the time, if you stood in front of Fink's time-reversal "mirror" and said "hello," you would hear "olleh," and even more bizarrely, the sound of the "olleh," instead of spreading throughout the room from the loudspeakers, would converge onto your mouth.

In a 1994 experiment, Fink and his colleagues sent sound through a set of 2000 steel rods immersed in a tank of water. The sound scattered along all the possible paths through the rods, arriving at the transducer array as a chaotic wave. These signals were time-reversed and sent back through the forest of rods, refocusing to a point at the source location.

In effect, time reversal is a way to undo scattering.

Combining The Tricks

Wang was aware of the work with time reversal, but at first couldn't see how it might help solve his problem with tissue scattering.

In 2004, Michael Feld, a physicist interested in biomedical imaging, invited Wang to give a seminar at the Massachusetts Institute of Technology (MIT). "At dinner we talked about time reversal," Wang says. "Feld was thinking about time reversal, I was thinking about time reversal, and so was another colleague dining with us."

"The trouble was, we couldn't figure out how to use it. You know, if you send light through a piece of tissue, the light will scatter all over the place, and if you capture it and reverse it, sending it back, it will still be scattered all over the place, so it won't concentrate photons." But then 13 years after the initial ultrasound-tagging experiments, Wang suddenly realized he could combine these two techniques.

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A comparison of time reversal and time reversal plus ultrasonic tagging

In both cases photons take random paths through tissue. Some are lost (blue) but others (green) will reach the mirror on the other side of the tissue.

The mirror is a special phase conjugate mirror that turns the light around and sends it back on its original path, as though time had been reversed. Clever as this is, by itself it isn't very useful because the light scatters again as is backtracks (left).

In the new method, called TRUE, ultrasound is focused into the tissue (small black ring). Light passing through the ultrasound field is tagged by it and selectively returned by the mirror to its virtual source, the ultrasound focus (right).

Instead of scattering, the light is brought to a focus inside the tissue.

Video courtesy of Lihong V. Wang and Washington University in St. Louis. Time: 00:00:18."If you added ultrasound, then you could focus light into tissue instead of through tissue. Ultrasound tagging lets you reverse and send back only those photons you know are going to converge to a focus in the tissue," Wang says. "Ultrasound provides a virtual guide star, and to make optical time reversal effective you need a guide star," Wang says.

Light Gets A Time-reversal Mirror

It is much easier to make a time-reversal mirror for ultrasound than for light. Because sound travels slowly, it is easy to record the entire time course of a sound signal and then broadcast that signal in reverse order. But a light wave arrives so fast it isn't possible to record a time course with sufficient time resolution. No detector will respond fast enough.

The solution is to record an interference pattern instead of a time course. The beam that has gone through the tissue and a reference beam form an interference pattern, which is recorded as a hologram by a special photorefractive crystal.

Then the wavefront is reconstructed by sending a reading beam through the crystal from the direction opposite to that of the reference beam. The reading beam reconstitutes a reversed copy of the original wavefront, one that comes to a focus at the ultrasound focus.

Unlike the usual hologram, the TRUE hologram is dynamic and constantly changing. Thus it is able to compensate for natural motions, such as breathing and the flow of blood, and it adapts instantly when the experimenter moves the ultrasonic focus to a new spot.

More Photons Do More Work

Wang expects the TRUE technique for focusing light within tissue will have many applications, including optical imaging, sensing, manipulation and therapy. He also mentions its likely impact on the emerging field of optogenetics.

In optogenetics, light is used to probe and control living neurons that are expressing light-activatable molecules or structures. Optogenetics may allow the neural circuits of living animals to be probed at the high speeds needed to understand brain information processing.

But until now, optogenetics has suffered from the same limitation that plagues optical methods for studying biological tissues. Areas of the brain near the surface can be stimulated with light sources directly mounted on the skull, but to study deeper areas, optical fibers must be inserted into the brain.

TRUE will allow light to be focused on these deeper areas without invasive procedures, finally achieving the goal of making tissue transparent at optical frequencies.

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