An ultrasound guide star and time-reversal mirror can focus light deep under the skin, a revolutionary advance in biomedical imaging technology.

Astronomers create an artificial star called a guide star and use its twinkling to compensate for the atmospheric turbulence. Lihong Wang, PhD, a professor of biomedical engineering at Washington University in St. Louis (MO, USA) , has devised a guide star for biomedical instead of celestial imaging, a breakthrough that has the potential for game-changing improvements in biomedical imaging and light therapy. Dr. Wang's guide star is an ultrasound beam that "tags" light that passes through it. When it emerges from the tissue, the tagged light, together with a reference beam, generates a hologram.

When a "reading beam" is then shown back through the hologram, it acts as a time-reversal mirror, creating light waves that follow their own paths backward through the tissue, coming to a focus at their virtual source, the area where the ultrasound is focused. The technique, called time-reversed ultrasonically encoded (TRUE) optical focusing, thereby allows the scientist to focus light to a controllable position within tissue.

Dr. Wang believes that TRUE will lead to more effective light imaging, sensing, manipulation, and therapy, all of which could be a benefit for medical research, diagnostics, and therapeutics. In photothermal therapy, for instance, scientists have had difficulty delivering enough photons to a tumor, to heat and kill the cells. Therefore, they have either to treat the tumor for a long time or use very strong light to get enough photons to the site, Dr. Wang reported. However, TRUE will allow them to focus light right on the tumor, ideally without losing a single tagged photon to scattering. "Focusing light into a scattering medium such as tissue has been a dream for years and years, since the beginning of biomedical optics," Dr. Wang said. "We couldn't focus beyond say a millimeter, the width of a hair, and now you can focus wherever you wish without any invasive measure."

The new technique was published online January 16, 2011, in the journal Nature Photonics. Ultrasound's advantages and pitfalls 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 does not 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. Dr. Wang had experimented with ultrasound tagging of light in 1994 when he was working at the MD Anderson Cancer Center (Houston, TX, USA). 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.

Ultrasound modulation of light allowed Dr. Wang to make clearer images of objects in tissue phantoms than could be produced with light alone. However, this technology selects only photons that have traversed the ultrasound field and cannot focus light. While Dr. Wang was working on ultrasound modulation of optical light, a lab at the Langevin Institute (Paris, France) led by Dr. Mathias Fink, was working on time reversal of sound waves. No law of physics is disrupted if waves run backward instead of forward. Therefore, 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 occur, however, one needs a time-reversal mirror, a device to send the waves backward along precisely the same path by which they arrived. In Dr. Fink's experiments, the mirror consisted of a line of transducers that detected arriving sound and fed the signal to a computer.

It is much simpler to construct a time-reversal mirror for ultrasound than for light, according to Dr. Wang. 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 is not 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 moved through the tissue and a reference beam form an interference pattern, which is recorded as a hologram by a customized 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. Dissimilar to the typical hologram, the TRUE hologram is dynamic and constantly changing. Therefore, 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.

Dr. Wang expects the TRUE technique for focusing light within tissue will have many applications, including optical imaging, sensing, manipulation and therapy. He also mentioned its likely impact on the emerging field of optogenetics. In optogenetics, light is used to probe and control living neurons that are expressing light-activated molecules or structures. Optogenetics may allow the neural circuits of living animals to be probed at the high speeds needed to examine brain data processing.

However, up to now, optogenetics has suffered from the same limitation that affects optical methods for studying biologic tissues. Regions of the brain near the surface can be stimulated with light sources directly mounted on the skull, but to examine deeper areas, optical fibers must be inserted into the brain.

TRUE will allow, according to Dr. Wang, 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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