A guide star lets scientists see deep into human tissue

February 11, 2011
A WUSTL scientist has invented the biomedical equivalent of the astronomers' guide star.To correct for atmospheric blurring, astronomers sometimes shine a laser into the sky near the spot where a telescope is pointing. The laser beam energizes sodium atoms naturally present above the stratosphere, producing a glowing artificial star called a guide star. The astronomers use the ‘twinkling’ of this guide star to continuously compensate for the effects of atmospheric turbulence on the light they are collecting from nearby stars. The guide star thus allows astronomers to obtain much sharper, more detailed images free of atmospheric blurring. Shown here is a laser beam projected into the night sky from the Keck-2 telescope on Mauna Kea, Hawaii. Credit: Paul Hirst/Creative Commons

Astronomers have a neat trick they sometimes use to compensate for the turbulence of the atmosphere that blurs images made by ground-based telescopes. They create an artificial star called a guide star and use its twinkling to compensate for the atmospheric turbulence.

Lihong Wang, PhD, the Gene K. Beare Distinguished Professor of Biomedical Engineering at Washington University in St. Louis, has invented a guide star for biomedical rather than celestial imaging, a breakthrough that promises game-changing improvements in biomedical imaging and light therapy.

Wang's guide star is an ultrasound beam that "tags" light that passes through it. When it emerges from the , the tagged light, together with a reference beam, creates a .

When a "reading beam" is then shown back through the hologram, it acts as a time-reversal mirror, creating that follow their own paths backward through the tissue, coming to a focus at their virtual source, the spot where the ultrasound is focused.

The technique, called time-reversed ultrasonically encoded (TRUE) optical focusing, thus allows the scientist to focus light to a controllable position within tissue.

Wang thinks TRUE will lead to more effective light imaging, sensing, manipulation and therapy, all of which could be a boon medical research, diagnostics, and therapeutics.

In photothermal therapy, for example, scientists have had 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. But TRUE will allow them to focus light right on the , ideally without losing a single tagged photon to scattering.

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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. Credit: Lihong Wang

"Focusing light into a scattering medium such as tissue has been a dream for years and years, since the beginning of biomedical optics," Wang says. "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 method was published in Nature Photonics, which appeared online Jan. 16, and has since been spotlighted by Physics Today (both online and in print) and in a Nature Photonics Backstage Interview.

The problem

Light is in many ways the ideal form of electromagnetic radiation for imaging and treating biological tissues, but it suffers from an overwhelming 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 you from seeing even a short distance through tissue; you can't, for example, see the bones in your hand. Light of the right color can penetrate several centimeters into biological tissue, but even with the best current technology, it isn't possible to 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.

Ultrasound tagging

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

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.

A conventional mirror (bottom) does not correct the distortion of a wavefront produced by the water-filled bottle in this illustration. A time reversal, or phase conjugating, mirror (top), on the other hand, produces a wavefront that precisely retraces the path of the light, as if time were going backward. It reverses the distortions introduced by the water, producing a perfect image of the tiger. Credit: Wikimedia Commons

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 was working on ultrasound modulation of optical light, a lab at the Langevin Institute in Paris led by Mathias Fink, was working on time reversal of sound waves.

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 , invited Wang to give a seminar at the Massachusetts Institute of Technology. "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."

"And then 13 years after the initial ultrasound-tagging experiments, I suddenly realized I could combine these two techniques.

"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."

"Ultrasound provides a virtual guide star, and to make optical time reversal effective you need a guide star," Wang says.

A time-reversal mirror for light

It's 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 to work with

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.

Explore further: Light's Answer To Ultrasound

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4.5 / 5 (4) Feb 11, 2011
Awesome! Depending on the resolution and penetration depth, this could be used to non-destructively scan neurons in the brain, and allow us to create backups of our brain state. Once computer technology improves, the brain states could be executed. Uploading.
5 / 5 (4) Feb 11, 2011
What an amazing piece of research and engineering, I particularly like the use of the reference beam to perform the hologram trick, such things are magical to me, a mere computer scientist, Go Science! :)
5 / 5 (2) Feb 11, 2011
I wouldn't go that far... Firstly, optogenetics only deals with those structures that interact with light in notable ways; this excludes a large swath of important chemistry and biology. Secondly, to image fine details of individual neurons, never mind individual synapses, you'd need light wavelengths well into (and probably past) the visible spectrum, which can't pass through the skin and skull, never mind the brain. Thirdly, you can't focus ultrasound down to such tight volumes as to image neuronal substructure.

At best, this technique would enable optogeneticists to image or stimulate some large sub-populations of brain cells, in bulk. It might still be good enough for something like lie detection or seizure locus determination and other therapeutic and research applications. But it won't let you "upload" (nor, in all likelihood, "download".)
not rated yet Feb 11, 2011
Well, maybe downloading the human brain is still well beyond our level of technology, but this technology will still allow us to amazing stuff. The ability to treat small tumors in places like the brain that are difficult to even detect today and impossible to effectively treat, for instance, will alone revolutionize cancer treatment. I can only imagine what it'll mean for other medical situations too...!
5 / 5 (1) Feb 12, 2011
This is like the advent of the microscope! We will refine the technique and expand the range of radiation that can be used, such as that described in the article about Video-Rate terahertz Interferometric and Synthetic Aperture Imaging.

It is a game changing technology.
not rated yet Feb 12, 2011
I think this is like the advent of the microscope! Yeah, that big.

Eventually, people will refine the technique and expand the range of radiation that can be used.

It seems like the time reversal physics might apply to most if not all of the electromagnetic spectrum. As I understand it, it could be described as a way to indirectly employ the wave nature of light by using the the wave nature of sound as a navigation tool. Time will tell what resolutions this line of development can deliver, but I think they will all be extraordinarily interesting and useful.

not rated yet Feb 12, 2011
Lets follow individual cells as though each one had a name and learn over time what all of them are up to in nano-sensor enhanced detail.

While this technique may not enhance vision in sufficient detail to directly observe phenomena, it also makes it possible to create smaller signal events to reveal the status of underlying conditions.

Like looking at in-situ radiologic makers with cameras, this is another way to create synthetic, real time auras that reveal flows and emergent patters. But now at any depth, so that 3D layers can also built. And done without a lot of expensive high energy equipment.

How small can this scale? Can a nanotechnology version of this be made? Could we use it to peer around inside of cells?
not rated yet Feb 12, 2011
Someone please engineer some molecules that will bind to specific places on specific cells, and that will reflect various wavelengths of light based on local conditions. Then lets shine lots of known bandwidth radiation at various depths to "see" what gets reflected back. We will able to learn lots of stuff, like the exact location and composition of a tumor.

Then lets use the same technique to send another frequency of light that triggers the molecules in specific locations into taking a new shape, one that has a therapeutic or destructive effect on the the cell.

See the tumor, reprogram/kill the tumor.

Can this technology help us focus more than one beam so that they combine at a specific depth to perform surgical procedures? Could not it's sister technology aid me in "seeing" what was being cut? Could we also use computer vision to guide the beams?

not rated yet Feb 13, 2011
First use, scan for breast cancer image, etc.

Second use, select photons frequncy and scan for sites with certain molecules identifying metabolism, enzymatic pathways, and/or disease.

Third use, select photon frequency, increase energy and fry cancer, block cancers metabolism, or enhance metabolic pathways, i.e. p53, to initiate healing. None of these are intended to be limited to healing only cancer.
not rated yet Feb 13, 2011
If this site really wants to be a medical site and not a science site, it should divide into two sites or at least compartmentalize better. It is irksome to look at the pic of a what would appear to be a physics or astronomy related content and read the headline kinda as a type as the pic and the headline do not match.....then find in the content that it really IS a medical artical. I look in here for science, physics, plasma dynamics, energy production and especially fusion energy..and other things. Medical articles masquerading as laser advances waste my time, sorry.

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