Signal-To-Noise

Light shines brightly on the future of imaging R&D
OCT, fluorescence, and other optical methods are breaking new ground in imaging

By Philip G. Drew, Ph.D.

Some years ago, one of the major medical imaging companies convened a special task force on innovation and, after considerable thumb sucking, concluded that beyond x-rays, ultrasound, magnetic resonance, and nuclear medicine, no other methods of medical imaging were feasible. The field had reached the end of its tether, hemmed in by immutable physical laws. Alexander the Great, too, is said to have wept because there were no more worlds to conquer. And then there was the (perhaps apocryphal) chief of the U.S. Patent Office who announced early in the last century that all important inventions had already been invented.

How many people foresaw the promise of MR imaging when Paul Lauterbur conceived the technology he quaintly labeled "zeugmatography"? Only a few people have the vision to see where novel ideas may lead, and only a handful have the determination to pursue such ideas. But a glance over the medical imaging landscape shows that several R&D groups, supported by universities and venture capital, are pursuing novel techniques.

Many of these nascent techniques are based on optical devices. Unlike x-rays and radioactivity, light has the virtue that, at the power and frequencies used in diagnostic imaging, it is harmless to tissue. Unlike ultrasound, its wavelengths are short compared with physiological structures, so images are not intrinsically limited in spatial resolution. Unlike the ponderous apparatus needed for MR, light sources and light pipes are small.

But light has its deficiencies. It does not penetrate tissue very well, photons scatter all over the place once inside, and ambient light messes up the signals.

Researchers have found ingenious ways to overcome these drawbacks, however. For example, optical coherence tomography, under development by Lightlab Imaging, uses light in a manner similar to ultrasound. A light pulse emitted at the skin's surface travels into the body where it is reflected at tissue interfaces. Measuring time of travel, as in ultrasound, is difficult because the time is so brief, but measuring the phase difference between the emitted and reflected signal is relatively easy and equivalent to measuring time. Multiple pulses allow construction of a tomographic image with exquisite resolution on the order of 10 micrometers.

The main limitation of OCT is the depth of penetration, only about 4 mm. Still, this is deep enough to support a number of useful applications. The device could be used intravascularly to characterize different kinds of plaque. It could be used to guide microsurgery, where its ability to see beneath the surface could help the surgeon. Because the appearance of malignant cells under OCT is different from that of normal cells, it could be used as a painless replacement for biopsy at accessible sites like the GI tract. Taking advantage of its ability to recognize malignant cells, it could also be used to examine animals in cancer studies. Longitudinal data on several mice may be more valuable than data on multiple mice at various stages, which have to be sacrificed for examination.

Another optical technique is being pursued by a number of companies, including Xillix, Spectrascience, and BioSpec. It exploits the fact that under certain kinds of illumination tissues fluoresce and, remarkably, malignant tissues fluoresce differently from normal tissues. Xillix has been marketing for several years a device based on the fluorescence of precancerous bronchial tissues, which look normal under white light used in bronchoscopy but look abnormal under ultraviolet stimulation. While the device improves the sensitivity of bronchoscopy, it is time-consuming, since it must be done in all the branches of the bronchial tree. Other companies seek to exploit the same effect on more accessible surfaces such as the cervix and uterus.

Yet another method, based on work done by Britton Chance at the University of Pennsylvania, exploits the fact that highly vascularized tissue, containing more red hemoglobin, absorbs less near-infrared radiation than less vascularized tissue. Since cancers tend to be highly vascularized, this fact can be used to recognize tumors, even when the tumor is well below the surface.

Breast Cancer

Breast cancer detection is a fertile field for new techniques, partly because the breast is more uniform than other parts of the body, and partly because the limitations of mammography are well known.

Imaging Diagnostic Systems has been pursuing a technique using light in somewhat the same manner as CT uses x-rays. Originally the company used early-arriving and ballistic photons, but they have shelved this approach and now use a continuous-wave laser diode as the source. They measure the transmitted and scattered light with a ring of about 100 detectors that surround the breast. A mathematical method derived from X-ray CT is used to reconstruct images of the interior of the breast.

In the early 1980s, thermography was the name given to passive observation of infrared radiation from the breast. The technology had been developed for night vision and other military applications, and it was applied almost without modification to breast imaging. The theory was that breasts with malignancies produce more heat (infrared radiation) than normal breasts, and the difference could be detected. But the degree of heat to produce a measurable effect turned out to be produced only by large tumors near the surface. Thermography fell into disrepute. among radiologists. Despite this disappointing history, Computerized Thermal Imaging has resurrected thermography. The company believes that modern signal processing can improve the accuracy of the technique and make it a useful adjunct to mammography. The company has submitted a PMA application to the FDA.

Ultrasound, too, can be employed in an unconventional way to infer the elastic properties of breast and other tissues and reveal pathology invisible with conventional ultrasound. One would expect the elasticity of tumors to differ from normal breast tissue, since they are sometimes detected by palpation. A technique to do this quantitatively with ultrasound is under development at the University of Texas.

Impedance imaging can be applied to any part of the body, but breast imaging seems to hold particular promise. The technique is under investigation at a number of academic research laboratories, and at least one company, TransScan Medical, has a commercial product. A small voltage applied across the breast produces a current whose magnitude is determined by the impedance of each element of the tissue through which the current flows.

The problem, however, resembles that encountered with light: the currents spread out, passing through the entire volume of tissue. However, by making multiple measurements and using a mathematical method similar to relaxation in CT, one can sort out the impedance of each tissue element. Once again, the hope is that images based on this property of tissue can reveal otherwise invisible pathology.

Dr. Robert Kruger at the University of Indiana is exploring another novel method called thermo-acoustic computed tomography. The method exploits the fact that pulses of electromagnetic energy (radio or light waves) cause sudden expansion of tissue, which in turn makes sound waves. Using an apparatus with multiple waveguides to irradiate the breast with electromagnetic energy and multiple ultrasonic transducers to detect the sound waves, one can reconstruct images that show tissue differences. Images published by Kruger show a palpable tumor that was not visible with mammography.

What is remarkable is that so many new ways to make in vivo images are being explored. Whether they will earn a place alongside current techniques, however remains to be seen.