A Look Ahead: Inside Optical Imaging

In-vivo ultrasound and thermal images of mouse tumor undergoing laser irradiation. Thermal images after 60, 120 and 180 seconds of therapy show the progressive increase of temperature in the tumor. Image source: Ultrasound Imaging and Therapeutics Research Laboratories, Department of Biomedical Engineering, The University of Texas at Austin.

Within the field of molecular imaging, there are quite a few techniques that are well established within routine clinical practice. Other techniques have earned the reputation of being powerful and innovative when it comes to experimental or preclinical research, but have had trouble translating into the clinic. That could be changing, particularly in the area of optical imaging.

“Optical imaging is very, very, versatile,” says Mathias Nahrendorf, MD, assistant professor of radiology, Harvard Medical School, and director of Mouse Imaging Program at the Center for Molecular Imaging Research. “It works in many applications over a wide range: microscopic all the way to in vivo.” And near infrared (NIR) imaging, with its ability to penetrate deep into the tissue being studied, offers particular promise.

In optical imaging there are three processes that affect how light photons interact with tissue—light absorption, light scattering, and fluorescent emission. At lower wavelengths, perhaps below 700 nanometers (nm), the rate at which light is absorbed and scatters increases, which means that the ability of those light photons to penetrate tissue is limited.

“So the first advantage of near infrared is the issue of depth,” says Nahrendorf. At wavelengths in the NIR range above 730 nm, the scattering and absorption of light decreases—-which means deeper tissue penetration. The second advantage, says Nahrendorf, is that there is less autofl uorescence with NIR.

The potential clinical applications? Nahrendorf points to endoscopy—where physicians are able to visually examine the colon and look directly for adenomas and colorectal cancer. “Colonoscopy can’t pick up all of the lesions,” says Nahrendorf. “But if you highlight those lesions that express high levels of proteases typically found in adenoma and carcinoma with a targeted molecular agent, they’re going to be much easier to see.”

Despite the fact that one of the significant advantages of NIR is its ability to more deeply penetrate into tissue, “it’s still not x-ray,” Nahrendorf says. The depth issue has to be overcome if optical imaging techniques—including NIR—are going to become more applicable in the clinic, he says.

“The dream is where one could really do non-invasive imaging. For instance, the carotid artery where stroke happens—what if you could look at that artery without a catheter?” he says.

Photo acoustic and magneto-acoustic imaging represent another emerging technology that may not be too far away from the clinic.

To understand the principle behind photo acoustic imaging, says Professor Stanislav Emelianov, one needs to appreciate a phenomenon understood by every boy or girl scout.

“It’s thunder and lightning,” says the University of Texas professor of biomedical engineering, who also heads the Ultrasound Imaging and Therapeutics Research Laboratory at the university. “It’s exactly the right analogy.”

In photo acoustic imaging, a laser pulse is directed into the tissue being studied. As the photons travel through the tissue, they’re absorbed, which results in the conversion of electromagnetic energy into heat and thermal expansion. “And like any other kind of effect in which there is a rapid expansion,” says Emelianov, “it will produce an acoustic wave.”

This is where the boy scout/thunder/lightning analogy comes into play. “When you were a boy scout, you were taught that if you saw a lightning bolt, and then heard thunder, and you were able to count up to 10 or so, then you knew it was sufficiently far away that you didn’t have to be too concerned,” says Emelianov. “But if it’s 1 – 2 – 3 and then you hear the thunder, you know it’s close, and you need to look for shelter. The reason you count the seconds is because the sound travels through air with a specific speed. The same thing is happening with tissue.”

In this case, Emelianov says, the “lightning” is created by hitting the tissue with a laser, and the tissue responds with the “thunder.” “So I can listen to that thunder and tell where there’s lightning—or where the actual absorption took place inside of the tissue,” he says.

The key is having the right kind of absorber to create the thunder. In Emelianov’s laboratory, they’re working with gold nanoparticles. “And if we make those nanoparticles targeted, which means they are becoming molecularly sensitive to a particular molecular signature that might be associated with a specific disease, then we should be able to see an accumulation of nanoparticles at the specific site.”

The delivery system is the same in magneto-acoustic imaging. There, the molecularly-sensitive nanoparticles—which are magnetized—are injected into the bloodstream. Once that nanoparticles lodge at the targeted site, a pulsed magnetic field is applied. If the tissue is moving at the frequency at which we apply the magnetic field, then a physician knows there are nanoparticles in that region, and if they are targeted that indicates that molecular signature is present at that particular site.

There could be several clinical applications associated with these technologies, says Emelianov, with two of the world’s major killers—cancer and heart disease—the major targets:

• Tumor Detection “The No. 1 application will be detecting pre-cancers and small cancers,” says Emelianov. “Obviously, when a tumor reaches a large enough size, we can detect it via various means, but to detect tumors early in their development, or even to detect precancerous cells, these nanoparticles could be wonderful mechanisms to find those precancerous and small amount of cancer cells, based on their molecular signature.”
• Combining Imaging & Treatment According to Emelianov, whether it is acoustic imaging, or magneto-acoustic imaging, once the nanoparticles have lodged in the targeted areas and been imaged, the laser can be turned from the imaging mode into the “therapeutic mode,” he says. Because the absorption of the light creates heat, “instead of looking at the tissue, I can start cooking the tissue. We can actually kill the cancer cells.”
• Metastasis A physician could inject the nanoparticles into the main tumor and lymph node, and if there is no metastasis, they will simply “pass by,” Emelianov notes. But, if the nanoparticles stay in the lymph nodes, then the physician will know the cancer has metastasized.
• Intravascular Imaging & Plaque Analysis “What is happening now is that it’s apparently not the amount of stenosis that kills the patient, but how vulnerable the plaque is,” says Emelianov. Acoustical or magneto-acoustical imaging will allow a physician to examine the anatomy, biology, and chemistry of that plaque before it ruptures and kills the patient.

As far as getting acoustic and magneto-acoustic imaging techniques into the clinic, Emelianov says there are several barriers that need to be overcome. The most obvious hurdle is that of the U.S. FDA. Since the technology relies on the use of nanoparticles, “it’s like drug design,” says Emelianov. “So realistically, it’s probably no sooner than five years to get FDA approval once we get to the FDA door and start banging on it.”

But, technology-wise, everything is pretty much in place. Devices such as lasers and ultrasound scanners are already widely used in clinic, which means there is nothing to approve or modify in those cases. “Other devices we are building in the lab, and once the industry picks it up, it will be a very rapid progression to the clinic.” Emelianov says. The problem will be getting and combining those technologies and commercializing them.

“My gut feeling is you won’t see it in true clinical practice for the next five years,” Emelianov says. “But there could be some clinical trials going in the next two years—that’s definitely true.”