This Vibrational Spectroscopy "Sees" Things That We Miss
When light hits a molecule, it vibrates and the scattered light creates a fingerprint of that molecule. This Raman spectroscopy opens new approaches in clinical diagnostics for many medical conditions. “It’s a biochemically specific technique that is sensitive to subtle changes in human biochemistry, physiology, and pathology,” says Anita Mahadevan-Jansen, Orrin H. Ingram Professor of Biomedical Engineering at Vanderbilt University in Nashville, Tennessee, and director of the Vanderbilt Biophotonics Center. “Raman spectroscopy can differentiate between subtle things like hormonal changes, things that many other techniques ignore.” Consequently, clinicians can use Raman spectroscopy to provide differential diagnoses with higher accuracy than ever. But all of Raman’s upsides come with challenges, and the biggest one is that the signal is weak. So capturing molecular information with Raman spectroscopy requires very sensitive instrumentation. As a result, this technology is really only beginning to reveal the extent to which it can change diagnostic science.
As explained by Haishan Zeng, distinguished scientist at the imaging unit in the integrative oncology department at the BC Cancer Agency Research Centre in Vancouver, British Columbia, “Raman spectroscopy is a very powerful analytical measurement that has been used in chemistry labs for many years.” Nonetheless, the time required to collect the data took too long for medical applications. “In the past decade,” Zeng says, “advances in laser technology, CCD cameras, and optics shortened the time for collecting Raman spectra.” That made it fast enough for medicine. “Now is the time to push for clinical applications,” he says.
Some of the “pushing” is underway. As Ioan Notingher, professor of physics at UK-based University of Nottingham, and his colleagues wrote in 2015 in Advanced Drug Delivery Reviews, “The key hypothesis underpinning this field is that molecular changes in cells, tissues, or biofluids that are either the cause or the effect of diseases can be detected and quantified by Raman spectroscopy.”
In addition, this group of scientists pointed out that data sets from healthy and diseased patients can be used to train a Raman-based system.
So far, only a couple of companies have Raman devices on the market for clinical applications. Richmond, British Columbia-based Verisante Technology, for example, offers devices for cancer detection. In Tokyo, Japan, Kanebo Cosmetics uses Raman spectroscopy to study changes in human skin.
In describing the status of using this technology in medical diagnostics, Mahadevan-Jansen says, “It’s mostly small start-up companies trying to penetrate the market.” She adds, “Only a few people are doing clinical Raman spectroscopy because it’s so challenging.” Nonetheless, she notes that the technology and computational power already exist to make this technique a valuable new diagnostic tool. “So, we just need to develop a database to show that it works well,” she says.
Scanning the Skin
More than a decade ago, Zeng started working on Raman technology as a potential diagnostic tool. At that time, it took about 20 seconds for one scan, and that, says Zeng, was too slow for clinical applications. In 2012, he and his colleagues reported in Cancer Research that Raman spectroscopy can distinguish between cancerous and benign skin lesions. “The first organ to attack is the skin, because it is easily accessible,” Zeng says.
With advanced optics, lasers, CCD technology, and a proprietary Raman probe design, Zeng and his team improved the signal-to-noise ratio by more than 16 times and accelerated the process so much that it takes them only 1.5 seconds to collect and analyze a Raman spectrum. “That opened the door to clinical applications,” Zeng says.
Zeng is working with Verisante to commercialize this process. “It helps physicians decide which lesions to biopsy,” he says, “and the likelihood that a lesion is cancerous or benign.”
This research produced the Verisante Aura to detect skin cancer. According to the Cancer Research study, this device can detect 95 percent of skin cancers and also reduce unnecessary biopsies by one- to twofold.
“At the moment, the only commercial application is in detecting skin cancers,” says Michael A. Short, senior scientist at Verisante. “Experimental devices at various stages of development are also being tested in collaboration with clinicians from various organizations.” For example, the company is working with colleagues at the BC Cancer Agency on lung and colon cancers and at Imperial College London on brain cancer. An initial collaboration with the Harvard School of Dental Medicine and the Dana-Farber/Harvard Cancer Center also showed that Raman had great potential in detecting oral cancers. For skin cancer, Verisante’s technology is approved for clinical use in Canada, Australia, and Europe, and the company is applying for approval from the U.S. Food and Drug Administration.
Better Breast Cancer Surgery
According to the World Health Organization (WHO), “Breast cancer is the top cancer in women, both in the developed and the developing worlds.” WHO also points out that longer life expectancy, increased urbanization, and lifestyle changes combine to increase the developing world’s incidence of cancer. Despite the increasing incidence, some of the tools for fighting this disease remain somewhat dated. During surgery, for example, a breast tumor gets removed—along with samples from some presumably safe margin to ensure excising all the cancerous tissue—and the samples go to histology, while the patient is stitched up and sent home to await the results. If the margin samples show cancer, the patient goes back for more surgery. Beyond the stress of waiting and the inconvenience of a second surgery, it also creates a second opportunity for infection.
With Raman spectroscopy, the outcomes of breast cancer surgery could improve. Mahadevan-Jansen is developing a tool that can be used to scan a tumor in the operating room and tell a surgeon in real time if all the cancer has been removed. Using a point-by-point scanning technique, Mahadevan-Jansen and her team have scanned entire tumors—usually a couple of centimeters in diameter—in about eight minutes. “We can scan the tumor while the surgeon is doing other things, like clotting blood,” she says. “It’s parallel processing.” Her team has also developed a 3-D scanner.
Although Mahadevan-Jansen’s technology is currently used to examine tissue removed from the patient, she is working on technology that can collect data from the surgical cavity. They are also using it to look at lymph nodes in the cavity to see if the breast cancer has spread.
Beyond the technological challenges, this field also faces financial ones. Like all diagnostic medical devices, ones based on Raman technology need to be developed and then approved through clinical trials, which usually requires a company licensing the technology. Although Mahadevan-Jansen has patented some of her technology, no company has stepped forward to develop it for commercial use. Still, she remains optimistic, despite other companies testing other techniques for similar applications. “We get better accuracy and reliability than others,” Mahadevan-Jansen says, “but that still requires translation for research and development to the market.”
The applications for Raman spectroscopy in cancer will also expand, because Mahadevan-Jansen says that it “can be used for other solid tumors.” As she points out, “It just requires studying them and developing a database and algorithms.”
And at some point, this approach could move beyond clinical diagnostics for cancer to surgical guidance. That is, a surgeon could use the information from a Raman signal in real time, essentially seeing what is cancerous tissue and what is not during an operation.
Beyond medical diagnoses, Raman spectroscopy can be used to explore the body for, perhaps, unexpected uses. Scientists at Kao Corporation, parent of Kanebo Cosmetics, use Raman technology to study the skin. As Shinji Yamada, manager of corporate public relations at Kanebo, points out, “We never use the device to diagnose medical conditions.” But he adds, “We do, however, use it to determine how age changes the moisture levels of the dermis.”
In fact, scientists at Kanebo use Raman spectroscopy to study many features of the skin. For example, Raman can measure the roughness of skin, which increases as the stratum corneum—the layer of skin that is exposed—gets thicker as people age. But this technology goes beyond the surface. As Yamada explains, “We use our Raman spectroscope to measure from the skin surface to the inner skin layers.” As an example, he says, “We can quantify the thickness of the stratum corneum and the moisture levels inside the skin—from the stratum corneum to the epidermis and the upper layer of the dermis.”
To make the best products for the skin, scientists need the best analysis of the tissue’s layers and how they change over time.
Breaking the Barriers
“The technology is sitting here, waiting for clinical translation,” Mahadevan-Jansen says. “The research just needs to be targeted to break this barrier and move forward with Raman as a clinical tool.” Once that can be done, physicians and surgeons will diagnose many medical conditions more efficiently and more accurately.
The ongoing research indicates that Raman-based devices can be used in a wide range of clinical diagnostic devices. In addition, this technology can be used in industries that examine the condition and health of specific tissues, such as the skin, and then develop commercial products accordingly.
The foundation of all these applications consists of technological advances that allow scientists and technologists to quickly collect data from the weak Raman signal of molecular vibrations. A decade ago this seemed unlikely, and a decade from now Raman spectroscopy could be used routinely in many diagnostic tools.