Although hurdles remain, the promise of quantum cascade lasers in medicine moves closer to realization with the commercial
introduction of a microscopy platform, demonstration of a prototype device for breath analysis, and continued research and development.
The first demonstration of the quantum cascade semiconductor laser 20 years ago opened a new door to the exploration and exploitation of mid-infrared light. Since then, the technology has found broad application in trace-gas analysis for explosives detection, environmental monitoring, industrial process control and more, according to Dr. Federico Capasso, one of the scientists who collaborated on the demonstration at Bell Labs in January 1994.
Despite their adoption by other industries, QCLs are not currently in widespread use in commercial medical applications.
Capasso, now a professor of applied physics and a senior research fellow in electrical engineering at Harvard University, believes that the technology has not yet reached its potential for highly selective, real time and reliable non-invasive detection of diseases such as diabetes, colon cancer and ulcer.
Capasso’s business, EOS Photonics, focuses on broadband QCLs that “allow the simultaneous and fast detection of many chemicals,” and unveiled a prototype product at Photonics West in January. Capasso offered a suggestion for a business model that could help broaden the use of QCLs in medicine: Central to this model is a company providing the QCL-based analyzer free of charge and making money as a percentage of the outpatient fees.
“Diabetes could be detected also from glucose monitoring in the blood using [QCLs], and it is known that some companies have been looking into it,” Capasso said. “Of course, any such tests would have to be FDA approved. What is needed is a lot of research, with doctors and biologists teaming up with QCL researchers and developers. But the promise and payoff could be huge.”
Demonstrating the power
One company at the forefront of QCL research and development – and banking on the promise and the payoff – is San Diego-based Daylight Solutions, a developer of molecular detection and imaging systems for use in scientific research, life sciences, industrial process control and defense applications. In March, the company introduced a QCL-based infrared microscopy platform powered by its broadly tunable source, and designed specifically for analyzing biomedical and materials research samples.
The instrument, Spero, is designed to provide high-fidelity spectral data for the identification of molecular and chemical components of complex, heterogeneous samples. Full-spectrum, high-resolution hyperspectral data cubes can be collected in minutes, the company says, and a live-mode capability lets users observe samples with discrete frequency illumination, allowing real-time imaging of individual spectral features. The instrument has a compact, desktop form factor and requires no liquid nitrogen cooling.
Spero from Daylight Solutions is a QCL-based infrared microscopy platform powered by the company’s broadly tunable source and designed for analyzing biomedical and materials research samples.
Using infrared microscopy for tissue analysis has been heavily researched over the past decade, with many papers showing a strong correlation between infrared signatures and various disease states in cells and tissue. Relatively small-scale clinical trials have shown very promising results, according to Matt Barre, business development manager at Daylight Solutions. The company, which has sold many off-the-shelf QCLs as well as lasers to research labs for use in building microscopes, felt that someone needed to take the microscope concept to the next level.
“We identified IR microscopy as an ideal entry point for QCLs into the biomedical space, and the release of Spero marks the first major milestone in this effort,” Barre said. “We believe that this platform will be hugely important in pushing not just IR microscopy but QCL-based systems in general out of the reseach space and into the clinic. The instrument offers several key advantages over existing techniques that can make IR microscopy both practical and cost effective in a clinical setting.”
Moving this technique into the clinic still faces some hurdles related to both technology and instrumentation, which Barre said are answered by the company’s new microscope. “Other hurdles are related to validation of the technique involving large-scale trials, establishing standards, generating databases, etc. We intend for our microscopy platform to contribute to these efforts as well.”
The company considers Spero to be a “beachhead” product, showcasing the power of IR spectroscopy and establishing QCLs as the ideal light source for these types of biomedical applications. “We’re getting the instrument out there
so people can see the power of the technique,” Barre said.
“We would like to see IR microscopy become a standard tool in the clinical pathology workflow. It is a non-destructive, label-free technique that can provide quantitative results very quickly,” he added. “It is very well-suited for automated, high-throughput applications and the data analytics can easily be automated as well.”
Daylight Solutions and others continue to increase the technical performance of QCLs, including optical power, wavelength tunability and efficiency, and Barre noted that the combination of these parameters enables high-performing systems in smaller packages with lower power requirements.
“Broad tuning is a key capability that differentiates QCLs from other IR technology,” Barre said. “As with most technologies, cost will come down as new applications emerge and drive volume.”
MIRTHE looks to medical niche
MIRTHE, Mid-InfraRed Technologies for Health and the Environment, is a National Science Foundation engineering research center established in 2006 and headquartered at Princeton University. The center develops mid-infrared sources and ultrasensitive sensor systems for environmental, medical and security applications.
At SPIE Photonics West in February, MIRTHE researchers – Yin Wang, a Ph.D. student; Dr. Michal Nikodem; graduate student Eric Zhang; and Dr. Gerard Wysocki from Princeton University Laser Sensing Laboratory – demonstrated a prototype Faraday rotation spectroscopy (FRS) sensor system designed to measure nitric oxide (NO) isotopes in human breath. A novel dual-modulation FRS signal-detection technology (DM-FRS) enables implementation with an optomechanical configuration, allowing construction of robust and reliable instruments suitable for a wide variety of measurement conditions, including in clinical settings.
“Nitric oxide (NO) is a highly reactive radical species that plays an important role in many chemical processes ranging from atmospheric chemistry (e.g., ground ozone formation) to biomedical science. Due to its high reactivity, NO occurs at very low concentrations, and its detection at sub-ppbv levels is often desired,” the team wrote. “Preliminary tests of NO isotopes detection in breath, urine and blood for metabolic studies have been performed [at] Cleveland Clinic, demonstrating [the] promise of future applications in noninvasive medical diagnostics.”
The system employs a quantum cascade laser source from Alpes Laser SA, operating at 5.4 μm, and a novel DM-FRS technique for signal-to-noise enhancement, yielding 14NO and 15NO detection limits of 3.84 and 0.53 ppbv/Hz1/2, respectively. The prototype is a 19-in. rack-mounted, transportable system that developers say can be further miniaturized from its current size.
Dr. Raed Dweik at Cleveland Clinic and Dr. Christina Kao at Baylor College collaborated to test the instrument.
Now, MIRTHE is advancing a plan to expand its research activities into medical applications of mid-IR technologies. Its leaders announced early this year that they had received a planning grant proposal from the NSF to develop a new I/UCRC (Industry & University Cooperative Research program) on mid-infrared medical systems (MIMeS). The proposed new center will focus on developing and deploying engineered systems with mid-IR technologies for medical applications. This new center was proposed because MIRTHE leaders saw a niche, based on discussions with companies and ongoing research, said Bernadeta Wysocka, MIRTHE’s industrial liaison.
The new center will focus on the following research points: development and identification of new breath biomarkers using improved mid-infrared trace-gas sensing technology; noninvasive glucose monitoring for diabetics using mid-infrared laser spectroscopy; living tissue as a new mid-infrared transducer, and laser-based manipulation, coagulation and ablation of tissue; and noninvasive breath diagnostics for drug discovery and patient health monitoring.
Dr. Claire Gmachl will serve as director and principal investigator, and Joe Montemarano will be the center’s executive director, roles the two currently hold at MIRTHE. The Cleveland Clinic has signed on as a clinical research partner, with Dr. Raed Dweik as clinical research director.
As many as 10 MIRTHE faculty – maybe more – currently are working on medical applications of mid-IR systems, many involving QCL sources, according to Montemarano. The projects range from a clinical trial for breath diagnostics and mid-IR eye laser surgery to noninvasive glucose and CO2 monitoring, as well as developing QCL sources and detectors at medically relevant wavelengths. Much of this work will transition in some form and be supported through MIMeS, and MIMeS will take the pioneering work coming out of MIRTHE and focus resources to create the medical impact the researchers would like to see, Montemarano said. QCL sources and overall systems have matured, and there is greater confidence that those sources can be efficiently produced at medically relevant wavelengths, he added. Further, company collaborators large and small are looking to develop commercially viable mid-IR products.
“Many of the potential health care/medical-device players appreciate the progress MIRTHE has made on environmental applications, but their business focus is life sciences, and medical mid-IR systems developments need focused support and nurturing in order to adequately progress and address the special needs and nuances of medical applications,” Montemarano said.
With confidence growing in the technology, and growing interest among companies and universities to develop products around QCLs, Montemarano believes that the remaining hurdles include developing a better understanding of what drives opportunities for innovation in the pharmaceuticals/medical-device sectors, as well as leveraging agencies such as NIH to clearly demonstrate the relevance and benefits of mid-IR medical systems beyond currently entrenched technologies such as mass spectrometry/gas chromatography.
“QCLs are inherently adaptable to a smaller footprint,” Montemarano said, “and eventually with larger-market applications will come lower cost.” Beyond that, it is important to demonstrate that QCLs provide noninvasive, real-time results, he pointed out, adding that marrying the advantages with smartphone formats will make QCLs the technology of choice for a large number of medical applications.
Communicating the best story with regard to moving a technology forward is a recent lesson learned, and an important one. Breath analysis or measurement was a longtime goal for the technology, but one that Montemarano thinks is about as complicated as building the technology itself. With that complexity in mind, the conversation can now shift from asking whether a drug will work to asking how the drug will be metabolized in an individual patient. Talking about “precision monitoring of human metabolism,” Montemarano said, “will make critical linkages between genomic differences and differences in actual metabolic expression. [These] differences will be seen on a subpopulation basis, and this will be key information for physicians when deciding which drugs will work best and with [the] least side effects for an individual.”
The proposed NSF I/UCRC will position industry partners to better connect with clinical researchers’ strong understanding of patient needs and motivate them to efficiently commercialize the technology that will emerge from the new center, he said.