“We are very good at developing novel optofluidic devices for research demonstrations; the challenges lie in transitioning these devices into commercially viable products.” – Arthur Nitkowski, Cornell University Optofluidics is a relatively young field but is growing rapidly to serve applications from analysis of biomolecules and cells to creation of novel optical switches and lasers. The discipline has emerged in only the past five or six years as two other important fields – microfluidics and nanophotonics – have reached their peak in terms of technology development, leading researchers to explore ways to combine their respective strengths into a single package. Optofluidics technologies are evolving, said David Erickson, director of the Integrated Nanofluidic Systems Lab in the Sibley School of Mechanical and Aerospace Engineering at Cornell University in Ithaca, N.Y. Indeed, many new technologies are already very mature at the lab scale, he said. The next step is to develop them for real-world, large-scale applications. David Erickson of Cornell University, along with Dr. Bernardo Cordovez, recently launched Optofluidics Inc. to develop products such as switches for biotechnology applications. Using fluids and optics together, Erickson said, might enable new forms of reconfigurable photonics. A number of groups are developing optofluidic technologies for lab-on-a-chip applications. Also at Cornell, Arthur Nitkowski, Antje Baeumner and Michal Lipson designed and built a microscale optofluidic device that measures optical absorption in color-producing enzymatic reactions for biochemical analysis. As reported in the Feb. 1, 2011, issue of Biomedical Optics Express, this employs cavity-enhanced laser spectrophotometry to probe analytes in a microfluidic channel with silicon nitride microring resonators. The device addresses a challenge often encountered with similar technologies. “Many researchers have used optical microcavities as refractive index sensors to measure binding events on the surface of a waveguide,” Nitkowski said. “Those devices work by measuring the shift in resonance wavelength of a microcavity, but this shift can be caused by nonspecific binding or thermal fluctuations.” Researchers at Cornell University recently described a microscale optofluidic device for biochemical analysis. With this device, cavity-enhanced spectrophotometry is performed on analytes in a microfluidic channel with microring resonators. Shown on left is an array of such resonators within a microfluidic channel. The small dots are enzymes; the rings are sensitive to color changes produced in the microchannel by the enzymes. Courtesy of Arthur Nitkowski. Microfluidic cytometry The investigators showed that they could measure the unique spectral signature of the analyte itself, eliminating the need to alter the surface of the ring to facilitate the binding of specific biological targets. They achieved this by using high-quality factor microcavities with high-index contrast materials. Low losses in the cavities allowed light to propagate many times around the circumference of the ring, thus extending the effective optical path length of the device. At the University of Alberta in Edmonton, Canada, Xuantao Su and colleagues are looking into optofluidic technology to aid in the development of the next generation of portable cytometers for point-of-care and other applications. Current commercially available flow cytometers employ multiple lasers and detectors, leading to a complex system that is expensive and massive, Su said. To achieve its goal, Su’s group had to compress the light excitement and detection system found in existing cytometers. At the University of Alberta, researchers reported a microscope-based label-free microfluidic cytometer that enables differentiation of normal from cancerous cells, for example, through analysis of 2-D light-scattering patterns. A schematic of the device is shown here. Courtesy of Xuantao Su. In the Jan. 3, 2011, issue of Optics Express, the researchers – including Ying Y. Tsui, Wojciech Rozmus and Anna Janowska-Wieczorek – reported a microscope-based label-free microfluidic cytometer that could serve as a prototype for point-of-care clinical applications. The system allows non-imaging observation of single cells, enabling differentiation of normal from cancerous cells through analysis of 2-D light-scattering patterns. This was made possible by incorporating a microscope objective into the cytometer which, in defocusing mode, functions in a way that is contrary to how these objectives are normally used, Su said. The numerical aperture of the optical objective improves the signal-to-noise ratio of light-scattering detection, enabling the system to obtain patterns from platelets, the smallest mature human blood cells. Optofluidic sensors represent the next generation of molecular detectors and may find application for cancer diagnostics. Courtesy of David Erickson. Optofluidic evolution Su recently moved to Shandong University in Jinan, China, where as principal investigator he leads an interdisciplinary team exploring optofluidic technology for the next generation of portable instruments. Having developed and successfully demonstrated a broad range of technologies, the optofluidics community can now also look toward commercialization of those technologies. “We are very good at developing novel optofluidic devices for research demonstrations; the challenges lie in transitioning these devices into commercially viable products,” said Nitkowski, who now works with a startup company developing nanophotonic devices for spectroscopy applications. To achieve this, he said, developers of the technology essentially need to divorce lab-on-a-chip devices from traditional laboratory equipment like microscopes, pumps and sample-prep instruments. “Optofluidics plays an important role here, but more functionality (electrical, pneumatic, etc.) needs to be integrated to develop stand-alone devices.” Erickson agrees that transitioning from the lab to the marketplace is the next step in the evolution of optofluidics. “We’re building a lot of demonstrative devices in the lab,” he said, “but the major challenges of the 21st century – the grand challenges – are all about big things: desalinization and energy, for example. The question now is, ‘How do we take advantage of physics at the micro- or nanoscale but upscale it so it’s useful for these large-scale applications?’ ” Global health challenges A new generation of researchers is also working to develop optofluidic technologies, using them to address some of the most serious challenges of the still-young century. In March, Guoan Zheng, a graduate student at the California Institute of Technology in Pasadena, was awarded the $30,000 Lemelson-MIT Caltech Student Prize in recognition of a simple, cost-effective, high-resolution on-chip microscope he designed – called the subpixel resolving optofluidic microscope. The instrument has a range of potential applications, particularly in the developing world. These include improved diagnosis of malaria and detection of blood-borne and water-borne parasites. The subpixel resolving optofluidic microscope, designed by Guoan Zheng, could contribute to a number of point-of-care applications in the developing world. Courtesy of Guoan Zheng. The microscope uses oversampling in the time domain to compensate for undersampling in the spatial domain; this is made possible by applying a superresolution algorithm. The basic principle of this image-enhancement technique is to get one high-resolution image from several low-resolution images, Zheng said. Zheng and his colleagues continue to develop the optofluidic microscope. For example, they are planning to implement a new, more robust version using glass-based microfluidic channels integrated at the wafer level. They also are looking to incorporate additional imaging modalities onto the current platform, he said, including dark-field and phase imaging capabilities. Providing health care in the developing world – in what are often described as “resource-limited settings” – is an important potential application of optofluidic devices. Accurate diagnosis is needed for treatment and prevention of a number of infectious diseases as well as for monitoring of health conditions, but this must be achieved without the trained personnel, established infrastructure and costly medical instruments found in the developed world. Creating technologies for use in resource-limited settings involves a range of challenges. Most importantly, devices must be inexpensive, portable and easy to use but as robust as technologies used in clinical settings in developed nations. “At the end of the day, the performance has to be comparable to that of the gold standard,” said Utkan Demirci, director of the Bio-Acoustic-MEMS in Medicine (BAMM) Laboratory at Brigham and Women’s Hospital and Harvard Medical School in Boston. The BAMM Lab develops microfluidics for low-cost CD4 counts and viral load detection for HIV in resource-limited settings for global health problems. “The information it provides has to be clinically relevant.” Pushing development Developers must consider a host of other factors, though. Since they are to be used at the point of care in resource-limited settings, the devices must be able to function under high heat and humidity, and must be able to withstand electrical outages, for example. Also, because patient populations are likely to be found in remote locations, the technologies must be rugged enough to survive lengthy rides or walks – often across difficult terrain – while stuffed in a backpack. And even if they come up with a device that can achieve all this, developers may face challenges in commercializing it. “If you are building a company in, say, Boston, the route is more clear,” Demirci said. “One can reach who the stakeholders are in the marketplace; you know who the buyers are. But if you are developing a technology for resource-limited settings, you have to figure out who the customer is, and who is going to fund it.” Getting to know the nongovernmental and governmental organizations working in these areas is essential, he said. Also, in recent years, social entrepreneurship and social capital concerns have begun to support such efforts. One example: the Bill & Melinda Gates Foundation which, in late April, announced 88 new global health projects to be funded by its Grand Challenges Explorations grants. “Although there are challenges, the needs are apparent for rapid diagnostic and monitoring technologies for the point of care,” he said. “Some of these technologies may also later contribute positively to the cost of health care and health care economics in the resource-rich settings.”