LI JIANG, PILGYU KANG, and DAVID ERICKSON
A decade of development has thrust optofluidics technologies to the forefront of biological and chemical analysis and molecular diagnostics research. This development is accompanied by the recent emergence of high-tech start-ups such as Optofluidics Inc. (Philadelphia, PA) and Liquilume Diagnostics (San Jose, CA), which use variations of optofluidic waveguides to evaluate and manipulate nanoparticles and biomolecules.1,2
As considerable technical achievements continue to be made in these areas, optofluidics technologies are poised to impact some major health-care engineering challenges. In particular, we envision applications in global health and drug discovery to be major areas of interest in the near future.
One of the most significant challenges of improving global health is providing high-tech diagnostics to the developing world. With the exception of a few centralized health-care facilities, most resource-limited regions do not have the infrastructure to support modern health-care technologies. People who are not close to such facilities or do not have the means to receive the best available care face long delays between developing a disease and receiving treatment, greatly reducing the chance for survival. In particular, our lab has focused on Kaposi's sarcoma (KS), an AIDS-related cancer caused by KS herpesvirus (HHV-8). In sub-Saharan Africa, KS is one of the most prevalent cancers and is associated with significant morbidity and mortality in adults and children. Early diagnosis and treatment is one key to increasing survivability, but limited resources make this goal extremely challenging to achieve.
To provide early near-patient diagnosis, new diagnostic devices must be usable in remote settings, where reliable electricity is rarely available. In such cases, sunlight may emerge as a more practical means to supply the necessary power through not only solar cells but also solar thermal energy. Optofluidics, with its ability to simultaneously manipulate light and the microfluidic environment, could lead to the advancement of such technologies in the coming years.
Our recent work utilizes solar heating of a microfluidic chip to drive a polymerase chain reaction (PCR), a biochemical technique that amplifies DNA for various diagnostic and sequencing applications.3 Through amplifying a specific DNA target, rare traces of bacterial or viral DNA can be more easily detected in a sample to determine the condition of a patient. Typically, PCR involves thermally cycling a sample between 95°C and 60°C to duplicate a specific DNA sequence. The act of repeatedly heating and cooling the sample is very power intensive, and traditional PCR machines require an electrical grid or high capacity batteries. By using sunlight in the right manner to heat a microfluidic system, we achieve the thermal conditions necessary for PCR while eliminating the high energy burden traditionally required for this process.
Figure 1 shows our portable system and how PCR is achieved. A stage with a concentrating lens and a microfluidics platform is built to rotate to face the sun through the day (Fig. 1a). The lens concentrates sunlight onto a microfluidic chip below, where it is masked by aluminum foil rings at specific locations (Fig. 1b). The light that goes through is then absorbed by a black film and converted to heat. By placing the chip at the right distance from the lens and masking the light in the right way, three temperature zones at 95°C, 72°C, and 60°C are created along the chip's radius. A microfluidic channel then repeatedly guides a sample through these three regions, effectively creating the thermal conditions that induce PCR (Fig. 1c).
A custom application on a smartphone measures the on-chip temperatures to ensure the correct temperatures are maintained throughout the test (Fig. 1d). After about 30 min, the amplified product exits the chip and is mixed with a fluorescent dye for which the fluorescence intensity correlates to the DNA concentration within the sample. The app then analyzes the intensity to determine the test result (Fig. 1e). Without the need to provide energy for heating, power is only required to run the app, reducing power consumption to 80 mW. Using a small solar panel for recharging in the field, a typical smartphone battery can potentially run the test indefinitely.
Biosensors for drug discovery
Despite progress in the understanding of biochemical systems and advancements in computer-aided drug design, drug discovery remains an extremely laborious and expensive process. For example, it is estimated that for one drug to reach the launch stage, 24 candidate drugs must be tested, requiring on average 13 years and $1.8B of R&D.4
To reduce the amount of wasted time and cost, technologies must be able to uncover the flawed candidate drugs as soon as possible. In this initial phase, analysis of molecular interactions is a critical component of drug development. For this step, biosensors can perform tasks for screening and developing drug compounds for receptor biomolecules. The optofluidic biosensing devices developed in our lab could provide comprehensive information on the binding affinity as well as the binding kinetics of the interactions between drug compounds and receptor biomolecules, making them well suited for drug discovery applications.Generally speaking, our efforts have been to integrate photonic-crystal resonant waveguides with microfluidics to create biosensing devices based on the optofluidic nanomanipulation techniques we developed (see Figs. 2a and b). We have used photonic-crystal-based resonant waveguides to signal the presence of antigens through inducing a change in the resonant frequency. The resonant waveguide confines electromagnetic energy by spatially localizing the optical field to a small mode volume. The resonant optical field, which has a distinctive resonant wavelength, is changed when the confined light energy interacts with molecular targets. The localized optical field enables strong light-matter interactions, which allows a detection level limit on the order of 10 attograms of target mass.
With this, we demonstrated monitoring of real-time binding kinetics by functionalizing a device with an antibody that binds with a target molecule.5 Multiplexing was also established with this platform, which consists of multiple photonic-crystal resonators evanescently coupled to light from a neighboring waveguide. In this case, multiple resonators allow the concurrent detection of multiple targets in a single device.
The silicon-based nanophotonic devices we previously developed work at a resonance wavelength of 1550 nm (which is generally used in telecommunication applications) due to high quality factors that allow stronger light-matter interaction. More recently, we have developed silicon-nitride-based nanophotonic devices that work at 1064 nm, making them more suitable for biological applications. This wavelength is considered biologically safe because of its low absorption in water, avoiding the heat that would otherwise be generated at 1550 nm and transferred to nearby biomolecules.
We have developed commercialized integrated systems such as the NanoTweezer from Optofluidic Inc., a nanophotonics-based optical tweezer. We are also developing novel label-free detection methods for bioassays with imaging techniques such as fluorescent microscopy and light scattering microscopy. The imaging techniques allow observation of biomolecular interaction solely by optical manipulations of biomolecules, whereas the previously developed method requires measuring the change in the resonant frequency using a spectrum analyzer.
Through integration with fluorescent microscopy, our technique allows us to observe the interactions of fluorescently tagged biomolecules, which are optically trapped sequentially by the nanophotonic tweezer (Fig. 2c). Using light-scattering microscopy, on the other hand, our label-free biomolecular-sensing method can be applied for pathogen detection and identification.
In many ways, global health and drug discovery represent opposite ends of the health-care spectrum. While large pharmaceutical companies endeavor to discover and develop new drugs, rural clinics in developing countries struggle to provide reliable diagnosis and care to its patients.
Effective health care, however, requires both successful diagnosis and treatment of patients, and thus advancements in both areas are critical. As shown by solar thermal PCR, optofluidics can be motivated by the limitations of the developing world to form new diagnostic tools that are inexpensive and do not rely on well-established infrastructure. Similarly, new optofluidic biosensors could dramatically reduce the burden of drug discovery, leading to faster and better treatment options. Through these innovations, optofluidics could in the coming years help transform the health-care landscape.
3. L. Jiang, et al., Sci. Rep., 4, 4137 (2014).
4. S.M. Paul, et al., Nat. Rev. Drug Discov., 9, 203 (2010).
5. S. Mandal, et al., Lab on Chip, 9, 2924 (2009).
Li JIANG and PILGYU KANG are mechanical engineering PhD candidates and DAVID ERICKSON is principal investigator at the Erickson Lab, Cornell University, Ithaca, NY; www.ericksonlab.org; email: [email protected].