Interferometric detection of microRNAs using a capillary optofluidic sensor
Introduction
Early diagnosis and treatment of many diseases require the knowledge of the concentrations of specific biomarkers in human bodies. Monitoring the change of biomarker in real time also allows the identification of the susceptibility to different therapies and interactive optimization of medical treatments with reduced time and costs, compared to clinical validation of therapies [1]. Among the diverse biomarkers, microRNA (miRNA), a small non-coding RNA molecule, plays an important role in transcriptional and post-transcriptional regulation of gene expression [2], [3], and serves as reliable molecular biomarker for cancer diagnosis and prognosis [4], [5]. Optofluidic sensors, which integrate microfluidics and photonics on a chip-scale system [6], have been developed for detection and identification of diverse biomarkers including miRNAs in aqueous environment with extremely low sample consumption [7], [8]. Optofluidic sensors based on photonic crystal (PC) [9], [10], [11], [12], [13], [14], microstructured optical fibers (MOFs) [15], [16], [17], [18], [19], [20] and liquid-core waveguides have been demonstrated. These optical structures incorporate air holes as high-quality microfluidic channels. The optical mode in these channels effectively overlaps with the analytes filled into the air holes [19]. A biomolecular binding event at the surface of fluid channel induces an excess polarizability to local light, which is translated to detectable optical responses in terms of changes in intensity, phase or wavelength. Take the MOF-based optofluidic sensors for example, fiber Bragg grating (FBG) [16], long period grating (LPG) [17] and/or interferometer [19] are formed in the fibers to translate the evanescent field interaction into detectable wavelength shift of the transmission spectra. However, the sensitivity of the optofluidic sensor is critical for biomolecular detection because the local light is usually confined in the substrate, with weak evanescent wave to interact with the bound analyte molecules.
In order to enhance the local evanescent field strength, the above optical structures can be designed to localize and enhance the electric field in a nanoscale air pore [21], which makes the sensors more sensitive to the biomolecule induced refractive index change [7], [14], [22], [23]. However, accessing the small liquid channel is troublesome [23]. Plasmon enhancement can also be achieved at metal-dielectric interfaces based on structures including planar nanofilms [24], [25], [26], periodic nanoarrays [27], [28], and single nanoparticle [29], [30]. Alternatively, optical microcavities have been used for biomolecular detections. The resonant recirculation of light within a microcavity allows the light to interact with the target molecules multiple times [31]. For example, by using a planar microcavity with a quality (Q) factor of 108, the light in the cavity interacts with the molecule for more than 100,000 times [31]. The target molecules directly change the optical path length and/or the cavity loss of the sensor and result in a shift of the resonance spectrum [31]. By measuring the resonance spectrum shift, the microcavity resonators have been applied for label-free detection of single virus [32], nanoparticle [33], and single molecule [31]. Resonant optofluidic sensors by using a micro-sized glass capillary as the cavity as well as the fluidic channel [34], [35], have been demonstrated for detection of glucose [36], volatile organic compounds [37], proteins [8], [38], DNAs [39], viruses [40], and cells [41]. However, the optical excitation of the resonator requires a lead-in fiber perpendicularly aligned along the capillary, which makes the resonator susceptive to environmental perturbations [38] and limited to laboratory conditions.
In this paper, we presented a capillary-based optofluidic sensor for interferometric detection of miRNAs, which was fabricated by tapering parallelly aligned silica capillary and optical fiber. The interference between two discrete optical modes in the taper structure creates a periodically oscillating transmission spectrum. When the biomolecules bind at the interior capillary surface, they interact with the evanescent wave, which induces a change in the phase difference of the two optical modes. By measuring the shift of the interference spectrum induced by the phase difference, an optofluidic sensor was demonstrated for the identification and detection of miRNA-let7a molecules (molecular weight: 6.75 kDa) [42], [43]. To capture the miRNA-let7a molecules, a pre-immobilized DNA probes was used. The sensor presents a log-linear response to concentration range from 2 nM to 20 μM and a minimum detectable concentration of 212 pM (1.43 ng/mL). The optofluidic sensor also presents the capability of differentiating miRNAs with only one-base mismatches. The sensor is fabricated by heat treatment with commercial facilities and is inherently connected to fiber optics, which enables easy fabrication and handling. It also presents improved portability and the resistance to environmental perturbations, indicating its feasibility in practical applications other than laboratory conditions.
Section snippets
Sensor fabrication and working principle
Fig. 1(a) schematically shows the fabrication of the optofluidic sensor. A bare 125-μm single-mode optical fiber is aligned with a silica capillary in lateral contact in the same direction. The fused silica glass capillary (Polymicro Technologies) has an outer diameter of 660 μm and a thickness of 65 μm. A flame is used as a heat source to taper the fiber as well as the capillary down by tens of times in dimension. This is done by heating up the silica glass at the softening temperature while
Materials
98% sulfuric acid, hydrogen peroxide, phosphate buffered saline (PBS), absolute ethanol, 25% glutaraldehyde water solution, and water-DEPC were obtained from Sangon Biotech (Shanghai, China). 99% 3-APTES was purchased from Sigma-Aldrich (Darmstadt, Germany). The aminated single-stranded DNA probe, target miRNA-7a miRNA-let7a and its modified sequences were provided by Sangon Biotech (Shanghai, China). The aminated single-stranded DNA probe had the sequence: 5′-NH2-AAC TAT ACA ACC TAC TAC CTC
Result
Fig. 5(b) shows the sensorgram during the surface functionalization (procedures (1) to (4)) and the miRNA hybridization (procedure (5)). Here the dip wavelength is recorded with static fluid and the result during 30-min rinsing with flow fluid is not given. The sensor shows a net spectral shift of 2.54 nm to miRNA with a bulk concentration of 20 μM, in good agreement with the calculated result. Fig. 6(a) shows the measured responses to different levels of miRNA-let7a concentrations by repeating
Conclusion
We have demonstrated quantitative detection of miRNA by using a microfiber-capillary optofluidic sensor. The optofludic device is based on a modal interferometer fabricated by aligning the fiber in lateral contact with the capillary, which is different from the orthogonal configuration in the conventional resonator. The binding events at the capillary interior can be detected by measuring the spectral change, as a result of the evanescent-wave interaction with the biomolecules as well as the
Acknowledgements
This work was supported by National Natural Science Foundation of China (61225023, 11374129, 61405074), the Planned Science and Technology Project of Guangzhou (2014J2200003), Guangdong Natural Science Foundation (S2013030013302), and the Department of Education, Guangdong Province (Yq2013021).
Lili Liang received the B.S. degree from Hebei University of Engieer in g, Handan, China, in 2011 and Master degree from Hebei University of Technology, Tianjin, China, in 2014. She is currently working toward the Ph.D. degree at the Institute of Photonics Technology, Jinan University, Guangzhou, China. Her research interests include optical fiber devices and optofluidic sensors.
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Lili Liang received the B.S. degree from Hebei University of Engieer in g, Handan, China, in 2011 and Master degree from Hebei University of Technology, Tianjin, China, in 2014. She is currently working toward the Ph.D. degree at the Institute of Photonics Technology, Jinan University, Guangzhou, China. Her research interests include optical fiber devices and optofluidic sensors.
Long Jin received the B.S. degree in applied physics and the Ph.D. degree in fiber optics from Nankai University, Tianjin, China, in 2003 and 2008, respectively. He joined the Department of Electrical Engineering, Hong Kong Polytechnic University, in 2008, as a Research Assistant, where he was also a Postdoctoral Research Fellow. Since 2010, he has been with the Institute of Photonics Technology, Jinan University, Guangzhou, China, as an Associate Professor. He has published more than 50 journals and conference papers. His research interests include fiber optic devices, specialty optical fibers, and photonic sensors.
Yang Ran received the B.S. degree from Dalian University of Technology, Dalian, China, in 2006, and the Ph.D. degree from Jinan University, Guangzhou, China, in 2013. He is currently a lecturer at the Institute of Photonics Technology, Jinan University, Guangzhou, China. His research interests include optical fiber devices and photonic biosensors.
Li-Peng Sun received the B.S. degree from the Hefei University of Technology, Hefei, China, in 2010 and Ph.D. degree from Jinan University, Guangzhou, China, in 2016. He is currently a lecturer at the Institute of Photonics Technology, Jinan University, Guangzhou, China. His research interests include optical fiber devices and sensors.
Bai-Ou Guan received the B.Sc. degree in applied physics from Sichuan University, Chengdu, China, in 1994, and the M.Sc. and Ph.D. degrees in optics from Nankai University, Tianjin, China, in 1997 and 2000, respectively. From 2000 to 2005, he was with the Department of Electrical Engineering, Hong Kong Polytechnic University, Hong Kong, first as a Research Associate, and then as a Postdoctoral Research Fellow. From 2005 to 2009, he was with School of Physics and Optoelectronic Engineering, Dalian University of Technology, Dalian, China, as a Full Professor, where he established the PolyU-DUT Joint Research Center for Photonics. In 2009, he joined Jinan University, Guangzhou, China, where he founded the Institute of Photonics Technology. His current research interests include fiber optic devices and technologies, optical fiber sensors, biomedical photonic sensing and imaging, and microwave photonics. He has authored and coauthored more than 240 technical papers and presented more than 30 invited talks at international conferences. He is a member of the Optical Society of America, and served as the General Chair of the 10th International Conference on Optical Communications and Networks, the General Co-Chair of the 2nd Asia-Pacific Optical Sensors Conference, and the Technical Program Committee Co-Chair of the 5th Asia-Pacific Microwave Photonics Conference 2010.