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Biomedical Optics & Medical Imaging

A nanoplasmonic sensor detects cancer proteins at the single-molecule level

Enhancements to the whispering-gallery-mode plasmonic biosensor enable a high level of sensitivity in detecting nanoscopic protein particles, with application to the early treatment of disease.
30 September 2013, SPIE Newsroom. DOI: 10.1117/2.1201309.005131

Tumor growth often leads to the presence or elevated levels of protein markers within body fluids. These may indicate early-stage infection or re-emergence of disease. Detecting such trace levels may allow treatment at a stage where its efficacy is increased or provide a means of determining the effectiveness of a particular medical approach. For example, in the case of thyroid cancer, the protein thyroglobulin (Tg) should be low or undetectable after treatment (typically surgery followed by radioactive iodine). However, the presence of Tg in serum would indicate that the disease is active and additional treatment is required.

Trace-level detection often requires an approach capable of amplifying the effects of the target in question. We initially considered resonant systems, which are highly sensitive to their local environment, and therefore provide a useful platform for monitoring small changes. However, many familiar resonant systems are macroscopic in form (violins, bells, or pipes, for example) and thus are not suitable for bionanoparticle detection. Rather, we require microscale systems, for which optical approaches have proven particularly effective. The whispering-gallery-mode biosensor, which builds on ideas conceived for telecommunications applications,1–3 is a good example. We use a narrow-band tunable laser source to stimulate resonances within micro-optical structures, such as glass spheres. Monitoring the specific resonant frequencies (the WGMs) enables detection of trace species.4

Purchase SPIE Field Guide to MicroscopyWe measure the system's response to the target through the shift in resonance frequency due to its adsorption on the sphere's surface, in much the same way the tone of a bell changes when a piece of chewing gum is affixed to its exterior. The physics behind the phenomenon is known as the reactive sensing principle,5,6 which states that the shift in the resonance frequency is directly proportional to the amount of adsorbed material and the electric field intensity at that position. However, the detection capabilities of the bare WGM biosensor (the glass spheres alone) are limited, and enhanced sensitivity is made possible by incorporating gold nanoparticles to form a nanoplasmonic-photonic hybrid transducer.7–9

In our previous work2,7 we showed that gold nanoparticles bound to the resonator could improve the response of dielectric nanoparticle adsorption. Our model, which invoked a smooth gold nanoshell, yielded good agreement with the observations of polystyrene and virus particles. Recently, we increased the sensitivity levels of the biosensor to detect smaller biological particles, including the proteins bovine serum albumin (with mass 66kDa) and Tg (660kDa). When we introduced these molecules, we observed larger than expected resonance shifts (2.4–15×) from this smooth nanoshell model. Their unexpected magnitude results from a short-range reactive field at the surface of the plasmonic nanoparticle due to random bumps comparable in size to the adsorbed protein (4–10nm). In our earlier work the virus particles were relatively large, so these bumps did not have a significant impact on the observed resonance shift. Our new research shows that the nanoscopic protein molecules are able to find their way to these bumps and interact strongly with the enhanced electric field, resulting in a much stronger reactive response (see Figure 1). Based on these findings, we project the detection limit for the WGM biosensor to be 5kDa, or ∼10 zeptograms (1zg =10−21g).

Figure 1. Illustration showing the experimental arrangement in which a thyroglobulin (Tg) molecule adsorbs onto a bumpy gold nanoshell affixed to the equator of the whispering-gallery-mode biosensor (the microsphere). λR: Resonance wavelength. Eo: Electric field within the resonance. The plot on the right shows steps associated with Tg adsorption events. For comparison, a trace in which no protein is present is also shown. fm: Femtometers. The inset is a photograph of the microsphere with the nanoshell attached (visible through scattering).

The increased sensitivity demonstrated in our work has implications for rapid screening and a variety of biomedical applications, including early detection and treatment of diseases such as cancer. In future, we aim to gain more access to analytes (molecules of interest), and thereby perform assays more quickly. To that end we are now working with the University of Michigan on a WGM resonator surrounded by a necklace of plasmonic receptors.10

Stephen Holler
Fordham University
Bronx, NY

Stephen Holler is an assistant professor of physics and engineering physics and heads the laboratory for micro-optics and biophotonics. Prior to joining the faculty he was an entrepreneur working on laser-based sensors for environmental monitoring.

Stephen Arnold, Venkata Dantham
Microparticle Photophysics Laboratory
Polytechnic Institute of New York University
Brooklyn, NY

Stephen Arnold is a professor of physics and chemical engineering and Thomas Potts Professor of physics. As director of the laboratory he has been involved for three decades in pioneering research on micro-optical cavities. He conceived and invented the WGM biosensor.

Venkata Dantham received a PhD in physics from the Indian Institute of Technology in Madras, India, in 2011. He is a National Science Foundation Postdoctoral Fellow with research interests in the detection and sizing of individual smaller viruses/proteins using a nanoplasmonic WGM hybrid microresonator.

1. V. R. Dantham, S. Holler, C. Barbre, V. Kolchenko, D. Keng, S. Arnold, Label-free detection of single protein using a nanoplasmonic-photonic hybrid microcavity, Nanotechnol. Lett. 13(7), p. 3347-3351, 2013. doi:10.1021/nl401633y
2. V. R. Dantham, S. Holler, V. Kolchenko, W. Zan, S. Arnold, Taking whispering gallery-mode single virus detection and sizing to the limit, Appl. Phys. Lett. 101, p. 043704, 2012. doi:10.1063/1.4739473
3. A. Serpengüzel, S. Arnold, G. Griffel, Excitation of resonances of microspheres on an optical fiber, Opt. Lett. 20(7), p. 654-656, 1995. doi:10.1364/OL.20.000654
4. F. Vollmer, D. Braun, A. Libchaber, M. Khoshsima, I. Teraoka, S. Arnold, Protein detection by optical shift of a resonant microcavity, Appl. Phys. Lett. 80(21), p. 4057-4059, 2002. doi:10.1063/1.1482797
5. X. Fan, I. M. White, S. I. Shopova, H. Zhu, J. D. Suter, Y. Sun, Sensitive optical biosensors for unlabeled targets: a review, Anal. Chim. Acta 620, p. 8-26, 2008. doi:10.1016/j.aca.2008.05.022
6. S. Arnold, M. Khoshsima, I. Teraoka, S. Holler, F. Vollmer, Shift of whispering-gallery modes in microspheres by protein adsorption, Opt. Lett. 28(4), p. 272-274, 2003. doi:10.1364/OL.28.000272
7. S. I. Shopova, R. Rajmangal, S. Holler, S. Arnold, Plasmonic enhancement of a whispering-gallery-mode biosensor for single nanoparticle detection, Appl. Phys. Lett. 98, p. 243104, 2011. doi:10.1063/1.3599584
8. M. A. Santiago-Cordoba, S. V. Boriskina, F. Vollmer, M. C. Demirel, Nanoparticle-based protein detection by optical shift of a resonant microcavity, Appl. Phys. Lett. 99, p. 073701, 2011. doi:10.1063/1.3599706
9. J. D. Swaim, J. Knittel, W. P. Bowen, Detection limits in whispering gallery biosensors with plasmonic enhancement, Appl. Phys. Lett. 99, p. 243109, 2011. doi:10.1063/1.3669398
10. S. Arnold, V. R. Dantham, C. Barbre, B. A. Garetz, X. D. Fan, Plasmonic enhancing epitopes on a whispering gallery mode biosensor, Opt. Express 20, p. 26147, 2012. doi:10.1364/OE.20.026147