Elsevier

Biosensors and Bioelectronics

Volume 23, Issue 5, 15 December 2007, Pages 627-632
Biosensors and Bioelectronics

Wide dynamic range phase-sensitive surface plasmon resonance biosensor based on measuring the modulation harmonics

https://doi.org/10.1016/j.bios.2007.07.015Get rights and content

Abstract

In this study, a novel phase-sensitive surface plasmon resonance (SPR) setup, based on temporal modulation of a pumping beam by a photoelastic modulator, and subsequent extraction of phase information at the second and the third harmonics of the modulation frequency, has been developed to study biomolecular interactions on SPR-supporting gold. We demonstrated that the design setup provides ultra-high phase sensitivity, together with a wide dynamic range of measurements. In particular, the proposed scheme was used to study real-time interaction of biotin–protein and streptavidin–BSA complexes. We have found that the proposed technique has a detection limit as high as 2.89 × 10−7 in terms of refractive index units (RIU). In terms of biosensing performance, a detection sensitivity of 1.3 nM from the streptavidin–maleimide/thiolated BSA complex binding reaction has also been demonstrated.

Introduction

The surface plasmon resonance (SPR) sensor technology has developed rapidly over the past decade. With the introduction of commercially available units (Biacore 3000, Biacore AB and Spreeta, Sensata Technologies Inc.), this technology has emerged as a powerful tool for biomolecular interaction analysis, drug discovery and life science research (Prasad, 2003, Homola, 2003). SPR sensors employ surface plasmons, or electromagnetic waves propagating along a metal/dielectric interface. Since the wave vector of plasmons, ksp, depends on the dielectric constants of both media, ksp=k0εmetalεsample/(εmetal+εsample) (where k0 is the free space wave vector of the optical wave), it is extremely sensitive to properties of the dielectric medium which is in contact with the metal. Surface plasmons are generally excited in the Kretchmann configuration by directing p-polarized light to a glass prism and reflecting from a gold film. When the tangential x-component of the incident optical wave vector, kx, is matched with ksp, the pumping light energy is transferred to surface plasmons:kx=k0nglasssinθinc=ksp,where nglass is the refractive index of the prism and θinc is the angle of incidence.

The plasmon coupling condition is normally accompanied by a dip of reflectivity at a specific combination of the angle of incidence and the wavelength. Here, the sensing effect comes from the fact that this resonance condition depends on the refractive index of a thin 200–300 nm layer, which is in contact with the SPR-supporting gold. Therefore, the information of biological binding (recognition) events on the gold film can be obtained by carefully monitoring the SPR coupling characteristics. In most SPR systems, the information of the biomolecular interactions is obtained from measurements of the angular or the spectral characteristics of light reflected under SPR. In this case, the detection limit is usually 10−5 in terms of the refractive index change (RIU), which corresponds to 1 pg mm−2 of the biomaterial accumulating at the biosensor surface (Liedberg et al., 1983, Spadavecchia et al., 2005, Margheri et al., 2003, Ho et al., 2001).

Several recent studies have demonstrated that the sensitivity of SPR could be improved by at least two orders of magnitude by monitoring the phase characteristics of light instead of the corresponding intensity (Kabashin and Nikitin, 1997, Kabashin and Nikitin, 1998, Wu et al., 2004, Chiang et al., 2005, Naraoka and Kajikawa, 2005, Su et al., 2005, etc.). Such a gain in sensitivity is due to the phase jump across SPR, which could be much sharper compared to the intensity change (Kabashin and Nikitin, 1997, Kabashin and Nikitin, 1998). However, phase-sensitive SPR schemes normally compromise much higher sensitivity with an insufficiently wide dynamic range of measurements, limited by a relatively narrow angular or spectral range of the whole phase variation.

The present system is based on the one we used in our previous work (Markowicz et al., 2007) where we measured the SPR phase, making use of a photoelastic modulator (PEM) to generate a weak retardation modulation at 42 kHz. In the course of the experiment, we found that the variable retarder (Q in Fig. 1) plays a very important role in the response of the second and the third harmonic signals to the polarization and the phase change caused by SPR. Without compensating the phase introduced by SPR, the second harmonic signal exhibits a shorter dynamic range than the third harmonic signal. In this paper, we propose to simultaneously monitor the second and the third harmonic signals under condition of full pre-compensation of the initial phase introduced by SPR. Indeed, these two signals are actually affected by two different properties of the optical beam, the former predominantly by the polarization amplitude and the latter by the phase. By utilizing these two characteristics simultaneously, our system can therefore detect a very small change of refractive index (or a tiny amount of biomolecular interaction) over a wide dynamic range. A quantitative study of binding reaction between the biotin–protein molecules and the streptavidin–BSA complexes in different concentrations is also presented.

Section snippets

SPR system setup

A schematic diagram of the design is shown in Fig. 1. A 40 mW solid-state laser (CUBE, Coherent) operating at the wavelength of 785 nm was used as the light source. A 45° linearly polarized laser beam was introduced to the prism coupling system containing a F2 glass equilateral prism (Melles Griot) and a glass plate (Platyus) with a 50 nm thick gold coating. The sensing chip was attached to one of the prism surfaces with refractive index matching oil (Santovac SL-5262). The estimated surface area

Materials

Commercially available chemicals were used as received. For the refractive index (RI) measurement, glycerin was used as a reference (from Fisher Scientific). Phosphate buffered saline (PBS) was obtained from Invitrogen. The Traut's Reagent was obtained from Pierce. Streptavidin–maleimide and its biorecognition partner, alkaline biotinamidocaproyl phosphatase (biotin–protein), bovine serum albumin (BSA) and ethylenediaminetetraacetic acid (EDTA) were obtained from Sigma–Aldrich.

Thiolated BSA preparations

Thiolated BSA was

Conclusion

We present a novel phase-sensitive surface plasmon resonance biosensor scheme which combines a wide dynamic range with high detection sensitivity. The scheme uses temporal modulation of the excitation beam by a photoelastic modulator and subsequent extraction of phase information at the second and the third harmonics of modulation frequency. We showed in model tests with glycerin that the detection limit of our system was 2.89 × 10−7 in terms of refractive index units (RIU). We also report a

Acknowledgements

Funding support from a RGC Grant (project # 2150473) from the Hong Kong SAR Government and the Shun Hing Institute of Advanced Engineering is gratefully acknowledged. The works at Buffalo and Montreal were supported, respectively, by the Center of Excellence in Bioinformatics and Life Sciences and a Strategic Grant from Natural Sciences Engineering Research Council of Canada (NSERC).

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