A surface plasmon resonance (SPR) biosensor, which contains an overlayer of titanium dioxide nanoparticles (TDNPs) to modify the plasmonic interface, has been developed and investigated. Owing to its large surface area and high refractive index, the TDNP overlayer significantly enhances the probing electric field intensity and detection sensitivity. This sensitivity is related to the TDNP overlayer thickness, which can be engineered by changing the TiO2–ethanol dispersion’s spin-coating concentration. The highest refractive index sensitivity for ethylene glycol measurement is 2567.3 nm/RIU, which is 38% higher than that of a conventional SPR sensor with an uncoated gold film. The proposed TDNP-SPR sensor also exhibits a 1.59-fold sensitivity enhancement in fetal bovine serum detection. Moreover, the proposed interface modification approach that is applied without additional biochemical amplification steps is chemical-free and contamination-free; therefore this TDNP-SPR sensor could be integrated into a sensitive, cost-effective, and biocompatible platform for rapid and label-free biochemical detection.
© 2018 Optical Society of America under the terms of the OSA Open Access Publishing Agreement
Label-free detection of biological molecules plays a significant role in drug development, healthcare diagnostics, the food industry, and environmental monitoring [1–3]. Over the past few decades, various label-free sensing techniques have been developed to provide rapid and sensitive detection, such as optical coherence-based  and charge transfer techniques . Among these techniques, surface plasmon resonance (SPR) sensing method has attracted great attention due to its inherent advantages of high sensitivity, precision, reproducibility, and its ability for rapid real-time and in situ detection . SPR sensors using a strong evanescent field to probe a slight refractive index (RI) change at the metal/analyte interface, have emerged as a very powerful tool for detection of biomolecules, such as biopolymers , DNAs , and proteins [9,10]. Unfortunately, SPR sensors are currently subjected to challenges because of their insufficient sensitivity for direct analyte detection of extremely dilute concentrations, small molecular weights, or low-affinity interactions [11,12]. To overcome this challenge of SPR sensors, various strategies have been proposed to enhance the sensitivity and thus extend their application scope, such as coupling the propagating SPR to the localized SPR by introducing noble metallic nanostructures , binding target molecules to a self-assembled probe molecule monolayer through host–guest affinity interactions , and covering a thin layer of two-dimensional materials on the gold surface to enhance the SPR signal [15–17]. However, the transformation efficiency from the propagating SPR to the localized SPR is limited. Self-assembly of probe and target molecules is short of universality in applications. In addition, for two-dimensional materials, such as graphene and tungsten disulfide (WS2), the inherent absorption in the visible range broadens the SPR spectral dip. Apart from modifying SPR sensing interface with metallic nanoparticles [18,19], other types of nanomaterials, such as magnetic nanoparticles , liposome nanoparticles , and carbon nanotubes , have been used as SPR signal amplification tags to modify the plasmonic interface. The introduced nanomaterial coating usually has a large surface area, relatively high RI, and strong charge transfer to the metallic sensing film surface, which can induce a large evanescent field enhancement and magnify the SPR signal.
As a type of wide band-gap and environmental-friendly semiconductor, titanium dioxide (TiO2) has attracted extensive interest in optoelectronics fields . Owing to their versatile optical and electronic properties , such as high aspect ratio, high dispersion ability, and good chemical stability and biocompatibility, TiO2 nanoparticles (TDNPs) have been found to have diverse applications in photocatalysis , photoelectric conversion , photoanodes , supercapacitors , and biosensors . More importantly, owing to its relatively high RI (2.32) compared with silica (1.458) [30,31], a TDNP overlayer coated on a substrate induces field confinement and enhancement in the interface between the substrate and TDNP coating, which is beneficial for sensitivity enhancement of evanescent field-based sensors. Furthermore, its large surface area, hydrophilicity, and adsorption ability offer a suitable platform for detection and analysis of biomolecules. Therefore, TDNPs show promise for performance improvement of SPR biosensors.
In this work, we propose and demonstrate a novel strategy for SPR sensitivity enhancement by using a TDNP overlayer to modify the plasmonic interface. Based on the Kretschmann attenuated total reflection structure, a 50 nm gold film was first deposited on a 5 nm adhesive chromium layer, followed by spin-coating a uniform TDNP overlayer. Using this chemical-free and environmentally friendly interface modification approach, the proposed TDNP-SPR sensor exhibits high sensitivities of 2567 nm/RIU in bulk RI measurement and 22.41 nm/VRU (volume ratio unit) in fetal bovine serum (FBS) detection, which provide 1.38-fold and 1.59-fold enhancement respectively compared with those of a conventional SPR sensor with an uncoated gold film. To the best of our knowledge, this is the first report on utilization of TDNPs to modify the sensing interface and enhance the measurement sensitivity of SPR biosensors.
2. Experimental details
2.1 Materials and reagents
TDNPs with average diameter of 10 nm and large surface area of 77.37 m2/g were purchased from MK Nano Co., Ltd, China. Different mass fraction concentrations of TiO2–ethanol dispersion were prepared by dispersing TiO2 powder in anhydrous ethanol with ultrasonic treatment for 30 min. Ethylene glycol was used to prepare aqueous solutions with different refractive indices, which were used to characterize the RI sensitivity of the sensors. The refractive indices of the aqueous solutions of ethylene glycol were measured with an Abbe refractometer (Edmund NT52-975, Edmund Optics Co., Ltd., China) at room temperature (25 °C). FBS was obtained from Life Technologies Corporation (Gibco, Origin: South America) and diluted with phosphate buffered saline (PBS) (Aladdin, Shanghai, China) in different volume ratios, and these FBS solutions were used for the serum solution measurements.
2.2 Fabrication of TDNP-SPR chip
The SPR chip is based on the classical Kretschmann configuration. A customized silica slide (Jiuyi Optics, Fuzhou, China) was used as the metal deposition substrate to maintain the reusable prism coupler. First, the contaminants adhered on the silica slide were removed by ultrasonic cleaning. A 50 nm thick gold film was then deposited on the slide by the vacuum evaporation technique using a thin chromium film (~5 nm) as the adhesion-promoting layer. In detail, gold film and chromium film were deposited by thermal evaporation and e-beam evaporation, respectively. The vacuum coating machine was operated at a chamber pressure of 10−3 pa. Observed by an inbuilt quartz crystal thickness monitor, the deposition rate was 0.2 nm/sec. Finally, TDNPs were spin-coated using the desired concentration TiO2–ethanol dispersion for 1000 s at a rate of 3000 rpm. The spin-coated TDNP overlayer acts as a modified layer to enhance the sensitivity of the sensor. The sensitivity is related to the thickness of the TDNP coating. By spin-coating TiO2–ethanol dispersions with different TiO2 concentrations (0.5%, 1%, 1.5%, 2%, and 2.5%, mass fractions), TDNP-SPR chips with different thickness of TDNP coatings were fabricated by the same procedure. In this step, the TDNP coating uniformity was kept under consideration by maintaining the same spin-coating conditions, such as rate and duration. Moreover, before each spin-coating, the TiO2 dispersions were treated again using ultrasonication to ensure a homogeneous dispersion.
2.3 SPR measurement system
The SPR spectral measurements were performed by coupling a tungsten-halogen light source (AvaLight-HAL-(S)-Mini, China) to the prism-based SPR device and recording the reflected light from 450 to 1150 nm with a spectrometer (AvaSpec-ULS2048XL, China). A schematic of the proposed TDNP-SPR sensor is shown in Fig. 1.
The TDNP-SPR chip is mounted on top of the prism and a thin layer of oil is applied between them for index matching. During the measurements, a broadband signal light from the tungsten-halogen light source is polarized into a transverse-magnetic wave (P-polarization light), and then travels through the prism substrate and strikes the gold film at a sufficiently large incident angle θ (~73°) with the SPR excited by the evanescent wave at the resonant wavelength. The SPR measurement setup is designed on the basis of fixing this incident angle and measuring the change of resonant wavelength. As the SPR is excited by the evanescent light, part of the input light is coupled into the surface plasmon wave on the gold film, thereby forming a resonance absorption dip in the reflection spectrum, which is recorded by the spectrometer. Because the excited SPR is highly sensitive to the ambient RI, a tiny variation of the sensing RI on the TDNP coating surface results in a resonant wavelength shift. Consequently, the sensing performance of the TDNP-SPR sensor can be characterized by examining the wavelength shift amount. In addition, a microfluidic chamber with an inlet and an outlet is used to flow the liquid analyte in the measurement experiment.
3. Results and discussion
3.1 Characterization of TiO2 coating
Five dispersions of TiO2 in ethanol with mass fraction concentrations of 0.5%, 1%, 1.5%, 2%, and 2.5% were obtained via ultrasonic treatment. As shown in Fig. 2(a), all of the dispersions were uniform and stable, which is beneficial for the following spin-coating procedure. The absorbance of the TiO2–ethanol dispersions was determined from 450 to 1150 nm, which corresponds to the SPR spectral range measured in the following part. The absorption spectra of the prepared TiO2 dispersions, using the spectrum of ethanol as the reference are shown in Fig. 2(b). The absorption spectrum of the ethanol sample is a straight line. For the TiO2 dispersions, there are no obvious absorption bands in the whole measured wavelength range, and extinction increase with increasing TiO2 concentration owing to increasing nanoparticles scattering. The moderate absorption spectrum evolution of TiO2 in the measured wavelength range excludes the influence of inherent absorption when we analyze the TDNP-SPR spectra in the following detection experiments.
Scanning electron microcopy (SEM) images of the SPR chip surfaces without and with a TDNP overlayer are shown in Figs. 3(a) and 3(b), respectively. The gold film surface is extremely smooth (Fig. 3(a)), which indicates successful deposition of a gold film on the surface of the glass slide. The TDNPs are dispersed on the gold film at a high void volume and form a porous surface morphology with some small clusters, shown as the SEM image in Fig. 3(b). The porous surface of TDNP overlayer results in a hybrid sensing layer because of the penetration of analyte solutions inside the voids and hollow regions. Additionally, TiO2 has a higher RI compared with SiO2, a strong SPR evanescent field along the interface of the gold film decays exponentially into the mixture of TDNPs and analyte, and promotes the interactions between analytes and probing evanescent field. Moreover, the TiO2 nanoparticles possess large surface area of 77.37 m2/g, which is another favorable factor for the sensitivity improvement.
Atomic force microscopy (AFM) images of the TDNP-SPR chips coated with TiO2 dispersions at different concentrations are shown in Fig. 4(a), which were used to observe and characterize the surface morphologies, thicknesses, and roughnesses of the TDNP overlayers. The AFM observations were performed with a Nanoscope IIIa controller (Veeco, USA) in tapping mode under ambient conditions with a scanning rate of 1 line/s. TDNPs with high aspect ratio can be identified in these 5 μm × 5 μm three-dimensional (3D) images. The surface morphology of the coating layer is uneven with some small clusters form on the substrate, which is consistent with the previous SEM results. The height profiles of the TDNP overlayers are shown in Fig. 4(b). The thicknesses of all of the TDNP overlayers present a normal distribution. The average coating thicknesses are 319.8, 384.7, 422.6, 504.6, and 565.6 nm for TiO2 concentrations of 0.5%, 1%, 1.5%, 2%, and 2.5%, respectively. There is a good linear relationship (linear coefficient R2 = 0.987) between the TiO2 concentration and the thickness of the TDNP overlayer as shown in Fig. 4(c). This can be easily understood because the coating thickness is directly related to the amount of TDNPs deposited on the substrate. The increase of TDNP overlayer thickness would change the volume fraction of analytes in the hybrid sensing layer and thereby change the practical analyte RI increment.
3.2 Bulk RI measurements
The sensing performance of the proposed TDNP-SPR sensors was evaluated by comparing their sensitivities to that of a conventional SPR sensor with an uncoated gold film operating in bulk RI solutions. The evolution of the reflectance spectrum with changing analyte RI for the SPR sensor with an uncoated Au film (as a control) is shown in Fig. 5(a). The resonant dip shifts to longer wavelength with increasing analyte RI (na), and the resonant wavelength has a redshift of 50.49 nm when the RI increases from 1.333 to 1.360. The reflectance spectra of TDNP-SPR sensors with different thickness TDNP overlayers are shown in Figs. 5(b)–5(f). In contrast to the control, all of the reflectance spectra exhibit obvious SPR absorption dips, and the resonant dip also shifts to longer wavelength with increasing analyte RI. However, the dip wavelengths show different shifts for different TDNP coating thicknesses. When the analyte RI increases from 1.333 to 1.360, the resonant dip shifts are 61.72, 66.67, 67.40, 33.30, and 24.83 nm for TDNP-SPR sensors with spin-coating TiO2 concentrations of 0.5%, 1%, 1.5%, 2%, and 2.5%, respectively. With increasing TiO2 concentration, the SPR dip broadens owing to stronger scattering by the large amount of nanoparticles on the gold film.
The spectra for na = 1.333 are compared in Fig. 6(a). The resonant dip monotonically shifts to longer wavelength with increasing TiO2 concentration for the same surrounding RI. The relationship between the resonant dip wavelength and the TiO2 concentration is shown in Fig. 6(b), where linear fitting is performed in the linear region. The relationship between the resonant dip and the TiO2 concentration shows relatively good linearity with a linear fitting coefficient of R2 = 0.968 for TiO2 concentrations from 0 to 2%. Above 2% TiO2, the shift amount of the resonant wavelength notably decreases. This is because of the weakened influence of the excessively thick TDNP overlayer on multilayer structure based SPR excitation .
To evaluate the performance of the proposed SPR sensor, all of the resonant wavelengths in Figs. 5(a)–5(f) and their corresponding refractive indices are shown in Fig. 7(a) for different TiO2 concentrations. Linear fitting was performed to more intuitively describe the dependence of the resonant wavelength on the sensing RI. It reveals that the resonant wavelengths of all of the TDNP overlayers linearly move toward the longer wavelength with increasing analyte RI. The slopes of the linear fitting lines of the experimental data represent the RI sensitivities of the sensors . Therefore, the sensing sensitivities are 2277.4, 2455.2, 2567.3, 1134.9, and 834.5 nm/RIU for the TDNP-SPR sensors coated with 0.5, 1.0, 1.5, 2.0, 2.5% TiO2, respectively. For the uncoated gold film-based SPR chip, the sensitivity is 1866.8 nm/RIU. It is worth mentioning that the resonant wavelengths show excellent linear relationships with the TiO2 concentrations.
The sensitivities for TDNP-SPR sensing chips with different TiO2 concentrations are shown in Fig. 7 (b). The sensitivity first increases from 1866.8 to 2567.3 nm/RIU, and then decreases to 834.5 nm/RIU with increasing TiO2 concentration. According to the corresponding relationship between TiO2 concentration and average thickness of TDNP overlayer shown in Figs. 4(b) and 4(c), it means that the sensitivity also first increases and then decreases with increasing the TDNP overlayer thickness. For TiO2 concentrations of 0.5%, 1.0% and 1.5%, the sensitivities are obviously higher than the sensor without a TDNP overlayer. The highest sensitivity of 2567.3 nm/RIU at a TiO2 concentration of 1.5% (i.e., at an average TDNP overlayer thickness of 422.6 nm) is 1.38-fold as high as that of the uncoated gold film SPR chip (1866.8 nm/RIU). This enhancement of the RI sensitivity can be attributed to the large surface area and high RI of the coated TDNP overlayer. Introduction of a TDNP overlayer on the gold film induces field confinement and enhances the probing electric field intensity, and simultaneously reduce the effective analyte RI increment of the hybrid sensing layer as well. As analyzed in our previous work , these are two opposite effects on the SPR sensitivity brought by high RI overlayer. Caused by the counter balance of these two opposite effects, the sensitivity first increases, and then decreases with increasing TDNP overlayer thickness. Moreover, the full width at half maximum (FWHM) for the resonance spectra measured at na = 1.333 is plotted in Fig. 7(c) to intuitively describe the variation of SPR dip width. With increasing TiO2 concentration, the rough TDNP overlayer stacked on the gold film causes stronger absorption and scattering, which leads to that the SPR dips broaden. However, an excessively thick overlayer (thicker than 422.6 nm) decreases the effective interaction area of the evanescent field and sensing medium and slows down the SPR dip broadening owing to the limitation of the decay depth of the SPR probing field intensity . Therefore, the sensitivity decreases and the FWHM nearly remains unchanged with a further increase in the TiO2 concentration, as shown in Fig. 7(c). Another typical quality parameter for accessing the performance of SPR sensors, the figure of merit (FoM) defined as the ratio between sensitivity and FWHM is presented in Fig. 7(d). When the TiO2 concentration increases from 0% to 1.5%, the FoM decreases due to the SPR dips dramatically broaden. Over 1.5%, although the FWHM is almost invariable, the sensitivity turns to significantly decrease from the highest value, which leads to the continued decrease of the FoM at an even faster pace.
3.3 Serum solution detection
To confirm the practical performance, the bulk RI-evaluated TDNP-SPR sensor was used for serum solution detection. FBS solutions with different volume ratios of FBS to PBS in the range 0–100% were prepared as the target analytes. The TDNP-SPR sensors with TiO2 concentrations of 1% and 1.5% were tested using the prepared analyte solutions, and compared with a control SPR sensor without a TDNP-modified interface. The reflectance spectra are shown in Fig. 8. As the volume ratio of the FBS solution increases from 0 to 100%, the resonant wavelengths are 14.18, 19.72, and 21.79 nm of the red-shift amount for the control SPR sensor and 1% and 1.5% TiO2-coated Au films, respectively. As expected, the presence of TDNPs facilitates a greater resonant wavelength shift for the same FBS concentration.
The resonant wavelengths of the three types of SPR sensors as the function of the FBS concentration are compared in Fig. 9(a). The fitted lines of the resonant wavelengths have high linear coefficients of 0.987, 0.998, and 0.995 for the uncoated Au film and 1% and 1.5% TiO2-coated Au films, respectively. The sensitivity of the TDNP-SPR sensor with the 1.5% TiO2/Au hybrid structure is 22.41 nm/VRU, which shows 1.59-fold as high as that of the control SPR sensor (14.05 nm/VRU). This sensitivity enhancement achieved in FBS detection is even higher than that in the pure bulk RI measurement under the same TDNP modification conditions (1.38-fold). This is mainly attributed to the porous TDNP overlayer having a large surface area, as shown in the SEM images in Fig. 3, which is beneficial for adsorption and accommodation of much more target substance in the sensing region compared with the uncoated plasmonic film. These serum solution detection results indicate that the TDNP-SPR chip is a promising candidate for the platform of label-free optical biosensors.
4. Comparison and discussion
The detection ranges, sensitivities, enhancement folds, analyte solutions, and interface-modification methods of various SPR sensors with different plasmonic interfaces are summarized in Table 1. The proposed TDNP-SPR sensor exhibits higher sensitivity and enhancement fold than the prism-based SPR sensors using graphene , double-layer metal , and WS2 nanosheets  to modify the plasmonic interfaces. Compared with other fiber-based SPR sensors, the sensitivity of the proposed Au–TiO2-nanoparticle-based SPR sensor is lower than those of the Ag–Si , Cu–TiO2 , and Au–graphene  SPR sensors. However, the interface-modified method (spin coating) of the TDNP-SPR sensor is simple, chemical-free, and low-cost without the complicated and expensive synthesis procedures used to prepare the other three sensors, such as thermal evaporation deposition and chemical vapor deposition. Moreover, the detection range of the proposed TDNP-SPR sensor is relatively wider. It should be pointed out that because of the large surface area and hydrophilicity of TiO2 nanoparticles to accommodate FBS components, the enhancement achieved in the FBS solutions is even higher than that in bulk RI solutions under the same TDNPs modification conditions. Overall, the above results suggest that TiO2 nanoparticles are an ideal candidate for modifying the plasmonic interface and enhancing the SPR sensor performance. The simple and effective enhancement technique used in this work indicates that TDNP-SPR sensing is a promising approach to overcome the challenges of trace-level biochemical detection.
We have proposed and demonstrated a novel method to enhance the sensitivity of SPR sensors by introducing a TDNP overlayer to modify the surface of the gold film. The sensitivity of the TDNP-SPR sensor depends on the TiO2 concentration and the highest sensitivity of 2567.3 nm/RIU is achieved for a TiO2 concentration of 1.5%. Compared with a conventional SPR sensor without a modified interface, the proposed sensor shows sensitivity enhancement folds of 1.38 and 1.59 in bulk solution RI measurement and FBS detection, respectively. By using a simple sensing interface modification approach without any chemical or biological amplification steps, the TDNP-SPR sensor with enhanced sensitivity is expected to address the current challenges and act as a universal and highly sensitive platform for label-free analysis of small molecules and ultralow concentrations of analytes.
National Natural Science Foundation of China (NSFC) (Nos. 61575084, 61705046, 61805108, 61475066, 61705087); Special Research Fund for Central Universities (21618404, 21617332); Natural Science Foundation of Guangdong Province (2015A030313320, 2014A030313377, 2016A030311019); Science and Technology Projects of Guangdong Province (2016B010111003, 2016A010101017, 201604016095); Science & Technology Project of Guangzhou (201707010500, 201807010077, 201604016095, 201605030002, 201704030105); Joint Fund of Pre-research for Equipment, Ministry of Education of China (6141A02022124); China Postdoctoral Science Foundation (2017M612608).
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