Large-Area Au-Nanoparticle-Functionalized Si Nanorod Arrays for

Large-Area Au-Nanoparticle-Functionalized Si Nanorod Arrays for Spatially Uniform SurfaceEnhanced Raman Spectroscopy Dongdong Lin,† Zilong Wu,§ Shujie Li,† Wenqi Zhao,† Chongjun Ma,† Jie Wang,† Zuimin Jiang,†,‡ Zhenyang Zhong,†,‡ Yuebing Zheng,§ and Xinju Yang*,†,‡ †

State Key Laboratory of Surface Physics and Department of Physics, Fudan University, Shanghai 200433, China Collaborative Innovation Center of Advanced Microstructures, Nanjing 210093, China § Department of Mechanical Engineering, Materials Science and Engineering Program, and Texas Materials Institute, The University of Texas at Austin, Austin, Texas 78712, United States ‡

S Supporting Information *

ABSTRACT: In this study, large-area hexagonal-packed Si nanorod (SiNR) arrays in conjunction with Au nanoparticles (AuNPs) were fabricated for surface-enhanced Raman spectroscopy (SERS). We have achieved ultrasensitive molecular detection with high reproducibility and spatial uniformity. A finite-difference time-domain simulation suggests that a wide range of three-dimensional electric fields are generated along the surfaces of the SiNR array. With the tuning of the gap and diameter of the SiNRs, the produced long decay length (>130 nm) of the enhanced electric field makes the SERS substrate a zero-gap system for ultrasensitive detection of large biomolecules. In the detection of R6G molecules, our SERS system achieved an enhancement factor of >107 with a relative standard deviation as small as 3.9−7.2% over 30 points across the substrate. More significantly, the SERS substrate yielded ultrasensitive Raman signals on long amyloid-β fibrils at the single-fibril level, which provides promising potentials for ultrasensitive detection of amyloid aggregates that are related to Alzheimer’s disease. Our study demonstrates that the SiNRs functionalized with AuNPs may serve as excellent SERS substrates in chemical and biomedical detection. KEYWORDS: Si nanorods, Au nanoparticles, surface-enhanced Raman spectroscopy, reproducibility, sensitivity, Aβ detection gaps.10−13 With the adsorption of molecules in hot spots, the Raman scattering light can be coupled with surface plasmons and be electromagnetically enhanced.14 However, the development of a practically applicable SERS-based sensor requires an efficient SERS substrate that features strong enhancement factors, robustness, stability, uniformity, and reproducibility. The poor uniformity (i.e., high spatial deviation in signals) in many state-of-the-art SERS substrates is mainly due to the

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urface-enhanced Raman spectroscopy (SERS) is a powerful analytical tool that provides information on the molecular structure and composition of analytes through Raman scattering that is enhanced by the electromagnetic (EM) field on plasmonic substrates.1,2 There have been extensive studies on different SERS-active substrates for molecular detection with high enhancement factors.3−5 Of particular attention is SERS for ultrasensitive molecular detection in biological and biomedical applications.6−9 Clusters of noble metal nanostructures, particularly those made of Au and Ag, have shown great SERS sensitivity due to sub-10 nm electromagnetic hot spots confined in the interstructure © 2017 American Chemical Society

Received: October 8, 2016 Accepted: January 6, 2017 Published: January 6, 2017 1478

DOI: 10.1021/acsnano.6b06778 ACS Nano 2017, 11, 1478−1487

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Figure 1. Schematic illustration of the fabrication of AuNP-conjugated SiNR arrays. Close-packed monolayer of PS nanospheres on a clean Sireduced diameter of PS by reactive ion etching, Au deposition, metal-assisted chemical etching, removal of Au/PS, conjugation with Au nanoparticles.

Therefore, three-dimensional (3D) nanostructures are explored to increase the density of metal nanostructures that support localized surface plasmon resonances (LSPRs).31−34 These include silica nanowires and InP nanowires decorated with Au nanoparticles (AuNPs),35−37 gold-coated cyclic olefin copolymer nanopillar arrays,38 silver-coated Si nanowire arrays,39,40 and Au-coated ZnO nanorods.41 Research found that nanowire arrays acting as frameworks have a Raman signal sensitivity significantly higher than that of a planar framework of AuNPs adsorbed two-dimensionally on a flat surface. Generally, two factors can largely reduce the formation of uniform hot spots and SERS reproducibility. One is that some of the 3D structures, such as SiNWs and ZnO nanorod clusters, are random and disordered. The disordered structures (leaning nanowires/nanorods) may have a higher enhancement than nonleaning ones due to the partially narrow gap.42 Although those close-packed nanowires/nanorods (usually at sub-10 nm) dramatically enhance the SERS signal, they have relatively poor reproducibility and could not load the DNA molecules and protein aggregates in the active interstices. The other is that the decorated metals are usually evaporated on the surface of nanostructures with heterogeneous particles/films in variable sizes and site distributions (especially, the evaporation of Au/ Ag would be accumulated on the top of nanowire/nanorod arrays), which leads to the nonuniformity of hot spots and reduction of hot spot areas. In practical application, the SERS techniques for detecting health-care-related protein targets have attracted wide atten-

inhomogeneous distribution of hot spots. The inhomogeneous distribution of hot spots causes the variegated intensity of Raman signals, which makes it especially challenging to study the long target molecules (DNA, protein, and polymeric species). For instance, the enhancement of the electric field varies from 105 to 108 when the interparticle gap changes from 4 to 2 nm.15 To overcome the mentioned problems, a number of ordered nanoarray SERS substrates have been reported. With selfassembly and lithography techniques (such as electron beam lithography and photolithography), abundant interesting twodimensional periodic geometries (e.g., nanoholes, nanoblocks, nanoparticles, nanoclusters, nanopyramids, and nanodisk arrays) have been made to enhance SERS measurements,16−27 some of which are quiet creative and superb. Many of those SERS substrates are usually designed in a narrow gap of nano/microstructures and tested with regular small analyte molecules (such as Rhodamine 6G (R6G), crystal violet (CV), and 4-aminothiophenol (4-ATP)), from which they achieved a high enhancement of SERS signals. However, the long-chain biomacromolecules (such as DNA molecules and protein fibrils) remain a significant challenge to obtaining sensitive and reliable SERS spectra.28−30 The challenge remains because the conjugation of those substrates with DNA molecules does not easily produce a sufficiently strong and reproducible signal in the small active hot spots with low Raman cross sections. Moreover, the sensitivity of these twodimensional substrates is limited by a low density of hot spots. 1479


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ACS Nano tion.43 It is critical for clinical diagnosis, gene therapy, forensic analysis, and so on.44,45 In various disease-related proteins, βsheet-rich amyloid aggregates are associated with neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease, and Huntington’s disease.46,47 SERS techniques provide a promising way to detect the amyloid proteins and diagnose the aggregates at low concentration. Several excellent works have been reported previously. For example, Au-decorated polystyrene beads engineered with a metallorganic Raman chemoreceptor were used for detecting amyloid-β (Aβ) oligomers.48 Au nanoshells were applied to detect Aβ oligomers by monitoring the signal from Congo red bound to the Aβ oligomers.49 Additionally, nanofluidic SERS were developed to detect Aβ conformational transition with AuNPs.50,51 However, substantial challenges still remained due to the inherently weak peptide signals by direct Aβ adsorption on conventional SERS substrates,52 as well as the inhomogeneous adsorption of long fibrils on small hot spots as mentioned above. In addition, the amyloid aggregates have multiconformations at different stages, such as soluble oligomers, protofibrils (hundreds of nanometers), and long fibrils (micron-size length).46,53 The reported studies mainly focus on Aβ oligomers and small Aβ aggregates with the absorption of AuNPs. Yet, it is an indispensable investigation in protofibrils/long fibrils, as the existence of Aβ fibrils would be accumulated into plaques in AD patients. Consequently, to obtain distinct and reliable SERS signals of Aβ fibrils, ordered three-dimensional Si-based SERS substrates with large interspace enhancement for the detection of labelfree Aβ fibrils deserve to be explored. Compared to the conventional SERS substrates, our proposed method has some advantages. For instance, the ordered SiNR arrays in conjunction with uniform AuNPs could exhibit a better uniformity than the disordered one. A tunable large gap allows for the detection of large molecules (amyloid fibrils). In addition, hexagonal-packed SiNR arrays provide a AuNP loading surface area and interaction space larger than that of square arrays, which improves the active region. Importantly, ordered Si nanohybrid-based SERS substrates are featured with a wide range of Raman enhancements because SiNR arrays could trap the incident light spatially by optimizing the diameter and gap between neighboring rods.54−56 In addition, SERS hot spots are efficiently coupled and stabilized through interconnection to the semiconducting Si substrates.57,58 In this paper, large-scale ordered hexagonal-packed SiNR arrays functionalized with homogeneous AuNPs (SiNRs@ AuNPs) were fabricated using top-down nanofabrication approaches. Due to the ordered SiNR arrays and widely decorated AuNPs, we have achieved highly sensitive and reproducible SERS signals of R6G with high spatial uniformity in a 2 × 3 cm2 substrate. Comparatively, randomly distributed SiNRs in conjunction with the same AuNPs exhibit poor reproducibility with large relative standard deviation. Furthermore, the SiNR@AuNP arrays with different diameters and gaps were investigated. Finite-difference time-domain (FDTD) simulations illustrate the zero-gap SERS system at ∼633 nm with wide-range electric field distribution in SiNR@AuNP arrays (200 nm in diameter and 300 nm in gap). More importantly, in the detection of label-free amyloid fibrils, the large 3D active space (300 nm in gap) from the SiNR@AuNP substrate yields ultrasensitive Raman signals at a single-fibril level.

RESULTS AND DISCUSSION SiNR arrays were fabricated by nanosphere lithography and metal-assisted chemical etching. As schematically shown in Figure 1, ordered hexagonal SiNR arrays were obtained from the following process: self-assembly of a polystyrene sphere (PS) monolayer; reduction of diameter of PS by reactive ion etching (RIE); Au deposition; metal-assisted chemical etching; removal of Au and PS; conjugation with AuNPs (detailed procedures are described in the Methods section). The key step in the presented procedures is the conjugation with AuNPs. For this purpose, 3-mercaptopropyltrimethoxysilane (MPTS) is used as its simple structure and can be easily removed by photolysis, which has no disturbance in the Raman spectra of target molecules.51,59 Three −OCH3 are strongly connected with silicon hydroxyl by a chemical reaction, while the sulfhydryl links to AuNPs on the other side. Scanning electron microscopy (SEM) images of uniform AuNPs with a 20 nm diameter is shown in Figure 2a, together with their UV−vis absorption spectrum measured in solution (Figure 2b). A strong absorption peak at 522 nm is observed from the solution of 20 nm AuNPs.60 The final fabricated SERS substrate

Figure 2. Fabricated AuNP-conjugated SiNR substrate measured by SEM. (a) SEM image of synthesized AuNPs (20 nm). (b) UV−vis spectrum of AuNPs in water solution. (c) SEM images of AuNPconjugated SiNR array (AuNPs = 20 nm) in large scale. The inset exhibits a sample with an area of 2 × 3 cm2. (d) Zoomed-in SEM image of AuNP-conjugated SiNR array from (c). 1480


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Figure 3. Raman measurements on different substrates. (a) Si Raman signals (520.7 cm−1) from planar Si, SiNR array, and SiNR array in conjunction with AuNPs (20 nm). (b) Raman signals of R6G molecule (10−7 M) from planar Si, SiNR array, and SiNR array in conjunction with AuNPs (20 nm).

Figure 4. Sensitivity and reproducibility measurements on SiNR@AuNP substrates. (a) Raman spectra of R6G molecules from 10−6 to 10−10 M. (b) Ten Raman spectra of R6G molecules over a scanning length of 100 μm on ordered SiNRs@AuNPs. (c) Relative standard deviation from 30 Raman spectra measured on ordered SiNRs@AuNPs. (d) Fifteen Raman spectra of R6G molecules over a scanning length of 100 μm on disordered SiNRs@AuNPs.

Since our SERS substrate is based on SiNRs, the first step to check the sensitivity was investigating the Si signal in the SERS measurement. As shown in Figure 3a, the Raman signals of Si (∼520.7 cm−1) are compared between planar Si, SiNRs, and AuNP-decorated SiNR (SiNRs@AuNPs) substrates. The planar Si substrate exhibits the lowest Si signal intensity. Interestingly, the signal measured on the bare SiNR substrate is very enhanced compared to that in the planar Si. We attribute this enhancement of Raman signal to the intensive absorption of incident light by the structural factor (enhanced reflection between SiNRs). After the conjugation of AuNPs, the Raman signal of Si is enhanced dramatically, indicating a strong enhanced plasmonic effect by the SiNR@AuNP substrate. Next, the R6G molecule, a typical model analyte, was applied as

characterized by SEM is exhibited in Figure 2c, and the hexagonal-packed SiNR arrays have a diameter of ∼200 nm and a length of ∼1.3 μm. The period between two SiNRs is ∼500 nm, which is large enough for large biomacromolecules to locate within the inter-rod space. From the SEM images (Figure 2d), it can be seen that abundant AuNPs (diameter 20 nm) are decorated on the surfaces of SiNRs. The inset picture shows the large area (2 × 3 cm2) of fabricated SERS substrates that cannot be easily obtained by electron beam lithography. In addition, we attempted to decorate the SiNRs with 40 nm AuNPs; however, it is unfortunate that only a few AuNPs were decorated on SiNRs unevenly (Figure S1). This is probably due to their heavier weight which prohibits SiNRs from being attached by MPTS. 1481


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Table 1. Relative Standard Deviation of Typical SERS Peaks (R6G) from 30 Raman Spectra Measured on Ordered SiNRs@ AuNPs and Disordered SiNRs@AuNPs wavenumber (cm−1) substrate

612

766

1126

1183

1312

1362

1509

1572

1649

ordered (%) random (%)

7.2 26.3

6.0 25.5

4.5 27.6

5.4 27.5

5.7 22.3

5.4 20.1

5.3 24.2

3.9 22.4

4.6 29.9

Figure 5. FDTD simulation of the near-field electric field distribution of ordered SiNR@AuNP arrays. (a) FDTD-simulated electrical field intensity image at 633 nm. (b) Line profile of electrical field intensity along z = −196 nm and −518 nm. (c) Top view of fabricated SiNR array. (d) Top view of FDTD-simulated electrical field intensity distribution. The polarization direction is set along the x-axis, monitor at z = −540 nm.

an example to investigate the sensitivity of the SiNR@AuNP substrates (Figure 3b). Due to the low concentration of R6G molecules (10−7 M), almost no signal is observed in the planar Si substrate, while very weak signals are obtained on the bare SiNR substrate. Obviously, highly enhanced Raman signals of R6G molecules are received on the SiNR@AuNP substrate. The typical enhancement factor (EF) of SiNRs@AuNPs (20 nm) is about 3.3 × 107 (EF calculation in Supporting Information), which indicates that our SiNR@AuNP SERS substrate has a high SERS activity. The sensitivity of the SiNR@AuNP SERS substrate was further investigated by varying the concentration of R6G molecules from 10−6 to 10−10 M. Figure 4a demonstrates that the Raman intensity increases gradually with increasing concentration. Distinguishable signals at the concentration of 10−10 M can still be observed, which reveals excellent Raman sensitivity in the AuNP-related SERS system. Furthermore, the SERS reproducibility was explored by spot-to-spot Raman scanning. A scanning of 10 Raman spectra over a length of 100 μm was obtained and is shown in Figure 4b. It can be observed that the 10 measurements are highly reproducible and stable. To evaluate the SERS reproducibility quantitatively, we calculated the relative standard deviation (RSD, the ratio of standard deviation to the mean) of noticeable peaks from 30 spectra (three sets of spot-to-spot scanning). Figure 4c shows that the RSD reaches as low as ∼3.9−7.2% for nine peaks, which indicates the outstanding SERS reproducibility. Additionally, to investigate whether the reproducibility is dominated by periodic Si structures, a disordered SiNR@AuNP (20 nm) substrate was fabricated by the same method. As shown in Figure S2, ∼3 μm long SiNRs without periodicity are decorated

with uniform AuNPs. Spot-to-spot Raman scanning results shown in Figure 4d reveal that the disordered SiNR@AuNP substrate has a relatively poor reproducibility on detecting R6G molecules compared with the results obtained by the ordered SiNR@AuNP substrate (Figure 4b). The RSD of disordered SiNR substrates (30 spectra) reaches ∼20−30%, which is 5 times larger than that of the ordered SiNR@AuNP substrate (Table 1). Therefore, ordered distribution of SiNRs plays an important role on the reproducibility of SERS signals. Further comparison is also made with the reported results of a similar ordered SiNW system; both the sensitivity and reproducibility in our SERS substrate are better than the results of ordered SiNWs deposited with Ag film (R6G 10−5 M, RSD 11−13%).40 Since the two systems (SiNRs@AuNPs and SiNWs@Ag film) have similar hexagonal-packed SiNRs (SiNWs), the improved sensitivity and spot-to-spot reproducibility could mainly be attributed to the large distribution of a strongly enhanced electric field by interaction of AuNP−AuNP and SiNR@AuNP arrays. To elucidate the electric field distribution of SiNR@AuNP substrates, we numerically simulated the electric field distribution using the FDTD method. A SiNR array with a length of 1.3 μm and a diameter of 200 nm was investigated, and the simulation model is given in Figure S3. First, the reflectance spectra of SiNR@AuNP arrays were simulated with the same dimensions as the as-fabricated SERS substrate. Compared with experimental results (Figure S4b), the simulated spectra in Figure S4a show the same tendency where the reflectance minima locates near ∼640 nm. The reflectance spectra obtained by experiments are much smoother as there is some fluctuation with the length and periodicity of 1482


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ACS Nano SiNRs during fabrication.61 Additionally, field intensity distributions with different wavelengths of incident light were investigated in Figure S5. The incident light is confined inside the top of SiNRs at 504 nm due to the diameter-dependent leaky modes (Figure S5a),62 while the light resonantly couples to the localized surface plasmons of SiNRs@AuNPs at 633 nm (Figure S5b), which yields strong electrical field enhancement on the surface and inter-rod space of SiNRs. The enhancement becomes weak with the increase of wavelength (750 nm). To have an insight into the enhanced electric field distribution, the LSPR-induced electric field at 633 nm is further analyzed (Figure 5a). Distinctly, the areas around AuNPs are significantly enhanced by LSPR, as well as the large space by LSPR coupling of AuNP−AuNP and AuNP−SiNR. In addition, the further space has also been enhanced by eight antinodes, which are constructed by the coupling of ordered SiNR@AuNP arrays to some extent. From Figure 5b, the decay of the electric field intensity in each antinode covers a distance of δ > 130 nm, indicating the zero-gap field distribution between two SiNRs horizontally. Here, δ is defined as the decay length that the electric field intensity drops to with 1/e times its maximum (z = −196 nm, no AuNP in the cross section). Corresponding to the distribution of SiNRs by SEM on the top view in Figure 5c, we illustrate the electric field intensity distribution in Figure 5d by FDTD. It can be found that the antinodes are connected with their neighbors, which gives evidence of the zero-gap electric field distribution perspicuously. Incident light of polarization on the y-axis is also simulated in Figure S6, in which the net connected antinodes build three-dimensional electric field distribution throughout the substrate. As a result, the great sensitivity and reproducibility of the SiNR@AuNP SERS substrate would be attributed to the following reasons: (a) the enhanced electric field on the surface of SiNRs is broadened by the coupling of AuNP-induced LSPR; (b) uniform nanostructure contributed homogeneous adsorption of analyte molecules; (c) the electric field in the inter-rod space of the substrate has been enhanced with zero gap by the coupling of ordered SiNR arrays. The SERS performance and electric field intensity distribution are critically dependent on the gap and diameter of SiNRs. As a result, three SiNR@AuNP arrays with different gaps and diameters (100, 200, and 300 nm gap; 400, 300, and 200 nm diameter, correspondingly) were investigated. To fabricate the small-gap hexagonal-packed SiNR arrays, we used the dry etching methods (ICP-RIE) to ensure the quality of SiNR arrays. From Figure 6a,b and the insets, we obtained ordered hexagonal-packed SiNR@AuNP arrays with a gap of 100 nm (a) and 200 nm (b). Together with 300 nm gap SiNR@AuNP arrays and random SiNRs@AuNPs, the Raman intensity of R6G molecules was measured, as shown in Figure 6c. The results show that the disordered SiNRs@AuNPs (leaning pillars) receive the strongest enhancement, which is in line with previous reports.42 With the increase of the rods’ gap, the Raman intensity finally decreases to ∼3200 for 300 nm gap arrays. However, it should be noted that the disordered SiNRs@AuNPs have the largest RSD, as the heterogeneous structures by randomly leaning rods. The 100 nm gap arrays also exhibit relatively large RSD. The reason might be the increase of hydrophobicity of the closed SiNRs,63 which would possibly prevent the AuNPs and R6G from entering the gap. Further FDTD simulation in Figure S7 demonstrates that the 100 nm gap arrays obtain excellent enhancement in the narrow gap at 633 nm. In contrast to 100 nm/300 nm gap arrays, the

Figure 6. SEM images and measured SERS intensity versus different gaps and diameters. (a,b) SEM images of ordered SiNR@AuNP arrays with 100 and 200 nm gaps, respectively. The insets are the top view of amplified images. The period is 500 nm, and the height is ∼1.3 μm. (c) Raman intensity (R6G) of disordered SiNRs@ AuNPs and ordered SiNR@AuNP arrays with 100, 200, and 300 nm gaps.

light is localized into the SiNRs in the 200 nm gap arrays in the same wavelength, which results in weak enhancement of the electrical field intensity in empty space. It will greatly reduce the SERS enhancement on large molecules located in the gap, whereas for R6G molecules adsorbed on the AuNPs’ surface, the influence is not significant compared with that of the 300 nm gap arrays (Figure 6c). Furthermore, the vertical lengths of the SiNR@AuNP arrays (700, 1000, and 1300 nm) were simulated under the same condition (Figure S8). It is found that the active space decreased gradually with the shortened length. At the same time, the inside trapping on the top of SiNRs becomes strong. The above results indicate that the gap, diameter, and length would dramatically influence the SERS enhancement. An appropriate tuning of the SiNR arrays can achieve spatially uniform SERS, which is suitable for the detection of large protein aggregates. The advantages of ultrasensitivity and the wide range of electric field enhancement of SiNR@AuNP substrates were further applied to the SERS detection of Aβ protein,which is related to Alzheimer’s disease. The different Aβ peptide 1483


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Figure 7. Morphology measurements and SERS (mapping) detection of Aβ aggregates. (a) Atomic force microscopy (AFM) image of Aβ oligomers (13 μM). (b) AFM image of Aβ fibrils (13 μM). (c) Raman spectra of Aβ oligomers (0.13 μM) and Aβ fibrils (0.13/1.3 μM). (d) Raman mapping of Aβ fibrils (1.3 μM); 400 spots over an area of 20 × 20 μm2 on the SERS substrate covered with Aβ fibrils.

aggregates (incubated from 13 μM peptides) were preexamined on a mica surface by atomic force microscopy (Figure 7a,b). The Aβ oligomers have a diameter of 2−3 nm, and the fibrils have a diameter of 6−7 nm and lengths of several microns (height profiles are shown in Figure S9). The large size and minute quantities of Aβ aggregates limit the sensitivity of a normal 1D/2D metallic nanoparticle SERS system. Although the enhancement of R6G molecules in 100 nm gap arrays is stronger than that of 300 nm gap arrays (Figure 6), we found that the 100 nm gap arrays have difficulty loading the micronlength Aβ fibrils. Most of the Aβ fibrils cover on the top of the arrays, which leads to a low SERS intensity. The detection results by 300 nm gap SiNR@AuNP arrays are given in Figure 7c, which exhibits highly sensitive Raman spectra of Aβ fibrils formed by 0.13 and 1.3 μM peptides. The resolved SERS spectrum (Figure 7c1) of the Aβ fibrils shows clear amide III bands (∼1220−1244 cm−1), Cα−H (∼1400 cm−1), and weak amide II bands (∼1560 cm−1). The band at 960 cm−1 (assigned to the C−C stretching in the Aβ peptides of the polypeptide backbone) can be attributed to the increase of hydrophobicity of protein because the Aβ fibrils are dominated by ordered βsheet structures.51 Significantly, the strong amide III bands (∼1225 cm−1) on the spectrum indicate that the fibrils contain β-sheet-rich structures, which agrees with the results of previous studies.64,65 Obviously, the SERS signals in Figure 7c2 are still distinguishable when the peptide concentration drops to 0.13 μM. Here, it should also be noted that the fibril density from 0.13 μM peptide formation is only about 0.6 fibril/10 μm2 (refer to 13 μM in Figure 7b), indicating that the Raman detection reaches the single-fibril level. Additionally, the 2D Raman mapping is measured at 1225 cm−1, as shown in Figure 7d. The mapping covers 400 spots over an area of 20 × 20 μm2 on the SERS substrate. From the Raman mapping, the singlefibril Raman signals were clearly obtained, indicating the high sensitivity and good uniformity of our SERS substrate. However, due to the nonplanar distribution of fibrils (spread into SiNRs) and the resolution of Raman mapping, the Raman intensity image of fibrils shows the fluctuation with dark and light spots. Unfortunately, we could not obtain the clear SERS spectrum of Aβ oligomers. The possible reason might be imputed to the distribution of Aβ oligomers, where the majority of Aβ oligomers have sunk to the bottom of the SERS substrate. Nevertheless, our SERS system exhibits high sensitivity on the detection of large-size Aβ fibrils by the greatly enhanced inter-rod electric field with a long decay length.

CONCLUSION In conclusion, we have fabricated a highly sensitive and reproducible SERS substrate composed by ordered hexagonalpacked SiNR arrays in conjunction with homogeneous AuNPs. With an optimized gap, diameter, and length, the SiNR@AuNP SERS substrate exhibits stable and reproducible Raman signals of analyte molecules (R6G) with high sensitivity and small RSD of ∼3.9−7.2%. This is mainly contributed by the coupling of AuNP-induced strong LSPR along the SiNRs, as well as the wide-range and zero-gap 3D enhanced electric field between SiNRs. More importantly, the SiNR@AuNP SERS substrate has been applied in the detection of long Aβ fibrils at a singlefibril level, which reveals the secondary structures of Aβ fibrils with high sensitivity and provides a potential method for the study of dynamic interaction of label-free amyloid protein. Furthermore, the large-area SERS substrate can be easily fabricated by low-cost methods of metal-assisted chemical etching and PS lithography. Overall, the ordered SiNR@AuNP array may serve as a highly sensitive and excellent reproducible SERS substrate for molecule/biomolecule detection. METHODS Materials. The suspensions (2.5 wt% in water) of polystyrene spheres (PS, 500 nm in diameter) were purchased from Duke Scientific (USA). The Si wafers were purchased from MTI (China). Acetone, methanol, H2SO4, H2O2, and HF for fabricating ordered SiNRs were purchased from Sinopharm Chemical Reagent (China). HAuCl4, trisodium citrate for the synthesis of AuNPs, MPTS for conjugation, and the analyte molecule of R6G were purchased from Sigma-Aldrich Corporation (China). Deionized water (DI, 18.2 MΩ· cm) was obtained from an ultrafiltration system (Milli-Q, Millipore, Marlborough, MA). Synthesis of AuNPs and Characterization. AuNPs were synthesized using citrate reduction of HAuCl4. All glass vessels were cleaned by aqua regia for at least 30 min and thoroughly rinsed with fresh DI water before use. A 40 mL aqueous solution of 0.01% HAuCl4 was stirred mechanically during heating in an oil bath at 130 °C. After being boiled, 400 mL of 1% trisodium citrate solution was added, and the solution was stirred vigorously for a set time. Size-dependent AuNPs were synthesized by different incubation times. The size and monodispersity of the AuNPs were checked by SEM. In this work, AuNPs with diameters of 20 and 40 nm were synthesized. For UV−vis absorption measurement, an Agilent 8453 UV−visible/NIR spectrophotometer with microquartz cuvettes of 10 mm optical path length was used. Fabrication of Ordered SiNRs and Conjugated with AuNPs. The methods of making ordered SiNRs were reported in our previous work.61 First, a monolayer of PS with diameters of 500 nm was self1484


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ACS Nano assembled on the chemically cleaned planar Si wafer, and the samples were baked at 80 °C for 3 min to remove the residual DI water and other adsorption material. Next, the PS-covered samples were etched by RIE with O2 gas (Samco, Japan). The gas flow rate was 30 sccm; the power was 30 W; chamber pressure was 74 mTorr, and the etching time was 280 s. Afterward, a 20 nm Au layer was sputtered onto the samples by an ion sputtering apparatus (Cressington, 108Manual, UK) at a constant current of 10 mA. After Au deposition, SiNRs were fabricated by wet etching using HF and H2O2 with a volume ratio of 4:1. The etching solution was stirred constantly, and the length of the nanowire could be adjusted by controlling the etching time. Finally, the PS was removed by RIE with O2, and the remaining Au layer was removed by soaking the sample in KI/I2 mixed solution (10 g of KI, 2.5 g of I2, and 100 mL of DI water) for 24 h. In order to decorate the AuNPs onto the surface of SiNRs, hybrid composites were prepared via a “grafting onto” strategy. First, the fabricated SiNR substrate was functionalized with a Si hydroxy group. The SiNR substrate was immersed in 5 mL of ethanol containing 50 μL of MPTS and 10 μL of aqueous NH4OH (27%). The immersed SiNR substrate was covered with aluminum foil for 24 h at 25 °C, and the MPTS-treated substrate was washed with ethanol and DI water several times. To coat AuNPs, the MPTS-treated SiNR substrate was thoroughly immersed in 1 mL of a AuNP solution (∼1 nM) for 4 h at 37 °C. The resulting Au-coated substrate was washed with water several times. Finally, the substrate was exposed under UV light for 30 min and washed with water to remove the residual MPTS by photodecomposition. The morphology of fabricated SiNRs and AuNP-decorated SiNRs were checked by SEM. Their optical properties were investigated by measuring the hemispherical optical reflectivity in the spectral range from 500 to 700 nm with a step of 5 nm via a UV−vis spectrophotometer (Zolix, China). All measurements were repeated three times. Incubation of Aβ Oligomers and Fibrils. Aβ16−22 peptides were purchased from Chinese Peptide Ltd. (Hangzhou, China). The final purity was greater than 98%. Aβ peptide solution (13 μM) was prepared by dissolving the peptide powder in DI water. Aβ oligomers were obtained by being incubated for 30 min at 37 °C, whereas Aβ fibrils require a 3 day incubation. Aβ fibrils with different concentrations were prepared by diluting the preformed Aβ fibrils to the required concentration. The morphologies of the oligomer and fibrils were characterized by atomic force microscopy. SERS Detection. The Raman spectra were recorded from a Jobin Yvon HR-Evolution 2 system with excitation wavelength at 633 nm (∼1.3 mW) and 785 nm (∼3.5 mW). In both measurements, the laser beam was focused in a spot of 5 μm diameter by a microscope objective with a magnification of 50×. The acquisition time was set to 5 s for the 633 nm laser measurement and 15 s for the 785 nm laser measurement. To obtain SERS spectra, 2 μL of R6G and Aβ oligomer/fibril solutions with different concentrations was dropped onto the AuNP@SiNR substrate. For the spot-to-spot Raman measurements, a scanning line of 100 μm with 10 points was set and repeated for three times in different places. In the Raman mapping, a microscope objective with a magnification of 100× was used, and the acquisition time was set to 15 s with a wavenumber of 500−1600 cm−1. Finite-Difference Time-Domain Simulation. We used Lumerical FDTD Solution (version 8.12.590) to perform FDTD simulations. As shown in Figure S3, the SERS substrate was placed in vacuum with the plane wave source in the head. The wavelength of incident laser was 400−750, with the polarization direction along the x-axis. The optical data of Au is from Johnson and Christy.66 Mesh enclosing of the entire model was set to 2 nm per grid and 0.5 nm for AuNPs locally. The z-axis boundary of the simulation region was set to perfect matching layer, and the x- and y-axes were set to periodic. The 2D monitor on the z-axis was placed to obtain absorption spectra. Nearfield cross-sectional electrical intensity profiles were obtained by a znormal 2D monitor passing the AuNP axis and y-normal 2D monitor across the SiNR. The simulation time was 300 fs. To check the wide-

range E-field enhancement, we also set the polarization direction along the y-axis.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsnano.6b06778. EFM images of SiNRs decorated with AuNPs (40 nm); EFM images of disordered SiNR@AuNP arrays; FDTD simulation model; reflectance spectrum of SiNR@AuNP arrays by FDTD and experiment; FDTD-simulated nearfield electrical intensity distribution with different incident light; electric field intensity distribution with vertical polarization of incident light; electric field intensity distribution with different gaps and diameters; AFM line profiles of Aβ oligomers and fibrils (PDF)

AUTHOR INFORMATION Corresponding Author

*Tel: +86 21 55665337. E-mail: [email protected]. ORCID

Yuebing Zheng: 0000-0002-9168-9477 Xinju Yang: 0000-0002-6434-4342 Author Contributions

D.L., X.Y., and Z.J. designed the research; D.L., S.L., W.Z., and C.M. performed experimental research; D.L., Z.W., and J.W. performed simulations; D.L., Z.W., X.Y., and Y.Z. analyzed data; D.L. and X.Y. wrote the paper. Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (No. 11274072). REFERENCES (1) Kneipp, K.; Wang, Y.; Kneipp, H.; Perelman, L. T.; Itzkan, I.; Dasari, R. R.; Feld, M. S. Single Molecule Detection Using SurfaceEnhanced Raman Scattering (SERS). Phys. Rev. Lett. 1997, 78, 1667− 1670. (2) Guerrini, L.; Graham, D. Molecularly-Mediated Assemblies of Plasmonic Nanoparticles for Surface-Enhanced Raman Spectroscopy Applications. Chem. Soc. Rev. 2012, 41, 7085−7107. (3) Sharma, B.; Frontiera, R. R.; Henry, A.-I.; Ringe, E.; Van Duyne, R. P. SERS: Materials, Applications, and the Future. Mater. Today 2012, 15, 16−25. (4) McNay, G.; Eustace, D.; Smith, W. E.; Faulds, K.; Graham, D. Surface-Enhanced Raman Scattering (SERS) and Surface-Enhanced Resonance Raman Scattering (SERRS): A Review of Applications. Appl. Spectrosc. 2011, 65, 825−837. (5) Dieringer, J. A.; McFarland, A. D.; Shah, N. C.; Stuart, D. A.; Whitney, A. V.; Yonzon, C. R.; Young, M. A.; Zhang, X.; Van Duyne, R. P. Surface Enhanced Raman Spectroscopy: New Materials, Concepts, Characterization Tools, and Applications. Faraday Discuss. 2006, 132, 9−26. (6) Luo, S.-C.; Sivashanmugan, K.; Liao, J.-D.; Yao, C.-K.; Peng, H.C. Nanofabricated SERS-Active Substrates for Single-Molecule to Virus Detection in vitro: A Review. Biosens. Bioelectron. 2014, 61, 232− 240. (7) Kneipp, K.; Kneipp, H.; Kartha, V. B.; Manoharan, R.; Deinum, G.; Itzkan, I.; Dasari, R. R.; Feld, M. S. Detection and Identification of a Single DNA Base Molecule Using Surface-Enhanced Raman Scattering (SERS). Phys. Rev. E: Stat. Phys., Plasmas, Fluids, Relat. Interdiscip. Top. 1998, 57, R6281−R6284. 1485


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