Nanofabricated SERS-active substrates for single-molecule to virus detection in vitro: A review
Introduction
Advances in nanofabrication have helped lower the detection limit of sensing small molecules and biomolecules for many detection technologies. The surface-enhanced Raman scattering (SERS) method is a technology that significantly benefits from progress in nanotechnology and nanofabrication. SERS is believed to be predominantly due to two mechanisms: electromagnetic (EM) and chemical effects. The respective contributions of these mechanisms to the overall SERS enhancement were debated during 1980s–1990s, but EM, a prior effect to the enhancement, is believed to be a few orders more than the chemical one (Albrecht and Creighton, 1977, Fleischm. et al., 1974, Jeanmaire and Vanduyne, 1977). The application of the SERS method for the detection of single molecules, biomolecules, and even biological cells has increased dramatically over the past few years. When the target species is trapped/adhered to the proximity of a metal nanostructure (NS) (usually Au, Ag, or Cu), the Raman intensity is enhanced due to the amplification of the EM field resonance (Kneipp et al., 1999, Otto et al., 1992). The enhancement is determined not only by the size and shape of the metal NS, but also the interactions among the target species, the metal surface, and the microenvironment (Banholzer et al., 2008, Kelly et al., 2003, Willets and Van Duyne, 2007). Researchers have investigated the formation of hot spots, which are small regions of a highly enhanced EM field that indicate high SERS intensity (Halas et al., 2011, Schatz et al., 2006, Xu et al., 2000). These regions can be observed or even predicted using computer simulation and modeling to describe the quantum effect on sub-nanometer gaps (Esteban et al., 2012, McMahon et al., 2012, Qin et al., 2006). It is well understood that the enhancement at nanometer gaps enables SERS-active signals to be detected with single-molecule sensitivity (Kneipp et al., 1997, Kneipp et al., 2008, Nie and Emery, 1997). In addition to its high sensitivity, the SERS method has several other advantages, including the ability to fingerprint individual molecules, narrower spectral peaks compared to fluorescence peaks, a single excitation source, and minimal photo-bleaching and low background from aqueous environments (Vendrell et al., 2013). These advantages make SERS a perfect fit for the development of detection tools and diagnostic assays. Hand-held SERS systems have been demonstrated to detect pesticides (Zheng et al., 2013), food-contamination-related molecules (Sivashanmugan et al., 2013a), bacteria (Cowcher et al., 2013), and tumors (Mohs et al., 2010).
Generally, there are two ways to create SERS-active substrates or platforms: using nanoparticles (NPs)/NSs produced from solution-based synthesis and using nano-assembly or nanofabrication. Using NPs is the most straightforward method. During the aggregation of NPs with a target species, characteristic Raman signals can be easily amplified because of being in the proximity of hot spots. Historically, the main drawback of NP-based systems has been the difficult control of their assembly (e.g., the formation of hot spots) and the detection of target species locations. This problem has been resolved using sophisticated NSs, which can generate well-defined hot spots and precisely locate the analyzers. NSs have been extensively applied to the detection of pollutants (Dasary et al., 2009, Schmidt et al., 2004), DNA (Kneipp et al., 1998, Lim et al., 2011), and proteins (Grubisha et al., 2003, Xu et al., 1999) and to the imaging of living cells (Chrimes et al., 2013, Lin et al., 2009, Palonpon et al., 2013) and tumors (Qian et al., 2008, Sangyeop et al., 2014).
Several recently published review articles have covered the principle and applications of SERS (Cialla et al., 2012, Jin, 2012, Kleinman et al., 2013, Le Ru and Etchegoin, 2012, Sharma et al., 2012, Vendrell et al., 2013, Wang et al., 2013). Researchers interested in NP/NS-based SERS platforms and SERS tags can refer to these articles.
The applications of SERS-active substrates have attracted increasing attention due to progress in nanofabrication. Compared to NPs/NSs in a solution system, SERS-active substrates provide several advantages: (i) they make it convenient to locate the target species and focus an excitation beam on a target species; (ii) they are easy to handle and stable for long-term storage; and (iii) they can be integrated with other measurement techniques such as tip-enhanced Raman spectroscopy via an atomic force microscope to approach the target species (Anderson, 2000, Hayazawa et al., 2002) and in situ electrochemical SERS via a potentiostat to control the potential or an electrochemical cell to proceed the reaction (Tian and Ren, 2004, Wu et al., 2008). However, SERS-active substrates have several drawbacks, including low substrate-to-substrate reproducibility and high production cost.
The present article summarizes developments made in nanofabricated SERS-active substrates in the last five years. During this period, researchers have fabricated sophisticated substrates by applying various top-down, bottom-up, and combination technologies to create robust and reproducible SERS-active substrates. Advances in nanofabrication technologies allow greater control of substrate NSs and their chemical compositions. Researchers can have a comprehensive understanding on the theory behind through evaluating the enhancement of hot spots from both experimental results and modeling and simulation. The fine-tuning of substrates using both physical and chemical means enables sensitive detection, from single molecules to biomolecules. This review highlights recent developments for SERS-active substrates as detection platforms used for detection. Future developments and several prospects for SERS-active substrates, especially for trace detection and disease diagnosis, are also discussed.
Section snippets
Nanofabrication
Researchers have developed many types of metallic NSs as SERS-active substrates via advanced nanofabrication processes. Fig. 1 highlights some breakthroughs in the last five years in the development of nanostructured SERS-active substrates. In general, strategies for fabricating NSs can be categorized as top-down, bottom-up, or combination techniques, which are summarized in Table 1. Details of these techniques are given below.
Average enhancement factor
A high EF is a criterion for ideal SERS-active substrates. For two-dimensional (2-D) nanostructured substrates, the distribution of EFs is very broad. Molecules in areas with hot spots are usually the main contributors to the average EF. Therefore, fabricating a nanostructured substrate with high-density hot spots greatly increases the average EF.
Le Ru et al. (2007) reviewed the measurement of EF. The EF for a substrate is commonly defined as follows:where ISERS is the
Biomolecule detection
In the last five years, SERS-active substrates have been extensively applied to detect not only small molecules, but also some relatively large biomolecules, as shown in Fig. 3. Researchers have utilized SERS-active substrates as platforms for the detection of all kinds of target species, including typical dyes (Hu et al., 2010), biomarkers (Cheng et al., 2009), nucleobases (Feng et al., 2009), drugs (Yang et al., 2012), pollutants (Zhou et al., 2013), and big biomolecules such as DNA (Bi et
Conclusion and perspective
With advances in nanofabrication, researchers have gradually found solutions to overcome the disadvantages of using SERS-active substrates, such as inconsistency and production cost. Sophisticated NSs have been applied to SERS-active substrates for trace detection and biosensing. It has been widely accepted that SERS-active substrates provide high sensibility. Although selectivity is still a large problem, several research groups have demonstrated strategies for overcoming this issue. Based on
Acknowledgment
This work was financially supported by Ministry of Science and Technology of Taiwan (102-2113-M006-013-MY2 and 100-2221-E-006-025-MY3) and Medical Device Innovation Center of National Cheng Kung University (D102-21007).
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