Development and evaluation of platform-based SERS substrates for detecting cancer biomarkers at ultra-low concentrations
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Surface Enhanced Raman Scattering (SERS) has proved to be a powerful spectroscopic tool since its discovery in 1973. Advances in nanofabrication techniques increasingly allow for the manufacture of complex nanostructured surfaces. However, an obvious constraint to developing suitable substrate topography, can be the complex and often expensive techniques required to manufacture them. The aim of this work is to evaluate the performance of SERS substrates, and so better understand the key parameters affecting their efficiency. Then, to investigate development of novel substrates produced via state of the art nanofabrication techniques. Finally, using a suitably characterised substrate, to develop a robust method of SERS biosensing for cancer biomarkers at ultra-low concentrations. In this study, Raman analysis was performed on commercially available, and ‘in house’ produced substrates functionalised with a Raman reporter; 2-Napthalenethiol (2-NT). The substrate types investigated were fabricated via different techniques. These techniques include: Reactive Ion Etching (RIE); Inkjet printed Nanoparticles (NP); Dynamic Oblique Deposition, Laser processing and Nanoimprint lithography (NIL). The characterisation was carried out to correlate fabrication methods and the surface geometry they produce to SERS performance. The Raman response of the substrates was interpreted using SEM analysis and Finite Difference Time Domain (FDTD) modelling. The FDTD software simulates an electromagnetic wave incident on nanostructures and outputs the local electric field maxima and spatial distribution. We discovered a number of factors that affect the SERS response of a substrate, including the size and shape of surface features, and material composition. However, the parameter that ultimately dictates the magnitude of the Raman signal enhancement is that of interstructure spacing. Substrates that achieve sub-10 nm gaps between structures cause strong interaction of adjacent electric fields and thus generate Coupled Plasmon Resonance (CPR). When CPR occurs the SERS enhancement factor is sharply increased. Following the substrate characterisation, a high efficiency SERS substrate was chosen to investigate SERS biosensing of proteins. An indirect method to detect protein was investigated, relying on a SERS-based nanostress immunoassay. The analytes tested were the cancer biomarkers p53 and Epidermal Growth Factor Receptor (EGFR). It was found that variation in antigen concentration influenced changes to the Raman linker spectra. This was observed in both a FWHM broadening and peak centre frequency shift for selected Raman peaks of interest. The lowest concentration measured in this work compares well with previously reported detection limits based on nanostress sensors. Not all of the linker/protein systems tested exhibited consistent and measurable peak changes. However, the differences in characteristic behaviour of linker/protein models can be exploited for multiplexed biosensing leading to better disease prognosis. With continued development, this nanostress sensing model could eventually be used in point of care clinical diagnostics.
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