# Enhancing Disease Diagnosis: Biomedical Applications of Surface-Enhanced Raman Scattering
## 6 Conclusions and Future Outlook
\begin{table}
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**Enhanced Raman Techniques** & **Brief Description** \\ \hline \multirow{4}{*}{\begin{tabular}{} \end{tabular} } & RR occurs when the incident frequency excites electronic energy (EE) states of specific molecules; e.g., aromatic chromophores, and this aids the detection of pathogens [161]. If the EE level is excited by laser frequency in the ultraviolet (UV) region, the technique is UVRR, and can be susceptible to photodissociation [162]. \\ \hline \multirow{4}{*}{\begin{tabular}{} \end{tabular} } & SORS collects distinctive chemical information and images from deep subsurfaces (including analytes in opaque containers) of a sample. SORS spectral signals are recorded when backscattered Raman photons are collected at points spatially offset (\(\Delta x\)) from the point of illumination (\(x\)). Negligible photodissociation, allowing for noninvasive deep medical diagnostics [163]. \\ \hline \multirow{4}{*}{\begin{tabular}{} \end{tabular} } & SORS combined with NPs that enable SERS: that is to say subsurface information is measured from molecules in the vicinity of or chemically bonded to SERS substrates. Negligible fluorescence and excellent background contrast, specificity and sensitivity with improved detection limit for various disease markers [164; 165]. \\ \hline \multirow{4}{*}{\begin{tabular}{} \end{tabular} } & A variant of SESORS where incident frequency matches the EE of molecules near SERS-active substrates. SESORRS increases spectral signals further by orders of magnitude to provide extra biochemical selectivity and sensitivity, theoretically better than SESORS, as demonstrated by [PERSON] et al. for breast cancer detection [166]. \\ \hline \multirow{4}{*}{\begin{tabular}{} \end{tabular} } & Similar to the SERS phenomenon, but here a single SERS-active AFM probe whose sharp pointed apex (tip) is covered in NPs and scans through biomolecules on a sample surface, resulting in highly confined plasmonic enhancement (electrostatic lightning rod and SPR effects). Improves lateral spatial resolution to as low as 10 nm, about the diameter of the tip probe. Achieves single molecule detection and discrimination of bacterial pathogens [167; 168]. \\ \hline \multirow{4}{*}{\
\begin{tabular}{} \end{tabular} } & Two lasers provide a pump (\(\omega_{p}\)) (similar to conventional Raman) and Stokes (\(\omega_{s}\)) beam frequencies that intersect at the sample surface. The energy difference (\(\Delta\omega=\omega_{p}-\omega_{s}\)) between the beams matches the frequency (\(\Omega_{\mathrm{eil}}\)) of molecular bond vibrations, leading to larger scattering cross-section as a consequence of stimulated Raman excitation. No nonresonance background [169], making SRS ideal for in vivo medical imaging to improve disease diagnostics [170]. \\ \hline \multirow{4}{*}{
\begin{tabular}{} \end{tabular} } & Like SRS, CARS employs two lasers of frequencies \(\omega_{p}\) and \(\omega_{s}\). When molecular bonds whose \(\Omega_{\mathrm{eil}}\) coincide with \(\Delta\omega\) (as in SRS), anti-Stokes (\(as\)) lines are produced at frequency \(\omega_{as}=2\omega_{p}-\omega_{s}\). Thus, analytes are excited twice, from the ground to first and second excited states before relaxing back to the ground state. Though prone to nonresonance background effects which may limit the quantification of target analytes [171], CARS is effectively applied for disease detection including differential diagnostics of cancers [172]. \\ \hline \hline \end{tabular}
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Table 1: A summary of different types of enhanced Raman scattering techniques commonly used in disease diagnostics. **Funding:** This research project was funded by the Commonwealth Scholarship Commission (CS) UK grant number ZMCA-2016-152 for M.C. and the UK Biotechnology and Biological Sciences Research Council (BBSRC) grant number BB/L014823/1 for R.G. **Conflicts of Interest:** The authors declare no conflict of interest.