Metal-oxide surface-enhanced Raman biosensor template towards point-of-care EGFR detection and cancer diagnostics

Abstract

Surface-enhanced Raman spectroscopy (SERS) is a non-invasive and powerful tool for identification of molecular species. Proposed SERS structures have thus far been restricted to noble metals such as Au and Ag. However, metal-oxide-based SERS represents a new frontier in the field of biosensing. While the implementation of semiconductor materials such as TiO₂ as a SERS template would enormously widen the range of use for this technique due to its biocompatibility, the detection sensitivity is still seriously impeded by inferior SERS enhancement. Consequently, the application of TiO₂ for molecular biosensing has been greatly hampered. Herein, we report on a novel concept of non-stoichiometric titanium dioxide, as well as the incorporation of self-assembled quantum scale structured (Q-structured) TiO_x as an ultra-high sensitive template to intensify the Raman response of tumor biomarkers, such as epidermal growth factor receptors (EGFR), to diagnose breast cancer. We demonstrate the incorporation of oxygen vacancies as a strategy to significantly increase the SERS enhancement of Q-structured TiO₂. We found that reducing the TiO₂ particles to quantum scale can increase the EF by up to 3.5 × 10⁵, while further enhancement can be achieved by inducing the oxygen vacancies to the Q-structured TiO_x. The detection limit was as low as 1 nM and the maximum EF was 3.4 × 10⁷, which, to our best knowledge, is within the highest sensitivities achieved among semiconducting materials, even comparable to noble metals. Measurements with breast and cervical cancer cells lines where used to demonstrate the clinical application of the proposed SERS template.