Recent Developments in SERS Microfluidic Chips: From Fundamentals to Biosensing Applications.

This paper reviews the latest research progress of surface-enhanced Raman spectroscopy (SERS) microfluidic chips in the field of biosensing. Due to its single-molecule sensitivity, selectivity, minimal or no preprocessing, and immediacy, SERS is considered a promising biosensing technology. However, the nondirectional interactions between biological samples and the substrate, as well as fluctuations in the sample environment temperature during signal acquisition, can affect the stability and reproducibility of SERS signals. Integrating SERS spectroscopy with microfluidic chips not only leverages the continuous sample flow, high reaction efficiency, high throughput, and multifunctionality of microfluidic chips to address challenges in biosensing applications but also expands the scope of microfluidic technology by providing a novel on-chip optical detection method. The combination of SERS and microfluidic chips not only enables the complementary advantages of both technologies but also offers a highly promising "combined technology" for the field of biosensing. This paper starts by introducing the enhancement mechanisms of SERS and presents both labeled and label-free SERS strategies. Based on the differences in substrate properties, we broadly categorize SERS microfluidic chips into colloidal nanoparticle-based SERS microfluidic chips and fixed substrate-based SERS microfluidic chips. Finally, we review the latest research progress on SERS microfluidic chips for biosensing biological targets such as nucleic acids, proteins, small biomolecules, and live cells. In the conclusion and outlook section, we summarize the challenges faced by SERS microfluidic chips in biosensing and propose feasible solutions. To better leverage the role of SERS microfluidic chips in biosensing, we also present an outlook on the future development of this combined technology.