Paper-based plasmonic substrates as surface-enhanced Raman scattering spectroscopy platforms for cell culture applications.

The engineering of advanced materials capable of mimicking the cellular micro-environment while providing cells with physicochemical cues is central for cell culture applications. In this regard, paper meets key requirements in terms of biocompatibility, hydrophilicity, porosity, mechanical strength, ease of physicochemical modifications, cost, and ease of large-scale production, to be used as a scaffold material for biomedical applications. Most notably, paper has demonstrated the potential to become an attractive alternative to conventional biomaterials for creating two-dimensional (2D) and three-dimensional (3D) biomimetic cell culture models that mimic the features of tissue environments for improving our understanding of cell behavior (e.g. growth, cell migration, proliferation, differentiation and tumor metastasis) in their natural state. On the other hand, integration of plasmonic nanomaterials (e.g. gold nanoparticles) within the fibrous structure of paper opens the possibility to generate multifunctional scaffolds equipped with biosensing tools for monitoring different cell cues through physicochemical signals. Among different plasmonic based detection techniques, surface-enhanced Raman scattering (SERS) spectroscopy emerged as a highly specific and sensitive optical tool for its extraordinary sensitivity and the ability for multidimensional and accurate molecular identification. Thus, paper-based plasmonic substrates in combination with SERS optical detection represent a powerful future platform for monitoring cell cues during cell culture processes. To this end, in this review, we will describe the different methods for fabricating hybrid paper-plasmonic nanoparticle substrates and their use in combination with SERS spectroscopy for biosensing and, more specifically, in cell culture applications.