dECM-Supported Printing of Plasmonic Pillars for SERS Monitoring of Chemotherapy in 3D Tumor Models

The development of antitumoral drugs is limited by the absence of in vitro platforms that simultaneously offer biological relevance, spatial complexity and analytical sensitivity to evaluate cellular responses. To overcome these challenges, we propose the integration of surface-enhanced Raman scattering (SERS) sensors into three-dimensional (3D) tumor models. We therefore engineered the incorporation of 3D printed SERS-active hydrogel pillars within a bioprinted breast cancer model featuring distinct tumor and stromal compartments. The model is manufactured using a breast-derived decellularized extracellular matrix bioink, loaded with tumoral and stromal cells, which supports cellular growth and provides the mechanical integrity required to preserve the core/shell organization of the tumor-stroma architecture. In parallel, the sensors are produced from a plasmonic hydrogel ink composed of thiolated alginate and methacrylated carboxymethyl cellulose, which can be chemically photo-cross-linked via thiol-ene click chemistry and loaded with plasmonic gold nanorods. This complex ink shows suitable rheological and mechanical properties for the direct 3D printing of pillar-shaped SERS sensors directly within the tumor-stroma model. These SERS-active pillars enabled the detection of the anti-cancer drug 6-thioguanine (6-TG) in the different compartments of the model, revealing asymmetric consumption of 6-TG by tumoral and stromal cells. These differences are proposed to correlate with a higher cytotoxic response in the tumor core. Therefore, our platform allows for real-time tracking of drug dynamics in a tissue-like environment, thereby offering a versatile tool for therapeutic screening.