Coaxial bioprinting of microsphere bioink to engineer heterogeneous vascularized lung cancer model

3D bioprinting is a promising strategy for engineering in vitro tumor models. However, replicating the intratumoral parenchyma-stroma heterogeneity remains challenging due to the poor formability of biomimetic bioinks. In this study, we developed a method to enable the direct extrusion of low-concentration gelatin-methacrylate (GelMA)/Matrigel by overcoming its rheological limitations. The bioink was then incorporated within a coaxial bioprinting system to engineer a defined tumor parenchyma-stroma interface. The coaxial lung cancer model featured a dual-layer tubular structure. In this structure, the inner microsphere bioink was designed to mimic the tumor parenchyma, and the surrounding HAMA/Fibrin hydrogel was used to reproduce the stroma. The model not only established the spatial heterogeneity but also recapitulated biological function such as fibroblast-driven angiogenesis, as demonstrated by a 3.4-fold increase in microvascular density and a 2.3-fold extension in total vessel length. Furthermore, the model exhibited 50-fold increase in drug resistance compared to two-dimensional (2D) cultures. Additionally, the long-term cryopreservation stability and scalability endowed the model with the potential to be a tool for on-demand use. This work provides a potential platform for drug screening and mechanistic investigation of tumor biology.