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3D tumor models are emerging as valuable tools for drug screening and nanoparticle based personalized cancer treatments. The main challenges in building microfluidic chip-based 3D tumor models currently include the development of bioinks with high bioactivity and the reproduction of the key tumor extracellular matrix (ECM) with heterogeneous tumor microenvironments. In this study, we designed a triangular multi-chamber tumor-on-a-chip (TM-CTC) platform, which consisted of three circular chambers at the vertices of a triangle connected by three rectangular chambers; it significantly improved the culture efficiency of 3D tumor tissues. MCF-7 tumor cells were cultured in a 3D ECM and then dynamically perfused for 7 days of culture to obtain abundant tumor spheroids with uniform size (100 ± 4.1 μm). The biological features of the 3D tumor tissue including epithelial transformation (EMT), hypoxia and proliferation activities were reproduced in the triangular multi-chamber tumor-on-a-chip (TM-CTC) platform. The permeability results of NPs confirmed that the ECM exhibited a significant barrier effect on the transportation of NPs when compared with free drugs, indicating that the ECM barrier should be considered as one of the key factors of drug delivery carrier development. In addition, this TM-CTC model provided a suitable platform for constructing a complex heterogeneous tumor microenvironment with multiple cells (MCF-7, HUVEC and MRC-5) involved, which was beneficial for exploring the dynamic interaction between tumor cells and other cells in the tumor microenvironment. The above results suggest that this TM-CTC model can simulate the dynamic transportation of NPs around 3D tumor tissues, and thus provide a reliable platform for NP evaluation.

The traditional evaluation of nanoparticles (NPs) is mainly based on 2D cell culture and animal models. However, these models are difficult to accurately represent human tumor microenvironment (TME) and fail to systematically study the complex transportation of NPs, thus limiting the translation of nano-drug formulations to clinical studies. This study reports a tumor model fabricated via 3D bioprinting with adipose decellularized extracellular matrix (ECM) enhanced hybrid bioink. Compared with 2D cultured cells, the 3D printed tumor models with multicellular spheroids formation are closer to real tumor in protein, gene expression and tumorigenicity both in vitro and in vivo. Two characteristics of TME, ECM remodeling and epithelial-mesenchymal transition, are tracked simultaneously under 3D conditions. Furthermore, the cellular uptake efficiency of two different NPs is significantly lower in the printed 3D tumor model than the 2D individual cells, and higher drug resistance is observed in 3D group, which suggest the ECM barrier of tumor can significantly affect the permeability of NPs. These results suggest that this 3D printed tumor model is capable of mimicking the multiple TME, potentially providing a more accurate platform for the design and development of NPs before moving into animal and clinical trials.