Microfluidic Droplet-Assisted Fabrication of Vessel-Supported Tumors for Preclinical Drug Discovery.

High-fidelity tumor models are important for preclinical drug discovery processes. Currently, the most commonly used model for drug testing remains the two-dimensional (2D) cell monolayer. However, the natural tumor microenvironment (TME) consists of extracellular matrix (ECM), supporting stromal cells and vasculature. They not only participate in the progression of tumors but also hinder drug delivery and effectiveness on tumor cells. Here, we report an integrated engineering system to generate vessel-supported tumors for preclinical drug screening. First, gelatin-methacryloyl (GelMA) hydrogel was selected to mimic tumor extracellular matrix (ECM). HCT-116 tumor cells were encapsulated into individual micro-GelMA beads with microfluidic droplet technique to mimic tumor-ECM interactions . Then, normal human lung fibroblasts were mingled with tumor cells to imitate the tumor-stromal interaction. The tumor cells and fibroblasts reconstituted in the individual GelMA microbead and formed a biomimetic heterotypic tumor model with a core-shell structure. Next, the cell-laden beads were consociated into a functional on-chip vessel network platform to restore the tumor-tumor microenvironment (TME) interaction. Afterward, the anticancer drug paclitaxel was tested on the individual and vessel-supported tumor models. It was demonstrated that the blood vessel-associated TME conferred significant additional drug resistance in the drug screening experiment. The reported system is expected to enable the large-scale fabrication of vessel-supported heterotypic tumor models of various cellular compositions. It is believed to be promising for the large-scale fabrication of biomimetic tumor models and may be valuable for improving the efficiency of preclinical drug discovery processes.