Near-physiological microenvironment simulation on chip to evaluate drug resistance of different loci in tumour mass

Abstract

Developing a bio-functional model in vitro to study cancer resistance, which is a big challenge for clinical cancer therapy, is of great interest. Such reliable model requires appropriate drug diffusion kinetics simulation and a microenvironment that allows cell-cell and cell-matrix interactions. In this work, a special hydrogel-based three-dimensional (3D) microfluidic chip was constructed to simulate tumour-vascular microenvironment. The self-healing hydrogel supports long-time cell survival and proliferation, effective cellular metabolism of cancer drugs and cell-cell interaction between different types of cells. In the effective near-physiological tumour-vascular microenvironment, the endothelial and fibroblast cells are spread on different sides of a porous membrane, while sensitive and resistant breast tumour cells are separately cultured in the dynamic hydrogel consisting of glycol chitosan and telechelic difunctional poly (ethylene glycol) in the upper chambers. Nutrients and drugs are introduced through the bottom channel and diffuse into the cancer cells. Doxorubicin molecules pass first through blood vessel endothelial cells and act on the tumour cells surrounded by fibroblasts. Tumour cells respond differently to drug when they are cultured in the microenvironment. Sensitive breast tumour cells have a 47% increase in viability than those cultured without fibroblasts and endothelial cells. Both sensitive and resistant tumour cells can be analysed under the same chemical environment. This work represents a multi-functional in vitro platform that allows near-physiological simulation, effective drug metabolism and cellular response to extracellular stimuli and has great potential to make drug discovery speedy and precise.