A gravity-driven tissue chip to study the efficacy and toxicity of cancer therapeutics†

Abstract

Tissue chip and organs-on-chip technologies have emerged as promising tools in preclinical studies. In oncology, this is driven by the high failure rates of candidate drugs in clinical trials mainly due to inadequate efficacy or intolerable toxicity and the need for better predictive preclinical models than those traditionally used. However, the intricate design, fabrication, operation, and limited compatibility with automation limit the utility of tissue chips. To tackle these issues, we designed a novel 32-unit tissue chip in the format of standard 96-well plates to streamline automation, fabricated it using 3D printing, and leveraged gravity-driven flow to bypass the need for external flow devices. Each unit includes three interconnected tissue compartments that model liver, tumor, and bone marrow stroma. The focus on liver and bone marrow stroma was due to their respective roles in drug metabolism and disturbances to the bone marrow niche from off-target toxicity of chemotherapies. We analyzed flow patterns, mixing, and oxygen transport among and within the compartments through finite element simulations and demonstrated the utility of the tissue chip to study the efficacy of commonly-used cytotoxic cancer drugs against tumor cells and their toxicity toward liver and bone marrow cells. The ability to simultaneously study drug efficacy and toxicity in high throughput can help select promising therapeutics in early stages of drug discovery in preclinical studies.