Integrated heart/cancer on a chip to reproduce the side effects of anti-cancer drugs in vitro

Abstract

Pre-clinical animal tests are used to assess drug efficacy and safety, but are limited by factors such as their suitability as a model for humans, robustness, cost, and ethical issues. While an organ-on-a-chip using human cells is promising for recapitulating human physiological conditions, it is highly desirable in investigations of the side effects of drugs to integrate more than one type of tissue using a designed circulatory system. We have developed a microfluidic device—an Integrated Heart/Cancer on a Chip (iHCC)—using human healthy heart cells (hCMs) and liver cancer cells (HepG2) to recapitulate the side effects of an anti-cancer drug, doxorubicin (DXR), to achieve individual cultures of cells from different tissues on a single device with three sets of artificial blood circulation loops, microfabrication technology for micro valves and a pump provides accurate fluid operation. Using improved soft lithography adopting numerical optimization simulation, the microfluidic device was fabricated with on-chip integration of pneumatic valves and a peristaltic micropump establishing precision fluid flow. The iHCC developed allows modelling of the side effects of DXR on heart cells caused by the production of toxic metabolites (doxorubicinol; DXRol) by HepG2 cells and the delivery of DXRol to heart cells via the circulation loop. Our findings open the door towards the development of a “Body-on-a-Chip.”