Drug compound screening in single and integrated multi-organoid body-on-a-chip systems

TLDR

Current drug development practices often approve compounds that are later withdrawn due to unanticipated toxicity, largely because preclinical models fail to accurately recapitulate human physiology. The study employs human primary cell‑ and stem cell‑derived 3D organoid technology to screen FDA‑recalled drugs. The platform comprises multiple tissue organoids—liver, cardiac, lung, vascular, testis, colon, and brain—that remain viable for at least 28 days and can be integrated into a body‑on‑a‑chip system. The 3D organoid system detected toxicity for many recalled drugs while non‑toxic compounds remained viable at clinically relevant doses, and integrated multi‑organoid systems maintained viability and functional biomarkers long‑term, demonstrating the platform’s potential to model interdependent metabolism and reduce drug development costs and failure rates.

Abstract

Current practices in drug development have led to therapeutic compounds being approved for widespread use in humans, only to be later withdrawn due to unanticipated toxicity. These occurrences are largely the result of erroneous data generated by in vivo and in vitro preclinical models that do not accurately recapitulate human physiology. Herein, a human primary cell- and stem cell-derived 3D organoid technology is employed to screen a panel of drugs that were recalled from market by the FDA. The platform is comprised of multiple tissue organoid types that remain viable for at least 28 days, in vitro. For many of these compounds, the 3D organoid system was able to demonstrate toxicity. Furthermore, organoids exposed to non-toxic compounds remained viable at clinically relevant doses. Additional experiments were performed on integrated multi-organoid systems containing liver, cardiac, lung, vascular, testis, colon, and brain. These integrated systems proved to maintain viability and expressed functional biomarkers, long-term. Examples are provided that demonstrate how multi-organoid 'body-on-a-chip' systems may be used to model the interdependent metabolism and downstream effects of drugs across multiple tissues in a single platform. Such 3D in vitro systems represent a more physiologically relevant model for drug screening and will likely reduce the cost and failure rate associated with the approval of new drugs.