Scientists from the Wake Forest School of Medicine and Ohio State University say they have developed a new multi-organ-on-a-chip to test how new drugs affect the human body’s vital organs. The team believes its new system, containing representations of liver, heart, vasculature, lungs, testis, and either colon or brain tissues, could help avoid such cases. In the study “Drug compound screening in single and integrated multi-organoid body-on-a-chip systems,” published in Biofabrication, the researchers demonstrated its effectiveness by using it to screen a selection of drugs that were recalled from the market by the FDA.
“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in drug development have led to therapeutic compounds being approved for widespread use in humans, only to be later withdrawn due to unanticipated toxicity.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,” write the investigators.
“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.”
“The development of new drugs can take a decade and a half, from preclinical studies to reaching the market. Around one in 5,000 drug candidates successfully completes this journey. Additionally, the cost for bringing a single drug to market, with all direct and indirect expenses accounted for, can climb as high as $2.6 billion,” said Anthony Atala, MD, from the Wake Forest Institute for Regenerative Medicine (WFIRM) and the study’s senior author. “Unfortunately, the human and financial costs can be even more dramatic if a drug is later found to be harmful and must be withdrawn. For example, Merck & Co. paid $4.85 billion to settle 27,000 cases and another $830 million dollars to settle shareholder lawsuits after one of its drugs caused adverse effects. The human costs of adverse drug reactions, meanwhile, manifest themselves as a leading cause of hospitalization in the United States, with up to 5.3 percent of hospitalizations related to adverse drug reactions. The rate of fatal adverse drug reactions is difficult to determine, and it is probably underreported. As both adverse human effects and drug development costs increase, access to more reliable and affordable drug screening tools is increasingly critical.”
“This increasing need to comprehensively screen new drugs for adverse effects is the driving force behind our research. In this context, we demonstrated our platform by screening a panel of FDA-recalled drugs for toxic effects,” added co-author Aleksander Skardal, PhD, formerly of WFIRM and now at Ohio State University, “To model the integrated nature of the human body, we designed an integrated platform, or chip, supporting six tissue types under a common recirculating media. When combinations of organoids are combined into a single platform, more complex integrated responses can be seen, where the functionality of one organoid influenced the response of another.”
To test their system, the researchers used it to screen six drugs that had been recalled due to adverse effects in humans: pergolide, rofecoxib, valdecoxib, bromfenac, tienilic acid, and troglitazone. For many of these compounds, the 3D organoid system was able to demonstrate toxicity.
According to Atala, “These compounds were tested by the pharmaceutical industry and toxicity was not noted using standard 2D cell culture systems, rodent models, or during human Phase I, II and III clinical trials. However, after the drugs were released to market and administered to larger numbers of patients, toxicity was noted, leading the FDA to withdraw regulatory approval. In almost all these compounds, the 3D organoid system was able to readily demonstrate toxicity at a human-relevant dose.”
As a control, they also tested the system with commonly-used drugs still on the market —aspirin, ibuprofen, ascorbic acid, loratadine, and quercetin. As well as not showing any toxicity, the organoids exposed to these non-toxic compounds remained viable at clinically-relevant doses.
“Further study will be needed,” said Skardal. “But based on these results our system, and others like it, using 3D human-based tissue models with nuanced and complex response capabilities, has a great potential for influencing how in-vitro drug and toxicology screening and disease modeling will be performed in the near future.”
