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

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in drug development have led to therapeutic compounds being approved for widespread use in humans, only to be later withdrawn due to unanticipated toxicity.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 cellderived 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.

A Rapid Crosslinkable Maleimide-Modified Hyaluronic Acid and Gelatin Hydrogel Delivery System for Regenerative Applications

“…To address these challenges, we aimed to combine defined ECM-derived components, rapid gelation kinetics for controlled deposition, crosslinking conditions amenable to high cell viability that do not employ photocrosslinking, to generate a natural ECM-based hydrogel platform with utility across applications in regenerative medicine and tissue engineering. We employ HA and gelatin base materials, based on our long-standing expertise in deploying these natural materials within a variety of hydrogel systems and subsequent applications including wound healing [25,38], bioprinting [17,[39][40][41][42][43], and organoid/tissue chip platforms [15,36,[44][45][46][47]. These past studies have largely utilized thiol, acrylate, or methacrylate modified HA, gelatin, and collagen, which have been effective tools.…”

Predicting Metabolism‐Related Drug–Drug Interactions Using a Microphysiological Multitissue System

“…[24] Such multiorgan devices have been used to simultaneously evaluate drug efficacy and safety aspects on a systemic level. [24][25][26][27] Probing off-target toxicity of compounds in multiorgan systems has proven to be particularly useful for prodrugs that are inactive without hepatic metabolism. [26][27][28][29][30][31] Multiorgan systems represent a potential solution to capture the full extent of complex DDI eventsranging from metabolizing organs to drug target organs-and to predict the safety of critical drug combinations.…”

3D Bioprinted cancer models: Revolutionizing personalized cancer therapy

“…In a more realistic bioprinted tumor constructs, chemotherapeutic agents can be administered through built-in micro- channels that mimic tumor vasculature [119] . Tumor constructs can also be printed on microfluidic chips or integrated with similar platforms to automate the screening assay and perform the analysis of a number of drugs simultaneously as well as determine the response and mechanism in real-time [ 120 , 121 ].…”