BIOREACTOR SCREENING PLATFORM FOR MODELLING HUMAN SYSTEMS BIOLOGY AND FOR SCREENING FOR INOTROPIC EFFECTS OF AGENTS ON THE HEART

摘要

A two-stage or two-tier system and method for rapid screening of compounds for inotropic effects is disclosed. The system comprises, in a first tier, an engineered cardiac tissue strip (CTS) comprising cardiomyocytes, such as human ventricular cardiomyocytes, embedded in a biocompatible gel wherein the gel comprises at least two biocompatible structural supports such as polydimethylsiloxane posts for elevating the gel. The system further comprises, in a second tier, an apparatus comprising at least one organoid module comprising at least one organoid cartridge, wherein each organoid cartridge comprises an organoid, and a mirror arrangement. The system further comprises at least one detection device, such as a high-speed camera, for detecting deflection of the CTS gel in the first tier of the system and/or for detecting tissue or organoid behavior in the organoid cartridge or cartridges of the second tier of the system. The method comprises application of a compound to the cardiac tissue strip and detection of any deflection of the gel in response to application of the compound to detect compounds showing a possible inotropic effect and introduction of such a compound to an organoid module, wherein modified contractility of the cardiac tissue or organoid in the organoid module identifies a compound having an inotropic effect.. A method of making a cardiac tissue strip is also provided. The second tier system is also useful in methods of producing and monitoring, characterizing, manipulating or testing one or more organoids (e.g., human organoids) ex vivo. The system, methods, apparatus, and compositions are useful in a variety of contexts, including the assessment of potential therapeutics for efficacy and/or toxicity.