Beyond the Chip: Development of a Micro-Physiological Multi-Organ Flux Analyzer

Organ-on-chip technology aims to replace animal toxicity testing, but thus far demonstrated few advantages over traditional methods. Current methods to evaluate toxicity still rely on end-point assays measuring tissue damage and cell death, resulting in limited kinetic and mechanistic information. In contrast, Tissue Dynamics aims to track the dynamics of tissue function from very onset of the molecular initiative event gaining critical information about compounds mechanism of action. Our microfluidic platform is capable of maintaining vascularized three-dimensional liver, cardiac, and neural micro-tissues for over a month in vitro. Micro-tissues acquire the native architecture, physiological activity and show complex metabolic zonation of in vivo organs. Tissue-embedded metabolic sensors for oxygen, glucose, lactate and glutamine permit the real-time quantification of intracellular fluxes and tissue level function. Change in metabolic function is the first indication of physiological stress, preceding any detectable damage. Using the Tissue Dynamics platform, we show a new CYP450-idependent mechanism of acetaminophen toxicity that may be responsible for clinically observed nephrotoxicity. We also show that troglitazone, a drug withdrawn from the market due to idiosyncratic toxicity, induces harmful metabolic changes at below the observed threshold for toxic damage. These metabolic changes may underlie troglitazone’s observed idiosyncratic toxicity. Our work marks the importance of tracing function in real-time, demonstrating specific advantages in predicative toxicology.