Beyond the Chip: Development and Application of a Micro-Physiological Flux Analyzer

Yaakov (Koby) Nahmias, Grass Center for Bioengineering, The Hebrew University of Jerusalem, Israel

Organ-on-chip technology aims to replace animal toxicity testing, but thus far demonstrated few advantages over traditional methods. Current methods to evaluate toxicity rely on end-point assays measuring tissue damage and cell death, resulting in limited kinetic and mechanistic information. We present the Tissue Dynamics platform capable of maintaining vascularized 3D liver, cardiac, and neural tissues for over a month in vitro. Tissues acquire physiological structure, physiological activity and show complex metabolic zonation. 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 We also show that troglitazone, a drug withdrawn from the market due to idiosyncratic toxicity, induces harmful metabolic changes at below the observed threshold for toxic damage.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. More recently, we studied the dynamics of human liver response to the epilepsy drug valproate. Our platform demonstated a rapid disruption of metabolic homeostasis below the threshold of cellular damage, and an increase in lipogenesis rather than distruption of beta-oxidation. Our work marks the importance of tracing function in real-time, demonstrating specific advantages in predicative toxicology.

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Abstract Reference & Short Personal Biography of Presenting Author

Prof. Yaakov Nahmias
Founder & CSO, Tissue Dynamics
Founder & CSO, Future Meat Technologies
Professor of Bioengineering, The Hebrew University of Jerusalem (HUJI)

Prof. Yaakov “Koby” Nahmias is a bioengineer and innovator, whose breakthroughs ranged from the first 3D printing of cells to the first commercial human-on-chip technology. He is a Magna Cum Laude graduate of the Technion, Israel Institute of Technology, and is the founding director of the Grass Center for Bioengineering of the Hebrew University of Jerusalem. Nahmias is a recipient of a NIH career award, two European Research Council (ERC) grants, the Kaye Innovation Award and the prestigious Rappaport Prize in Biomedical Research. He is the first scientist outside Britain to win the Rosetrees Trust Prize. Nahmias is the co-founding director of BioDesign-Israel. An entrepreneurship program that educated over 120 fellows, raising $3M in investment and 10 startup companies including Guide In Medical, CardioVia and VenoVision. Nahmias is the founder and CSO of two biotechnology startups, including Tissue Dynamics that is developing a groundbreaking human-on-chip instruments for drug development, and the Tyson Foods-funded Future Meat Technologies focusing on the cost-effective production of cultured meat.