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ICCVAM Biennial Report 2018-2019

Biennial Progress Report 2018-2019 Interagency Coordinating Committee on the Validation of Alternative Methods

Phenotypic Screening Platforms for Cardiotoxicity, Hepatotoxicity, and Neurotoxicity

CCDC CBC is developing, assessing, and implementing approaches that use MPS to assess complex phenotypes such as organ function. In this manner, three-dimensional, human cell-based platforms are being developed to better represent organ function and, more importantly, potential perturbation of normal phenotypes critical to health. These target organ effects are measurable on a phenotypic level, which serves as a mechanism to observe potential toxic effects without screening for a specific target of interest. Some examples of implementation efforts include:

  • Cardiotoxicity can be measured in iPSC-derived cardiomyocytes that synchronously beat in culture, with toxicity measured in real-time using impedance-based technology.
  • Hepatoxicity can be measured using the Emulate Biotech liver chip system and the CN Bio PhysioMimix system, which have allowed success in the prolonged maintenance of a fully functional and viable liver environment in vitro. As a result, CCDC CBC can confidently assess both acute and chronic physiologically relevant, molecular-level hepatic effects of chemical threats without having to use an animal model.
  • Neurotoxicity can be measured in two- or three-dimensional cultures of primary or iPSC-derived neurons that can be functionally assessed using microelectrode-based measurements of synaptic firing or cytotoxic endpoints measured via high-content fluorescent imaging.