Development of an integrated 4-organ animal model

Project Summary AbstractWe propose to construct multi organ microphysiological systemsBody on a Chipor BoaCsfrom human and rat cells to use as a basis to understand species differences in response to exposure to drugs or chemicals in this new platformThe results will then be compared to clinical datawhere availableand to archived in vivo animal dataThis work will directly test whether such in vitro models can accurately reproduce species differences in response to known drugsA preclinical model based on human cells that can accurately predict human response should lead to better decisions on whether exposure to a chemical or chemical mixture will be harmful to humansAn advantage of this in vitro approachcompared to standard in vitro systemse gsuch as multiwell platesis that the tissues can exchange metabolites and the dose dynamics in the body of both parental compounds and metabolites are better represented than when a single cell type is exposed to a bolus doseAlsoby comparing acute to chronic effects it will enable prediction on clinical trial success as well for determining PK of the compoundsIn additionthe comparison of animal cells derived from iPSCs will enable the assessment of whether they can be substituted for primary animal cellsIf successfulthis could lead to stable cell sources for the animal models and reduce the number of animals needed for these studiesFor this proposal we will build upon a four organ model we recently published in Nature Scientific ReportsOleagaet alwhich included model tissues for the livercardiacskeletal muscleand neuronal compartments that correctly predicted clinical response to five compoundsTo construct a well defined system we will use a common serum free medium which mimics key features of bloodHickman has developed microelectrode arrays and cantilever systems that are integrated on chip that allow for noninvasive electronic and mechanical readouts for not only acute but also chronic tests as wellTo improve operability and enable a low volume system for eventual metabolite evaluationwe will use a pumpless systemSunget aland self contained devicesWe will also utilize microfluidic analytical components for rapid and sensitive biomarker assessmentHoweverthe number of biomarkers to be monitored for cell health and function will be greatly reduced in our systems from use of the function readoutsThe system will be modeled by simulation using CFD to establish acceptable ranges for consumption of nutrients and drug metabolism as well as shear stress and to predict drug concentration profiles in the system to also enable PK PD prediction capabilitiesWe believe that this technique will lead to more accurate and cost effective assessment of the efficacy and toxicological potential of drugs chemicals or chemical mixtures and this approach will have a major impact on improving human health NarrativeWe propose to construct multi organ on a chip systems from human and rat cells to use as a basis to understand species differences in response to exposure to drugs or chemicalsThis work will directly test whether such in vitro models can accurately reproduce species differences in response to known drugsA preclinical model based on human cells that can accurately predict human response that is validated against an animal version should lead to better decisions on whether exposure to a chemical or chemical mixture will be harmful to humans and lessen the reliance on in vivo experiments for the evaluations