GOAL: Development of a Cell Culture Analog Device to Assess MultiDrug Resistant Suppressors

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0342985ShulerA key factor in improving human health is determining the response of the human body to various pharmaceutical and environmental chemicals. A device or system to provide this information can then be used to formulate guidelines for acceptable doses and exposure. Current approaches to predicting in vivo human response to chemicals fall into two basic categories: in vivo work with non-human animals and in vitro work with human or non-human cells and tissues. Animal studies may be lengthy and expensive and difficult to extrapolate to humans over a wide range. In vitro studies using isolated cells of a single type do not allow for exchange of metabolites between tissues. A more realistic approach is to build a micro cell culture analog (microCCA) that uses mammalian cells cultured in interconnected chambers to physically represent a physiologically based pharmokinetic model (PBPK). PBPK models mathematically simulate animal/human metabolism by modeling the adsorption, distribution, metabolism, and elimination kinetics of a chemical in interconnected tissue compartments. In prior work, the PI demonstrated "proof of concept" through fabrication of three and four chamber microCCA devices to model liver, lung and fat. The proposed work will focus on significant engineering challenges related to the operation of the microCCA, e.g., integrating a micropump capable of maintaining recirculating flow and fabricating the device from an optically clear substrate in order to integrate sensors for data collection.The GOALI activities are focused on developing a microCCA and PBPK combination that can be used to assess chemicals as potential agents to suppress multidrug resistance (MDR) in colon cancer. The PI will design a CCA system that will be transferred to Gene Network Sciences, Inc. (GNS, Co-PI). GNS has constructed a biologically detailed model of a colon cancer cell that will be modified to incorporate different mechanisms of multidrug resistance. The PBPK and CCA will be matched to include the same organ/tissue compartments allowing direct comparisons of simulation to responses of the in vitro CCA. A large variety of MDR suppressors and chemotherapeutics will be screened to treat MDR colon cancer. GNS will provide all of the modeling expertise and share both simulation and experimental results with the PI.