Pharmacokinetic-Pharmacodynamic Model On A Chip For Testing Toxicity Of Chemotherapeutic Agents
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Human response to drugs and environmental chemicals is often dramatically different from predictions made by conventional cell-based assays. Current in vitro methods for testing drug toxicity use a single cell type in a static culture environment, treated with a bolus dose. Such experiments do not capture the complex, dynamic response of the body to drug absorption, distribution, metabolism and excretion (ADME). Integrated pharmacokinetic-pharmacodynamic (PK-PD) models allow prediction of pharmacological outcome from a give dosage, but have limitations in building realistic models. A micro cell culture analog (mu-CCA) is a microfluidic device based on a physiologically-based pharmacokinetic (PBPK) model, with multiple chambers each representing an organ or tissue on a silicon chip, with these chambers connected to emulate the blood circulation. This thesis work describes the combined approach of a PK-PD modeling and a mu-CCA platform, for testing the toxicity of chemotherapeutic agents. A PK-PD model was developed to predict tumor growth in a rat, treated with the chemotherapeutic agent, Tegafur. Various dosing scenarios and the effect of metabolizing enzyme levels were tested. As an experimental approach, the mu-CCA was improved in design, to accommodate 3-D hydrogel cell cultures and to enable a long-term operation. Using the mu-CCA, metabolism-dependent toxicity of Tegafur was observed. A PK-PD model for a mu-CCA was developed, and differential responses of three cell lines (representing the liver, tumor, and marrow) to the drugs in static and dynamic conditions were analyzed. A major challenge in developing microfluidic systems is prevention of bubble formation. A microscale bubble trap was developed, and it was demonstrated that the presence of a bubble trap significantly alleviated the bubble interference. To address the issue of detection and analysis in a microfluidic device, an in situ, fluorescence optical detection system was developed and integrated with a mu-CCA, and a real-time detection of cell viability and metabolic activity was demonstrated. This thesis work demonstrates the use of a microfluidic device, mu-CCA for a pharmacokinetic-based drug toxicity study and its combination with a mathematical modeling for a quantitative analysis of cell death kinetics. We envision that the combined approach will be useful in improving the productivity of drug development process by supplementing animal and human studies.
dissertation or thesis