A microfluidic device for a pharmacokinetic–pharmacodynamic (PK–PD) model on a chip

Abstract

Drug discovery is often impeded by the poor predictability of in vitro assays for drug toxicity. One primary reason for this observation is the inability to reproduce the pharmacokinetics (PK) of drugs in vitro. Mathematical models to predict the pharmacokinetics-pharmacodynamics (PK-PD) of drugs are available, but have several limitations, preventing broader application. A microscale cell culture analog (microCCA) is a microfluidic device based on a PK-PD model, where multiple cell culture chambers are connected with fluidic channels to mimic multi-organ interactions and test drug toxicity in a pharmacokinetic-based manner. One critical issue with microfluidics, including the microCCA, is that specialized techniques are required for assembly and operation, limiting its usability to non-experts. Here, we describe a novel design, with enhanced usability while allowing hydrogel-cell cultures of multiple types. Gravity-induced flow enables pumpless operation and prevents bubble formation. Three cell lines representing the liver, tumor and marrow were cultured in the three-chamber microCCA to test the toxicity of an anticancer drug, 5-fluorouracil. The result was analyzed with a PK-PD model of the device, and compared with the result in static conditions. Each cell type exhibited differential responses to 5-FU, and the responses in the microfluidic environment were different from those in static environment. Combination of a mathematical modeling approach (PK-PD modeling) and an in vitro experimental approach (microCCA) provides a novel platform with improved predictability for testing drug toxicity and can help researchers gain a better insight into the drug's mechanism of action.

A living system on a chip

“…Michael Shuler, a bioengineer at Cornell University in Ithaca, New York, is credited with coining the phrase 'animal on a chip' in the late 1990s, after he and a colleague, Gregory Baxter, began etching silicon wafers to form tiny compartments that would hold gut, liver and fat cells, all linked by microfluidic channels. The approach, which Shuler calls a "microscale cell-culture analogue", is a physical manifestation of mathematical models used to predict how drugs move through and accumulate in various organs 2 .…”

Modeling Life

“…More recently, 19 we have demonstrated that the external pump in the above system can be removed, and a ''pumpless'' chip used. Using the same cell lines and compounds, we demonstrated that a similar system using gravity as a motive force would give results that compare well to the system with an external pump.…”

“…Thus, using PBPK models and experimental results, the investigator should be able to obtain a deeper insight into possible underlying mechanisms. 19,20 Another advantage of the microCCA approach is the extrapolation of response of animals to humans. For example, rat tissue can be used in a microCCA and tested with a drug; the predicted results can then be confirmed with animal studies.…”

Multiphase microfluidic synthesis of micro- and nanostructures for pharmaceutical applications

“…12) (Imura et al, 2012). In another study, a colon tumor, liver, and bone marrow were combined to explore the in vivo metabolism and cytotoxicity of the anticancer drug 5-fluorouracil (5-FU) (Sung et al, 2010). Similarly, Ma et al reconstituted liver and brain tumor on a microchip, and found that the activation of ifosfamide by the liver led to enhanced brain tumor cytotoxicity .…”