COMPUTATIONAL FLUID DYNAMIC ANALYSIS OF A CELL-BASED MICROFLUIDIC DRUG SCREENING PLATFORM
About 50% of all candidate drugs that make it past Phase-I clinical trials ultimately fail to receive U.S. Food and Drug Administration (FDA) marketing approval due to human toxicity or bioavailability problems that the drug develops. To remedy this state of affairs, in recent years, researchers have attempted to develop improved in vitro assays which can be applied pre-clinically to produce data with a higher degree of correlation to in vivo responses, and which circumvent the allometric limitations inherent in animal models. Such in vitro assays are intended to enable preclinical research and development groups to better predict the pharmacokinetic and pharmacodynamic action of candidate molecules prior to clinical trials, thereby reducing high late-stage failure rates. While most such in vitro systems comprise a static cell culture environment, microfluidic systems have been shown to provide better results. For example, experiments performed with the HμREL® microfluidics system demonstrated increased clearance rates and better in vitro–in vivo correlation (IVIVC) than that observed with static culture systems. Several hypotheses were suggested to account for these improvements: (1) enhanced mass transport resulting in better functional efficiency; (2) a flow-induced transduction of gene and protein expression and function; and (3) a flow-induced effect resulting in increased cellular uptake. In this paper, we describe a framework, utilizing computational fluid dynamics (CFD), that can be used to study culture systems with a level of scrutiny and spatial precision not offered using standard in vitro assays. Using this approach, we were able to successfully model experimental observations of increases in the clearance rates of high and medium clearance compounds in the microfluidics system. Based on these results we posit that the increase in clearance is most likely due to the addition of convective transport, and a thinning of the boundary layer present in static and mixed plate cultures systems.