Regulating microfluidic-based cell culture systems with the use of network models

Microfluidic-based cell culture systems are getting more and more important in biotechnology especially for the recently developed ""organ-on-a-chip"" [1] systems with several human tissues in one branched microvascular system [2]. Due to the high complexity of those systems flow and nutrient adjustment is essential. Hereby presented is an approach which uses a mathematical model of the microfluidic system to calculate how fluidic actuators like valves and pumps have to be set to ensure specific nutrient and growth factor gradients. The oxygen content in a branched multilayer cell culture device [3] with integrated micro pumps, valves and tissue chambers was measured in two parallel fluidic paths. By operating the oxygenator with different process gases (nitrogen, air) the amount of dissolved oxygen can be varied. Furthermore the perfusion of each cell culture chamber was regulated with the help of closing valves positioned in each fluidic branch. Due to permeation processes the oxygen content in the fluidic system could be slightly reduced within several minutes by applying nitrogen to the included membrane oxygenator. The flow directing valves are sequentially actuated so that repeatedly n pump cycles are pumped in chamber A and k cycles are flowing in chamber B. By varying the n/k ratio one can influence the deoxygenation curve or keep the cell culture at a certain oxygen level. The last operating mode can be used for repeated hypoxia assays which are currently performed in animals [4]. By dying the cells for example with CYTO-® ID one can observe the oxidative stress for the cultivated cells under different hypoxic conditions.