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This brief presents modeling and control of a nonlinear mechanism for long-term and high-speed flow regulation in a three-lane microfluidic system. The principle of this mechanism is to modulate a mechanically coupled variable resistance and variable volume reservoir for pressure control at the inlets of microfluidic systems. We developed a dual-loop control system that consists of an inner-loop position controller and an outer-loop pressure controller. We show excellent agreements between analyses, simulations, and experimental results, and demonstrate bandwidth of 10 Hz and duration of 15 hours. We envision that this system will be useful to researchers in areas such as flow cytometry, chemical synthesis, drug delivery, and investigation of spatiotemporally integrated biological responses at molecular, cellular, and tissue levels.