Modeling-based design specifications for microfluidic gradients generators for biomedical applications

Abstract

This work proposes a comprehensive approach to optimize the design of microfluidic concentration gradient generators (MGGs) for biomedical applications. Exposing biological systems to controlled gradients enables fast screenings of induced concentration-dependent signals and surpasses several limitations of conventional cell culture techniques. The MGG working principle is the formation of diffusion-driven concentration gradients between a source and a sink, both connected to a cell culture chamber through an array of microchannels. The devices were modeled with Comsol Multiphysics®, in a combined fluid-dynamic and mass-transport study allowing prediction of the internal fields and guiding design optimization. Ideal MGGs must ensure fast transients (< 1 h) to reach a steady gradient. To identify the key features determining the device performance, we analyzed design specifications and operating parameters including: the shape of the source and sink (width 1–2 mm), the number and length of the microchannels (17–34, and 2.5–5 mm), the flow rate (5–10 μl/min). Our results prove that the formation and shape of the gradient are strongly affected by the device geometry, and mostly by the microchannels length. In addition, higher flow rates lead to the generation of stagnation zones and increase the gradient steepness. The model optimized MGG was fabricated and proved successful in the generation of stable concentration gradients over cell monolayers inside the culture chamber.