Modelling and optimisation of microfluidic devices for bioanalysis applications

摘要

The small size of integrated microfluidic systems offers many advantages such as cost, speed and portability for bioanalysis applications. However, due to the small scale the careful consideration of the transport of analytes in the bulk of the integrated microfluidic system and the interaction of analytes with surface immobilised analyte recognition molecules (receptors) is crucial for an efficient device operation. This thesis is concerned with the mathematical analysis and optimisation of the convective and diffusive transport of analytes and the analyte-receptor interaction in integrated microfluidic affinity systems with the aim of creating design guidelines for more efficient bioanalysis systems.The first part of this thesis considers device configurations where every analyte molecule can reach the surface immobilised receptors. In this case, which is important for sensing and separation applications, the transport-reaction model is solved analytically. This analytical solution is analysed for two bioanalytical applications: (i) affinity separation and (ii) affinity sensing. For fast analyte-receptor interactions, which are essential for affinity separation systems, the analysis of the analytical solution reveals simple expressions for the retention and the dispersion of the analyte due to the interaction with the receptors. With these expressions, which depend only on global device parameters, a framework for the design of multiplexed separation systems for the separation of proteins from complex sample mixtures is developed. Subsequently, the analytical solution of the transport-reaction model is used in the derivation of improved design strategies for microfluidic affinity sensors for the detection of analytes from small sample plugs. Three design strategies, which achieve a high capture fraction and a significantly increased uniformity of the bound analyte concentration over the sensor surface, are presented. The first two strategies rely on the variation of one device parameter, i.e. the flow velocity or the surface immobilised receptor concentration, as the analyte plug is flowed through the channel. The third approach is based on non-rectangular devices where the analyte plug is replenished by a narrowing of the flow channel. This third design strategy is applied to the redesign of a biosensor for the detection of low cytokine levels from small sample volumes.In the second part a novel microfluidic system for the generation of concentration gradients across microfluidic channels is developed. In this design the analytes are transported by surface groove induced secondary flow from the source to the sink stream. Numerical optimisations over the shape and size of the surface groove result in gradient generators which yield a well-defined linear or exponential concentration gradient across the width of the microfluidic channel. The resulting gradient generators have a much smaller footprint than conventional gradient generators and are thus more suitable for highly integrated lab-on-a-chip systems.