Droplet-based microdialysis-Concept, theory, and design considerations

The capability of continuously sampling the extracellular fluid opens up a wide range of applications of microdialysis in biological, pharmaceutical, and clinical studies. Existing microdialysis, however, faces challenges in sampling analytes with fast clearance and limited diffusivity because sampling resolution is limited by device size. Size reduction in probes and interconnected cannulae is a promising solution to improve temporal and spatial resolution. But the back pressure produced by resistance to laminar flows will be magnified in smaller channels, raising a concern as to whether it is feasible to operate continuous perfusion for miniaturized microdialysis. We demonstrate that a 10-fold smaller channel will exhibit 100-fold larger back pressure in response to the increase in the flow rate to maintain the relative recovery. In order to overcome the foreseen back pressure issue, this paper discusses a new concept using discrete droplets instead of continuous flows to operate dialysis in a miniaturized probe. This conceptual design is referred to as droplet-based digital microdialysis, in which droplets are produced, controlled and advanced within microchannels at a rate that in theory should allow for analytes to equilibrate with the extracellular fluid under no flow conditions. Expecting that a digital droplet design will entirely eliminate back pressure by introducing air between droplets, we numerically compare the equilibration kinematics of droplets to that of continuous flow. Results suggest equilibration of low molecular weight analytes between intermittently stationary droplets and the extracellular fluid in a few seconds. Considerations in design, prototyping, calibration and quantification, and the integration with other devices are suggested.