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Microfluidic Combinatorial On Demand Systems: a Platform for High-Throughput Screening in Chemistry and Biotechnology

Final Report Summary - MICROCODE (Microfluidic Combinatorial On Demand Systems: a Platform for High-Throughput Screening in Chemistry and Biotechnology.)

The project focused on the development of new techniques for handling microdroplets in microfluidic systems and on applications of these techniques across chemistry, material science, biochemistry, biology and medical diagnostics. Within the project we have developed the microfluidic technologies in two main directions. The first one comprises automated systems – systems in which the microdroplets are prepared (generated) and then routed and manipulated (split, merged, cycled etc.) with the use of automated electric actuators and controlled with computer programming. These systems were also interfaced with various optical detection strategies interconnected with the control architecture for monitoring the chemical and biological processes undergoing in the droplets and for feedback for physical manipulations on the droplets. The second major direction of development of the microfluidic techniques for handling droplets had the goal of constructing systems that could execute even complicated (i.e. comprising diverse unit operations and being multistep) liquid handling protocols, while being outstandingly easy to operate – without any specialized infrastructure and with minimum expertise of the user. Within this direction of research we have created a host of modules that we called microfluidic ‘traps’ – specialized microgeometries of channels and chambers that perform precise operations on droplets travelling through them. We have shown the use of these systems in e.g. a standalone microfluidic chip capable of performing an antibiotic susceptibility test on micro-volumes of liquids while being operated only with an automated pipette. Other applications include a system for passive generation of monodisperse nano liter droplets without the requirement for precise control of the rate of flow, for splitting of microliter droplets into nanoliter droplet libraries, or generation of highly precise dilutions in droplets.
We have used both of these sets of technologies in the major applied directions of research in the proposed programs. Within the direction of biochemistry and biology, we constructed-among others-an automated system of cultivating bacteria over extended periods of time, a system for automated screening of crystallization conditions for proteins, a system for enumerating bacterial cells, a system for screening of the function of membrane proteins in model lipid bilayers, and a system for research on dynamic chemical networks. We have also developed the microfluidic techniques towards the use in chemistry, with results including simple to use organic flow reactors and a technique for rapid screening of the conditions of organic synthesis with integrated detection and monitoring of yield via high performance liquid chromatography. We have worked out a number of solutions aimed at their use in analytical chemistry and medical diagnostics. These included both the point-of-care microfluidic solutions, as e.g. a system for separation of a tiny portion of blood and subsequent execution of an immunoassay, or the system for antibiotic susceptibility testing. We have also described a host of new algorithms for digital assays – assays that do not require calibration. In particular we described optimized methodology that reduces the number or partitions of the sample by orders of magnitude in comparison to the state of art, or that allows to execute digital PCR assays on standard real-time PCR devices. We have also developed a large number of very interesting new results in building new materials in immiscible liquids, with techniques for generation and understanding of the stability of both partially wetted multiple-droplet morphologies and of completely engulfed multiple liquid cores in liquid shells.