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Radiochemistry in microdroplets: technologies and applications


Despite the increasing importance of positron emission tomography (PET) imaging in research and clinical management of disease, access to myriad new radioactive tracers is severely limited due to their short half-lives (which requires daily production) and the high cost and complexity of tracer production. Digital microfluidic radiosynthesizer technology can reduce the cost of equipment and facilities for tracer production, and could increase access to diverse tracers by reducing the cost of each batch (by reducing reagent consumption, reduced synthesis time, higher yield, etc.) and by enabling decentralized production closer to the point of use.

Previously, our group has demonstrated that electrowetting on-dielectric (EWOD) microfluidic platform can be used to efficiently synthesize several tracers with minimal reagent usage and with high “specific activity”. However, widespread adoption of this new approach has not yet occurred in the field of radiochemistry, due in part to the operating complexity, suboptimal robustness (Teflon delamination, electrical breakdown of dielectric layer) and high cost of prototype chips.

To address the robustness issue, one project I worked on was to optimize several aspects of the fabrication of EWOD chips (Teflon adhesion to dielectric layer, deposition of dielectric layer) to improve their reliability and then demonstrated the successful production of several tracers with the improved chips.

However, even after optimization, the fabrication cost remained too high for use as a disposable components. To lower the cost, I developed a new, simpler microfluidic chip leveraging an alternative passive method of droplet manipulation method for tracer production. Cost was reduced through elimination of fabrication steps and reliability was increased due to elimination of electrodes and dielectric layers. After successful synthesis of several tracers, the chip was integrated with a fully-automated standalone [18F]fluoride concentrator to produce higher (clinically-relevant) amounts of clinical-grade tracer (i.e., that passes all quality control (QC) tests).

Then, I developed an even further simplified microfluidic chip for microdroplet radiosynthesis and an ultra-compact system for operating the chips. A further advantage of this platform was that the reaction site was identical to that of the “model chips” we use for initial optimization when implementing syntheses in microdroplet format; this avoided the need for re-optimization when transitioning from optimization experiments to automated syntheses.

To further reduce the time needed for reaction optimization, I also worked on developing some new methods and technologies (high-throughput radio-TLC analysis, high-throughput multi-reaction microfluidic chip) to enable radiochemistry to be performed in a high-throughput fashion. These techniques relieve operators from tedious and repetitive work and facilitate extensive synthesis optimization for new tracers in a short time-frame.

Finally, I applied these new technologies (high-throughput optimization platform and the compact microdroplet reactor) for optimization and then automation of the synthesis of [18F]FDOPA.

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