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Expanding the capabilities of microfluidic systems for positron emission tomography (PET) tracer synthesis and analysis


The increasing diversity of, and demand for, PET radiotracers have stimulated development of emerging technologies such as microfluidics for more flexible and efficient radiotracer supply. Since the mid-2000s, various microfluidic radiosynthesizers have been reported, demonstrating the potential for smaller footprint and reduced need for radiation shielding. However, there are still a few challenges preventing microfluidic systems from being adopted into the mainstream to replace conventional macroscopic radiosynthesizers.

One of the significant challenges for batch microfluidic reactors has been the incompatibility with harsh radiosynthesis conditions (i.e., high pressures, high temperatures, and the use of organic solvents), limiting the diversity of PET tracers that can be synthesized. To overcome this challenge, a batch microreactor was developed that incorporates phase-change microvalves - a type of valve with the ability to withstand remarkably high pressures. A new phase-change material was used that is compatible with the organic solvents and anhydrous conditions required in radiochemistry. The radiofluorination step in the synthesis of 1-(2'-deoxy- 2'-[18F]fluoroarabinofuranosyl)cytosine ([18F]FAC), a radiotracer with a very challenging synthesis, was successfully demonstrated.

Another challenge with small-volume reaction platforms is the lack of online chemical analytical methods to evaluate the reaction progression and to analyze the products. Such online analytical tools are essential to accelerate the development and optimization of tracers on the microfluidic platform. Furthermore, such capabilities could potentially enable integration of the quality control testing required after synthesis to ensure the product is safe for injection, revolutionizing the current pipeline of PET tracer production steps. Detection of electrical properties of droplets in electrowetting-on-dielectric (EWOD) digital microfluidic devices was investigated as a means of achieving these goals. For the first time, conductivity measurement of sample droplets in EWOD platform with high sensitivity and wide dynamic range (3 orders of magnitude of conductivity) was demonstrated. As an example application, this technique was applied to perform on-chip conductometric measurements of a HCl-NaOH neutralization reaction. This reaction is similar to reactions and processes encountered in the production of many radiotracers (e.g., the hydrolysis/deprotection reaction, and the pH neutralization procedure at the end of synthesis).

By addressing two important limitations in microfluidic radiochemistry, the work in this dissertation expands the capabilities of microfluidic platforms for diverse radiotracer synthesis development and production.

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