Due to their compact size and small operating volumes, batch microfluidic devices for radiochemistry (e.g. electrowetting on dielectric) offer significant benefit for the synthesis of short-lived radiotracers and could form the basis of a benchtop instrument for on-demand tracer production. When considering using small reaction volumes, one must also consider how to produce sufficient quantity (radioactivity) of the tracer for the particular application needed. For preclinical imaging, generally a few mCi is sufficient for a study involving several animals, and with modern scanners, <25-50 µCi is sufficient for a single mouse. On the other hand, imaging of a single patient requires on the order of 10 mCi, while producing a large batch in a radiopharmacy for distribution to imaging centers would require 100s-1000s of mCi. Even higher amounts of the radioisotope are needed at the beginning of the synthesis due to non-ideal yields and fluid handling, as well as losses due to decay.Cyclotrons can readily generate multiple Ci levels of [18F]fluoride in [18O]H2O to satisfy any of these applications. However, the output volume is typically in the milliliter range, while the capacity of the current EWOD chip (12 mm diameter reaction zone x 150 µm droplet height) is only ~17 µL, i.e. 1% of the volume from the cyclotron. From a high-radioactivity bombardment, it would be possible to load as much of tens of mCi of radioisotope into the chip without special measures, but it is not desirable to waste the majority of the radioisotope, and several methods for efficiently concentrating the radioisotope have been developed.
One approach is to concentrate the [18F]fluoride prior to loading it into the chip via a solid-phase extraction (SPE) process. First, the [18F]fluoride/[18O]H2O is flowed through a strong-anion exchange cartridge (e.g., quaternary methyl ammonium, QMA) to trap the [18F]fluoride. After removing residual water (e.g. with an inert gas flow), an eluent solution (e.g. aqueous K2CO3/ K2.2.2 or tetrabutylammonium bicarbonate (TBAB), sometimes with MeCN) is passed through the cartridge to release the [18F]fluoride. If the cartridge has sufficiently small bed volume, the volume of eluent solution needed to efficiently collect the [18F]fluoride can be quite low. Our group and others have shown efficient concentration of at least Ci-levels of [F-18]fluoride into volumes as small as 5-10 µL. We have developed an automated system for preparing concentrated [F-18]fluoride that can be loaded onto microfluidic chips.
A different approach is to perform the [18F]fluoride concentration directly on chip. Using a special chip where the bottom plate extended beyond the edge of the cover plate to create a platform. A large droplet of [18F]fluoride solution (with phase transfer catalyst) was loaded onto this platform adjacent to the gap between the two EWOD chip plates and then rapidly evaporated down to a small volume that could be transported between the plates. This approach has the advantage of not requiring any valves, but the disadvantage of requiring larger chip real estate.
Figure 1: (A) Cartridge-based method for concentration. Using an HPLC injection valve with small internal volume, the flow path can be configured in trapping mode, where the [F-18]fluoride/[O-18]H2O is flowed through a micro-cartridge and the [F-18]fluoride trapped, or a release mode, where a small volume of eluent solution is passed through the cartridge to release the [F-18]fluoride and deliver it onto the chip. (B) Scheme for evaporative concentration of [F-18]fluoride radioisotope on chip. The top images show cross-section schematics of the concentration process, and the bottom images show Cerenkov (radioactivity) images of the top-view of the chip at corresponding times. Orange lines and circles were added to depict the cover plate edge and the reaction site, respectively. Initially, a 200 μL droplet of [F-18]fluoride solution is loaded to the cover plate edge. By activating a nearby heater, the volume of the droplet is reduced to ~5 µL, and then pulled into the chip by electrode actuation.
Current Status and Next Steps
The cartridge-based concentrator is in routine use in the laboratory for radiosynthesis at small volumes scales and one has been installed at Harvard Medical School / Masssachusetts General Hospital for clinical production of [F-18]5-FU.
- A. M. Elizarov, R. M. van Dam, Y. S. Shin, H. C. Kolb, H. C. Padgett, D. Stout, J. Shu, J. Huang, A. Daridon, and J. R. Heath, “Design and Optimization of Coin-Shaped Microreactor Chips for PET Radiopharmaceutical Synthesis,” J Nucl Med, vol. 51, no. 2, pp. 282–287, Feb. 2010.
- S. Chen, M. R. Javed, H.-K. Kim, J. Lei, M. Lazari, G. J. Shah, M. van Dam, P. Y. Keng, and C.-J. Kim, “Radiolabelling diverse positron emission tomography (PET) tracers using a single digital microfluidic reactor chip,” Lab Chip, Dec. 2013.
- Philip Chao (graduate student)
- Maxim Sergeev (postdoctoral scholar)
- Jeffery Collins (staff radiochemist)
- Mark Lazari (graduate student)
- Mark Eddings (postdoctoral scholar)