Positron emission tomography (PET) is a powerful, non-destructive technique that allows for high resolution images of the body to be taken using gamma-emitting radiotracers that take residence in different parts of the body. This is useful not only in standard medical diagnostics but in drug development as well, as the passage of radiolabelled drugs can be tracked around the body.

Microfluidic devices offer benefits for PET radiotracer synthesis, allowing for quicker and more efficient reactions (so less radioactive decay). The small volumes handled on-chip mean less radiation and less waste, lowering shielding requirements. There are a wide variety of devices available for many different parts of preparation, ranging from purification of radionuclides to radiotracer synthesis and quality control.

The PET Research Centre at the University of Hull provides a unique infrastructure for bench to bedside development of PET imaging agents. Our research-dedicated facilities on the University campus include a mini-cyclotron (ABT Biomarker), 68Ga (iThemba) and 99mTc generators (Curium) as well as a SuperArgus PET/CT scanner and a Mediso NanoSPECT-CTPlus scanner. This links in with state of the art PET imaging facilities, GMP laboratories and a GE cycltron at the local Castle Hill Hospital.

Production of Gallium Radiotracers

Gallium-68 based radiotracers are rapidly becoming a vital addition to the diagnostic toolset and can be produced on-site with portable gallium generators. However, the generator eluate is frequently contaminated by other metal ions, such as aluminium, along with other issues that inhibit complexation. Through MRC funding, we are developing microfluidic devices for 68Ga processing at the generator using functionalised silica monoliths to perform cation exchange and pre-concentrate gallium. We are working with the local NHS trust to expand the prototype to provide synthetic capabilities, interface with a control unit and allow routine operation upon which trials will begin at the Castle Hill Hospital.

Publication: He, Burke, Clemente, Brown, Pamme, Archibald, React. Chem. Eng., 2016, 1, 361.

An example schematic of a silica monolith based purification system for a gallium-68 generator similar to one developed in this reasearch with an SEM of the monolith shown on the right

For imaging, the 68Ga needs to embedded within a complexing agent such as DOTA to allow specific targeting within the body. Microfluidic reactors allow this reaction to occur in minutes, reducing losses. We have developed a range of glass microfluidic devices that allow mixing and reaction enhanced by herringbone mixing features.

Quality Control of FDG Radiotracer

Quality control (QC) is an important part of radiotracer production to prevent any unwanted compounds entering the body and ensure the dosage of radiation is correct. We have been working towards integrating all the required QC tests onto one microfluidic cartridge.

Electrochemical analysis of carbohydrates. We have designed a microfluidic flow cell to hold a disposable screen printed electrode. We have tested this for on-chip analysis of carbohydrate-based radiotracers, i.e. the glucose analogue 18F-FDG. One procedure uses amperometry and cyclic voltammetry. The magnets in this chip allows for easy replacement of the electrode, reducing downtime and increasing efficiency. Publication: Patinglag et al., Analyst, 2020,145, 4920.

Microfluidic spectroscopic analysis. Using a chip with a channel cut through the middle allows for suitable path lengths for spectroscopy. This has been proven to work with optical clarity and pH determination (when indicator solution is pumped through the second inlet). Fibre cables are used to transmit and recieve light, allowing for spectroscopic method to be straightforwardly changed. Publication: M. D. Tarn et. al., 18th International Conference on Miniaturized Systems for Chemistry and Life Sciences, 2014, San Antonio, Texas, USA

Microfluidic radiation detection. The interactions between silicon photomultipliers (SiPMs) and positrons allows radiation levels to be measured. The winding passage allows the full area of the SiPM to be fully exposed to radioactivity from a known volume of radiotracer. This method has been used to determine radiochemical identitiy by measuring half life and comparing it to known values as well as measuring activity levels. Publication: M. P. Taggart et. al., Lab Chip, 2016, 16, 1605

Scintillator-based radiation detection. We have designed a chip with a bottom layer consisting of a plastic scintillator seated on a SiPM. This has been tested with 18F samples to simulate 18F-FDG detection as part of a radioHPLC system. Such a procedure allows real time detection of radiotracers in clinically relevant concentrations while needing less space than conventional radio-HPLC detectors. Publication: M. D. Tarn et. al., Chem. Eur. J., 2018, 24, 13749

Synthesis of FDG Radiotracer

Purification of radionuclides. 18F must be separated from 18O before synthesis can take place. Electrochemical microfluidic cells can be used to this end to reversibly bind 18F anions. This also allows solvent exchange and preconcentration to occur at the same stage, further increasing yield and reducing reaction time. Upon testing, it was shown that up to 99% of 18F could be trapped and up to 80% could be released. Publication: S. J. Archibald et. al., J. Label. Compd.Radiopharm., 2013, 56:S1-S492

An example schematic of the purification electrode capable of separating the cyclotron eluate for use in FDG synthesis based on a cell by Saiki et. al in 2010

It is possible to use functionalised silica monoliths for purification and synthesis of 18F-FDG. There are multiple ways to make silica monoliths suitable for such applications, such as mounting the column in heat shrinking tubing while filling any void with powdered functionalised monolith. It is possible to trap and release 18F with an efficiency of up to 95% for both steps obtain a pure product with radiochemical yields of more than 80%. Publication: S. Archibald et. al., J. Nucl. Med., 2015, 56, 167

P. He, S. J. Haswell, N. Pamme and S. J. Archibald, Appl. Radiat. Isot., 2014, 91, 64-70 DOI 10.1016/j.apradiso.2014.04.021

Radiochemistry on Chip (ROC) Project

Regenerable anion exchange chips. Part of our contribution to the ROC project was in fabricating chips capable of trapping 18F reliably and repeatably. Utilising particles of functionalised silica and polystyrene packed into wells allowed over 20 trap-and-release cycles to occur with no significant loss of capacity with a single cycle requiring 6 minutes. Publication: F. De Leonardis et. al., J. Chromatogr., 2011, 1218, 4714

Combined 18F-FGD synthesis system. We collaborated with other professionals across Europe to produce a multi-chip system for 18F-FDG synthesis. This consisted of four modules for isolation, radiolabelling, solvent exchange and base hydrolysis (Modules 1 through 4 respectively). Modules 2 and 4 operated under elevated temperature. Enough 18F-FDG was collected after 19 minutes of operation for one dose. Publication: V. Arima et. al., Lab Chip, 2013, 13, 2328