Batch-reactor microfluidic device: first human use of a microfluidically produced PET radiotracer.

The very first microfluidic device used for the production of (18)F-labeled tracers for clinical research is reported along with the first human Positron Emission Tomography scan obtained with a microfluidically produced radiotracer. The system integrates all operations necessary for the transformation of [(18)F]fluoride in irradiated cyclotron target water to a dose of radiopharmaceutical suitable for use in clinical research. The key microfluidic technologies developed for the device are a fluoride concentration system and a microfluidic batch reactor assembly. Concentration of fluoride was achieved by means of absorption of the fluoride anion on a micro ion-exchange column (5 µL of resin) followed by release of the radioactivity with 45 µL of the release solution (95 ± 3% overall efficiency). The reactor assembly includes an injection-molded reactor chip and a transparent machined lid press-fitted together. The resulting 50 µL cavity has a unique shape designed to minimize losses of liquid during reactor filling and liquid evaporation. The cavity has 8 ports for gases and liquids, each equipped with a 2-way on-chip mechanical valve rated for pressure up to 20.68 bar (300 psi). The temperature is controlled by a thermoelectric heater capable of heating the reactor up to 180 °C from RT in 150 s. A camera captures live video of the processes in the reactor. HPLC-based purification and reformulation units are also integrated in the device. The system is based on "split-box architecture", with reagents loaded from outside of the radiation shielding. It can be installed either in a standard hot cell, or as a self-shielded unit. Along with a high level of integration and automation, split-box architecture allowed for multiple production runs without the user being exposed to radiation fields. The system was used to support clinical trials of [(18)F]fallypride, a neuroimaging radiopharmaceutical under IND Application #109,880.

Microfluidic single vessel production of hypoxia tracer 1H-1-(3-[18F]-fluoro-2-hydroxy-propyl)-2-nitro-imidazole ([18F]-FMISO).

We report an automated synthesis of [(18)F]-FMISO utilizing a prototype microfluidic radiochemistry module. The instrument allows for production of the tracer with 58%±2% (11 runs) decay corrected yield. Total time of production, including synthesis and purification averages 60 min. Use of the microfluidic platform results in a specific activity of 138.6 GBq/µ mol, which is higher than previously reported for conventional reactors.

Flow optimization study of a batch microfluidics PET tracer synthesizing device.

We present numerical modeling and experimental studies of flow optimization inside a batch microfluidic micro-reactor used for synthesis of human-scale doses of Positron Emission Tomography (PET) tracers. Novel techniques are used for mixing within, and eluting liquid out of, the coin-shaped reaction chamber. Numerical solutions of the general incompressible Navier Stokes equations along with time-dependent elution scalar field equation for the three dimensional coin-shaped geometry were obtained and validated using fluorescence imaging analysis techniques. Utilizing the approach presented in this work, we were able to identify optimized geometrical and operational conditions for the micro-reactor in the absence of radioactive material commonly used in PET related tracer production platforms as well as evaluate the designed and fabricated micro-reactor using numerical and experimental validations.

Pre-clinical evaluation of a 3-nitro-1,2,4-triazole analogue of [18F]FMISO as hypoxia-selective tracer for PET.

Hypoxia in solid tumours is associated with the promotion of various metabolic mechanisms and induces resistance to radio- and chemotherapy. Non-invasive positron emission tomography (PET) or single photon emission computed tomography by use of selective biomarkers has emerged as valuable tools for the detection of hypoxic areas within tumours so treatment can be modified accordingly. The aim of this investigation was to evaluate [(18)F]3-NTR, a 3-nitro-1,2,4-triazole analogue (N(1) substituted) of [(18)F]FMISO as a potential hypoxia selective tracer. 3-NTR and its (18)F-radiolabelled isotopic isomer were synthesised and compared with FMISO in vitro and in vivo. Their physicochemical properties were measured, the enzymatic reduction was evaluated, and the reactivity of their metabolites was investigated. Biodistribution and PET scans were performed on CBA mice bearing hypoxic CaNT tumour cells, using (18)F-labelled versions of the tracers. [(18)F]3-NTR uptake within hypoxic cells was lower than [(18)F]FMISO and [(18)F]3-NTR did not exhibit any better selectivity than FMISO as a PET tracer in vivo. Both (18)F-radiolabelled compounds are relatively evenly distributed within the whole body and the radioactive uptake within hypoxic tumours reaches a maximum at 30 min post injection and decreases thereafter. Xanthine oxidase exhibited a nitroreductase activity toward 3-NTR under anaerobic conditions, but reduced metabolites did not bind covalently. It is confirmed that 3-NTR is an electron acceptor. It is postulated that radiolabelled metabolites and fragments of [(18)F]3-NTR are freely diffusing due to their poor binding capacities. Thus [(18)F]3-NTR cannot be used as a hypoxia selective tracer for PET. The investigation provides insights into the importance of the propensity to form covalent adducts for such biomarkers.

Coherent structures of the near field flow in a self-oscillating physical model of the vocal folds.

Current theories of voice production depend critically upon knowledge of the near field flow which emanates from the glottis. While most modern theories predict complex, three-dimensional structures in the near field flow, few investigations have attempted to quantify such structures. Using methods of flow visualization and digital particle image velocimetry, this study measured the near field flow structures immediately downstream of a self-oscillating, physical model of the vocal folds, with a vocal tract attached. A spatio-temporal analysis of the structures was performed using the method of empirical orthogonal eigenfunctions. Some of the observed flow structures included vortex generation, vortex convection, and jet flapping. The utility of such data in the future development of more accurate, low-dimensional models of voice production is discussed.

Flow-induced patterning of Langmuir monolayers.

Insoluble monolayers on water have been patterned at the macroscopic scale (i.e., at the centimeter scale of the flow apparatus) as well as the mesoscopic scale (i.e., down to the micron scale resolvable via optical microscopy). The macroscopic patterning at the air/water interface results from a hydrodynamic instability leading to a steadily precessing flow pattern. The velocity field is measured, and the associated shear stress at the interface is shown to be locally amplified by the flow pattern. The resulting hydrodynamic effects on two different monolayer systems are explored: (1) the pattern in a model monolayer consisting of micron-size, surface-bound particles is visualized to show that the particles are concentrated into isolated regions of converging flow with high shear, and (2) Brewster angle microscopy of a Langmuir monolayer (vitamin K1) shows not only that the monolayer is patterned at the macroscopic scale but also that the localized high-shear flow further patterns the monolayer at the mesoscale.

Non-newtonian behavior of an insoluble monolayer: effects of inertia.

Interfacial velocity measurements were performed in an optical annular channel, consisting of stationary inner and outer cylinders, a floor rotating at a constant rate, and a flat free surface on which an insoluble monolayer was initially spread. Measurements for essentially inviscid monolayers and some viscous monolayers on water show good agreement with numerical predictions for a Newtonian interface (Boussinesq-Scriven surface model) coupled to a bulk flow described by the Navier-Stokes equations. Here, we consider in detail a viscous monolayer, namely hemicyanine, and find that above a certain concentration, the monolayer does not behave Newtonian at a Reynolds number of about 250. We show that the discrepancies between the measurements and predicted Newtonian behavior are not due to compositional effects (i.e., nonuniform monolayer distribution), Reynolds number (i.e., inertia and/or secondary flows), or surface dilatational viscosity (which does not play any role in the parameter regime investigated). We show prima facie evidence that the observed shear thinning nature of the velocity profile is associated with a phase transition at C approximately 0.9 mg/m(2) at low Reynolds numbers. At large Reynolds numbers (Re=8500), hemicyanine is found to flow like a viscous Newtonian monolayer on the air/water interface, with viscosity dependent only on the local concentration.