Radiolabelling diverse positron emission tomography (PET) tracers using a single digital microfluidic reactor chip.

Radiotracer synthesis is an ideal application for microfluidics because only nanogram quantities are needed for positron emission tomography (PET) imaging. Thousands of radiotracers have been developed in research settings but only a few are readily available, severely limiting the biological problems that can be studied in vivo via PET. We report the development of an electrowetting-on-dielectric (EWOD) digital microfluidic chip that can synthesize a variety of (18)F-labeled tracers targeting a range of biological processes by confirming complete syntheses of four radiotracers: a sugar, a DNA nucleoside, a protein labelling compound, and a neurotransmitter.

ELIXYS - a fully automated, three-reactor high-pressure radiosynthesizer for development and routine production of diverse PET tracers.

Background: Automated radiosynthesizers are vital for routine production of positron-emission tomography tracers to minimize radiation exposure to operators and to ensure reproducible synthesis yields. The recent trend in the synthesizer industry towards the use of disposable kits aims to simplify setup and operation for the user, but often introduces several limitations related to temperature and chemical compatibility, thus requiring reoptimization of protocols developed on non-cassette-based systems. Radiochemists would benefit from a single hybrid system that provides tremendous flexibility for development and optimization of reaction conditions while also providing a pathway to simple, cassette-based production of diverse tracers.

On-demand droplet loading for automated organic chemistry on digital microfluidics.

Organic chemistry applications on digital microfluidic devices often involve reagents that are volatile or sensitive and must be introduced to the chip immediately before use. We present a new technique for automated, on-demand loading of ~1 μL droplets from large (~1 mL), sealed, off-chip reservoirs to a digital microfluidic chip in order to address this challenge. Unlike aqueous liquids which generally are non-wetting to the hydrophobic surface and must be actively drawn into the electrowetting-on-dielectric (EWOD) chip by electrode activation, organic liquids tend to be wetting and can spontaneously flood the chip, and hence require a retracting force for controlled liquid delivery.

Accurate dispensing of volatile reagents on demand for chemical reactions in EWOD chips.

Digital microfluidic chips provide a new platform for manipulating chemicals for multi-step chemical synthesis or assays at the microscale. The organic solvents and reagents needed for these applications are often volatile, sensitive to contamination, and wetting, i.e.

On chip droplet characterization: a practical, high-sensitivity measurement of droplet impedance in digital microfluidics.

We demonstrate a new approach to impedance measurement on digital microfluidics chips for the purpose of simple, sensitive, and accurate volume and liquid composition measurement. Adding only a single series resistor to existing AC droplet actuation circuits, the platform is simple to implement and has negligible effect on actuation voltage. To accurately measure the complex voltage across the resistor (and hence current through the device and droplet), the designed system is based on software-implemented lock-in amplification detection of the voltage drop across the resistor which filters out noise, enabling high-resolution and low-limit signal recovery.

Micro-chemical synthesis of molecular probes on an electronic microfluidic device.

We have developed an all-electronic digital microfluidic device for microscale chemical synthesis in organic solvents, operated by electrowetting-on-dielectric (EWOD). As an example of the principles, we demonstrate the multistep synthesis of [(18)F]FDG, the most common radiotracer for positron emission tomography (PET), with high and reliable radio-fluorination efficiency of [(18)F]FTAG (88 ± 7%, n = 11) and quantitative hydrolysis to [(18)F]FDG (> 95%, n = 11). We furthermore show that batches of purified [(18)F]FDG can successfully be used for PET imaging in mice and that they pass typical quality control requirements for human use (including radiochemical purity, residual solvents, Kryptofix, chemical purity, and pH).

Specific binding and magnetic concentration of CD8+ T-lymphocytes on electrowetting-on-dielectric platform.

In the quest to create a low-power portable lab-on-a-chip system, we demonstrate the specific binding and concentration of human CD8+ T-lymphocytes on an electrowetting-on-dielectric (EWOD)-based digital microfluidic platform using antibody-conjugated magnetic beads (MB-Abs). By using a small quantity of nonionic surfactant, we enable the human cell-based assays with selective magnetic binding on the EWOD device in an air environment. High binding efficiency (∼92%)of specific cells on MB-Abs is achieved due to the intimate contact between the cells and the magnetic beads (MBs) produced by the circulating flow within the small droplet.

Fluidic conduits for highly efficient purification of target species in EWOD-driven droplet microfluidics.

Due to the lack of continuous flows that would wash unwanted specifies and impurities off from a target location, droplet microfluidics commonly employs a long serial dilution process to purify target species. In this work, we achieve high-purity separation for the case of electrowetting-on-dielectric (EWOD) based droplet microfluidics by introducing a "fluidic conduit" between a sample droplet and a buffer droplet. The long and slender fluidic path minimizes the diffusion and fluidic mixing between the two droplets (thus eliminating non-specific transport) but provides a conduit between them for actively transported particles (thus allowing the specific transport).

EWOD-driven droplet microfluidic device integrated with optoelectronic tweezers as an automated platform for cellular isolation and analysis.

We report the integration of two technologies: droplet microfluidics using electrowetting-on-dielectric (EWOD) and individual particle manipulation using optoelectronic tweezers (OET)-in one microfluidic device. The integrated device successfully demonstrates a sequence involving both EWOD and OET operations. We encountered various challenges during integration of the two different technologies and present how they are addressed.