Droplet microfluidics for continuous chemical monitoring

Abstract

In a variety of fields such as disease diagnostics, clinical monitoring, drug development and environmental science, there is a need to continuously measure chemical and biomolecule concentrations over long periods. Continuous monitoring of chemicals has proven to be particularly challenging even for the current state-of-the-art electrochemical sensors, which can suffer from surface degradation and measurement drift. The gold standard “bulk” assay techniques require large sample volume and laborious professional time, making them unsuitable for many continuous monitoring applications. This has led research attention to microfluidics (the study and manipulation of microlitres to picolitres volumes of fluid in microchannels 1-1000 µm in diameter), which can carry out biochemical analysis consuming less sample and reagent and providing higher throughput. Microfluidics has seen several successful applications including the development of "Micro Total Analysis Systems" (µTAS) or “lab-on-a-chip” devices, which carry out all the necessary steps for chemical analysis of a sample and have been exploited for a wide variety of processes. Indeed, many modern point-of-care tools also incorporate some element of microfluidics, notably lateral flow devices (e.g. glucose testing for diabetics and home pregnancy tests). This thesis focuses on a subset of microfluidics called droplet microfluidics. While standard “continuous flow” microfluidics handle fluids in a single phase (mostly aqueous phase) under laminar flow regimes, droplet microfluidics is based around the production of many individual and separate chemical reactors in an immiscible carrier fluid. Droplet microfluidics greatly improves the possible temporal resolution and throughput of assay and analysis by eliminating Taylor dispersion and band broadening exhibited by continuous flow microfluidics. Surface contamination is avoided as droplets never come into contact with the channel wall. Chaotic advection within the droplets greatly improves mixing of sample and reagent and reduces reaction time. These properties of droplet microfluidics make it particularly suitable for the task of in-situ monitoring requiring high temporal resolutions and low volumes of reagent and sample consumption per measurement. Currently, most droplet microfluidic systems are still “chip-in-a-lab”, requiring bulky and extensive supporting equipment such as microscopes, external pumps and valves. This thesis addresses the challenges of taking droplet microfluidics from a useful laboratory tool to field applications. With a focus on robust droplet generation and miniaturisation of the fluidics suitable for portable/wearable applications. Droplet generation is most commonly achieved by introducing aqueous and oil phases into a T-junction or a flow focusing channel geometry. This method produces droplets that are sensitive to changes in flow conditions and fluid composition. Here I present a new novel form of droplet generation utilising pulsed flows. This pulsed droplet generation regime is robust and invariant to both flow conditions and fluid composition. This method offers controllable droplet dynamics, with droplet volume and composition solely determined by pulsation volumes, which are defined by the design of a peristaltic micropump. Gareth Evans Importantly, sequences of droplets with controlled composition can be hardcoded into the pump, allowing chemical operations such as titrations and dilutions to be easily designed into the system, as well as including in-situ standards etc. for the calibration of droplet microfluidic sensors and accomplishing more complicated assay procedures in a droplet format. In this thesis, I showcase two prototype platforms, which utilise this pulsed droplet generation regime coupled with in-line spectrophotometer flow cell. The platform contains a compact and low power 3D-printed peristaltic micropump, capable of continuously collecting samples, generating droplets close to the sampling site and with short stabilisation time. This has allowed for the first ever system capable of continuous in-situ sampling and real-time chemical measurement using droplet microfluidics as well as the integration of complex multiple step assays into a portable droplet platform. One application of this platform technology is the in-situ monitoring of water chemistry in rivers, lakes and oceans based on this novel approach. This prototype device has been tailored for the measurement of nitrite and nitrate, two of the most important macronutrients in natural water that are important for determining the health of aquatic ecosystems and studying biogeochemical changes. Traditional manual sampling and laboratory analysis is logistically challenging and costly, in-situ measurement using small and low power analytical devices removes the need for sample transport, allowing for larger and more temporally detailed data collection. All previously reported state-of-the-art in-situ microfluidic analysers have been based on continuous (single-phase) microfluidics. Shifting to a droplet-flow regime results in great improvement in temporal resolution, fluid and power economy. Furthermore, as an example application in healthcare, I present a prototype device capable of producing ‘trains’ of droplets. The device is tailored to carry out a multiple step competitive heterogeneous assay for continuous measurement of cortisol when coupled with other custom tools. Cortisol is a stress related steroid hormone, its concentration in the body varies rapidly and abnormal changes are associated with a variety of disease states. The ability of continuous and in-situ monitoring of its concentration, rather than the current single snapshot measurement, opens the door to trend-related diagnostics and treatment.

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