A scalable microfluidic technology  for combinatorial drug discovery

Microfluidic technology has been impactful in the field of molecular biology. It has enabled cellular separation, single cell studies and RNA analysis. Microfluidic systems have also provided environments to model organisms. The research conducted, and that will be presented in this thesis, focuses on a microfluidic platform that is capable of mixing and analysing compounds in an automated fashion and at a high level of throughput. It was designed to create microfluidic droplets or bioreactors, by segmenting and mixing using a novel gap switch technology, which can house biological substances. The gap switch technology allowed fluids to flow from one capillary to another by introducing a short section of tubing called a shuttle to bridge the gap. The primary biological example of this study was to use the microfluidic platform to analyse drugs for possible therapeutic benefits in the treatment of type 1 diabetes (T1D). T1D is a disease most common in childhood. It results from the autoimmune destruction of pancreatic beta cells and is an irreversible disorder with no known cure to date.

The system exhibited a scalable and robust microfluidic platform capable of cellular studies and combinatorial drug discovery. This thesis demonstrated the flow regime of a newly developed pipe flow design where the carrier fluid, silicone oil, is exposed to atmosphere at two points along its course. The first instance is where the fluid flows into the shuttle and the second is as it flows out and into the incubation tube. The gravity driven head in each was optimised to 29mm and 30mm respectively, therefore, the pressure drop in both is very similar. The flow rate and the Reynolds number were also calculated in both instances. Experimental results agreed well with the theory. Tolerances were significantly important as the design was based on viscosity, surface tension and gravitational phenomena. The platform established multiple advantages, including: small reagent volumes, 3D culture environment and no pumps. It performed well in planned biological applications and achieved most prerequisites set out in the objectives; such as: analysing the efficacy of novel drug combinations, demonstrating scalability and preforming as theoretically anticipated. One objective that was not entirely achieved was preventing the sedimentation of cells; however, their terminal velocity was sufficiently slowed down to consider the issue negligible.

As part of this research, three drugs were chosen to examine their potential therapeutic effects on pancreatic beta cells and to demonstrate the platforms capabilities of combinational drug screening. Two of these drugs were metformin and repaglinide, both are existing oral type 2 diabetes medicines used to control high blood sugar. The third drug or medicinal compound was harmine which is derived from the Middle Eastern plant Syrian rue. The findings from this thesis suggests Harmine shows efficacious outcomes, although these results would require much more scrutinous biological testing to prove such findings.