Designing Bioreactors for in vitro Clinical-Scale Red Blood Cell Manufacture

With an expanding global population there is an ever-increasing need for blood units for both routine and emergency transfusion. Furthermore, conditions of the blood such as thalassaemia and sickle cell disease place increased demand on supplies, often requiring extensively typed and rare blood types. Shortages in donated blood, especially for rarer blood types, can be overcome if blood (particularly the red blood cell (erythroid cell) component) could be reliably produced externally (in vitro). Additionally, clinical-scale manufacture can enable reduced risk to patients of blood-borne disease. If such technologies can be combined with emerging gene editing techniques there is further possibility of customising blood products to suit individual needs or to create a single blood product suitable for the vast majority of the world's population. Existing approaches to in vitro manufacture of red blood cells involve the use of progenitor cells and do not currently represent a financially- or clinically-viable approach. As such, improved methods are required to achieve clinically-viable manufactured red blood cell products, with manufacturing design and optimisation of culture conditions key to this goal.
This project aims to design and develop bioreactor systems to expand and differentiate erythroid progenitor cells in vitro. I will be studying the design parameters affecting cell behaviour, optimizing conditions to enable large-scale manufacture at maximal economic efficiency. In particular, I will be focussing on the fluidized bed reactor systems. Fluidised bed reactors have found extensive applications in the field of chemical engineering for catalysis, for instance in the manufacture of fuels and polymers, the processing of radioactive waste, and the drying of solid materials, due to their superior mass transfer characteristics. I will initially compare performance of the fluidized bed reactor to existing bioreactor designs for mammalian cell culture, such as hollow fibre and continuous stirred tank reactors, to determine optimal culture strategies. Within this, the design parameters (for example flow rate and shear stress) and operating conditions for maximal cellular expansion, differentiation, and viability will be optimised. The findings from these experiments can then be used to develop hybrid reactor systems, combining useful elements from the different reactor systems to improve outcomes, and to predict the design of a large (industrial) scale reactor based on the bench-scale experimental results.
The ability to manufacture these cells in vitro will enable cost reduction through economies of scale and a reduced labour requirement, with the potential for automation of much of the process. This research fits within the EPSRCs theme of transforming healthcare and holds the potential to improve quality of life and physical wellbeing, as well as contributing towards affordable healthcare and economic growth.