Developing scalable and standardised manufacturing methods for human pluripotent stem cells

So that people can live longer and more active lives there is a need to develop new affordable and effective medicines. In some cases cells that we have within our own bodies can be used to repair damaged tissues. However, in adults, this repair mechanism is very limited and often inefficient. The cells that make up the very early developing embryo are those that can go on to make all of the cells in the human body and these so called 'stem cells' when harvested from embryos have the potential to repair many types of diseased tissue in adults. Although stem cells from embryos can now be grown in laboratories, one highly trained person can only grow a few million cells in a week. Since it takes 5 billion heart cells to repair the heart muscle of a heart-attack patient, growing these cells manually is useful for research but not for treating multiple patients in practise. This project aims to combine the expertise of both stem cell scientists and engineers, to create large-scale systems for the 'manufacture' of large numbers of stem cells so the potential of stem cell therapies can be realised. This is not a trivial task since the way we culture stem cells manually is very different from those grown in 'factories'. Therefore this project will identify the parts of the manual cell culture process that need to be improved for the large scale cost effective manufacture of stem cells for therapeutic purposes. Once enough stem cells can be routinely grown and harvested, it is more likely that they can be made into enough heart, nerve and pancreas cells to begin to treat disease.

Pluripotent hESCs are a major emerging platform for a wide range of therapeutic cell based products and pharmaceutical assays, however there are major barriers to their commercial-scale production. Our multidisciplinary collaboration will improve the understanding and reliability of cell expansion for pluripotent human embryonic stem (hESC) and induced pluripotency (hIPSC) cells by: 1) investigating properties of pluripotent cells that influence their processing and scale-up using our experience of multiple cell lines and culture conditions to scope generic process conditions 2) optimising and validating automated bioprocess protocols to enable robust and reproducible manufacture of hESC-based products at commercial scales. To maximise the range of manufacturing scales that are likely to be required for e.g. pharmaceutical screening processes or regenerative medicine applications, we will develop medium scale (entirely automated 90 X T175 flask T-flask culture in the CompacT SelecT) and larger scale (for potentially up to 1000L bioreactor) systems in parallel, using the same source of highly characterised cells. The processes that we deliver will have improved cost-effectiveness over current systems and will allow standardised culture protocols to be applied to multiple human pluripotent cell lines. Statistically-designed factorial experiments, underpinned by systematic process improvement, will identify the variables in manual culture methods that affect the practicality of scaled hESC manufacture. Factorial experimentation & quality optimisation (biological function, variation & cost) of the bioprocessed cell product will be achieved through gaining an understanding of all relevant variables through a unique collaboration between stem cell biologists and bioprocess/biomanufacturing engineers.