Scaling up the production of cancer organoids for use in drug discovery

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Organoids pose a potential route in terms of drug development; allowing a reduction in animal testing, provision of a model more closely resembling human anatomical function, and presenting more complex testing opportunities[1].In organoid growth a framework to allow 3D culture is required. Current culture procedure uses a supporting matrix in the form of Matrigel. Matrigel is produced from mouse sarcoma cells. The use of this at an industrial scale is challenging due to high cost, and low availability as mouse sarcoma is not easily sourced in a consistent manor.As Matrigel is a natural product it is a source of inherent variability. This project will focus on the development and testing of a full or partial replacement synthetic matrix to be used in place of or in combination with Matrigel to provide a more consistent environment for organoid growth. Said synthetic alternative biomaterial will be required to at least match Matrigel alone in efficiency of organoid production[2], [3].Use of a synthetic alternative brings benefits in terms of consistency with reduced batch to batch variability. A synthetic matrix could allow more simplistic storage and handling conditions to allow increased application, and usage. In turn could increase tunability as more conditions would be viable[4].With the successful use of synthetic matrix, increased structural and mechanical properties could be provided to the organoids during maturation. Matrigel alone cannot form a self-supporting structure, the addition of a synthetic matrix could provide this ability. A self-supporting structure would also increase the scalability of organoid production providing a growth foundation which would be suitable within a bioreactor[5].The intended result is development of a novel hydrogel which will be tested and optimised; resulting in a matrix providing an increase in both consistency, and quality of organoids produced on an industrial scale. Within the research other avenues of optimisation of organoid growth will be investigated including: testing the effect of lactate on organoid growth; and testing the effect of hypoxic conditions. These will sit alongside the optimisation of a synthetic matrix to increase the ease of organoid use on an industrial scale.These finding will hope to maximise organoid growth. Benefits of this research lie in testing of new potential drugs namely for the treatment of cancers within differing tissues. Testing this way provides opportunities in personalisation of medicine; higher quality testing; reduction in development costs; decreased issues in clinical trials; and reduction in animal testing which provides ethical benefits as well as increasing the reliability of results through the use of human tissue which provides closer representation to actuality. These potential benefits align with the EPSRC priority areas through healthcare optimisation focusing on drug discovery, alongside the intention to provide increased affordability resulting in more inclusive healthcare[6].[1]M. A. Lancaster and J. A. Knoblich, 'Organogenesis in a dish: Modeling development and disease using organoid technologies', Science, vol. 345, no. 6194, Jul. 2014, doi: 10.1126/science.1247125.[2]A. Fatehullah, S. H. Tan, and N. Barker, 'Organoids as an in vitro model of human development and disease', Nat. Cell Biol., vol. 18, no. 3, Art. no. 3, Mar. 2016, doi: 10.1038/ncb3312.[3]'Biomaterials and tissue engineering - EPSRC website'. https://epsrc.ukri.org/research/ourportfolio/researchareas/biomaterials/ (accessed Sep. 30, 2020).[4]M. C. Kibbey, 'Maintenance of the EHS sarcoma and Matrigel preparation', J. Tissue Cult. Methods, vol. 16, no. 3, pp. 227-230, Sep. 1994, doi: 10.1007/BF01540656.[5]N. Gjorevski et al., 'Designer matrices for intestinal stem cell and organoid culture', Nature, vol. 539, no. 7630, Art. no. 7630, Nov. 2016, doi: 10.1038/nature20168.[6]K. Daniel, 'EPSRC Healthcare Technologies Strategy Summary', p.12