Isogenic human neurovascular unit on chip: towards a disease on chip model of stroke
SummaryStroke is the largest cause of adult disability and a leading cause of death worldwide, yet despite significant research efforts over 1000 treatments investigated have failed to reveal an effective neuroprotective treatment. This is in part due to the difficulty of testing drugs for diseases of the brain. Drugs may be tested in experimental animals however there is a significant evolutionary gap that may hinder translation into humans. On the other hand human cells grown in a flat dish, do not adequately represent the complex organisation and environmental conditions found in the body. As such the use of human cell culture models of stroke is rare. Of 300,000 studies on stroke investigated in 2011, only 30 were performed in human cell culture models.
This project will use an ‘organ on chip’ device, which provides a 3D, physiologically relevant micro-environment to grow human cells, and establish a novel platform to test prospective stroke drugs. In order to use the most relevant cells, whilst avoiding the ethical and technical challenges involved in directly obtaining human brain cells, this project will also exploit recent advances in stem cell technologies. Blood or skin cells donated by adults can be genetically ‘reprogramed’ to become induced stem cells (iPSCs) which may then be turned into any cell in the body. Prof Hughes lab, at which part of this work will take place, have recently developed a protocol to turn iPSCs into a brain cell type ‘pericytes’ which play an important role in supporting the brain blood vessels. Our lab has demonstrated that these cells constrict blood flow when they die following stroke, which may increase brain damage.
The model developed in this project will enable the study of this phenomena in human cells, by bringing together expertise in microfluidic engineering (Prof Lee), stem cell and vascular biology (Prof Hughes) and stroke biology (Prof Buchan and Dr Holloway) to provide a novel model of stroke and a new way to test drugs.
Key OutputsAnimal Free Research UK - Pilot Grant: £4919, 2020 – 2021, Buchan & Holloway
FRAME Summer Studentship: £3,000, 2021, Holloway
Oxford biotech company EVOX grant through winning the Oxford-Evox Alliance grant: ~ £150,000, 2020 - 2023
Developing microfluidic in vitro models of ischemic stroke: OOAC e-Symposium March 2021, abstract presentation, Paul Holloway
OOACTN Early Career Advisory Group (chair), https://www.organonachip.tk/ecr/
Organ-on-a-Chip Shop, Science Museum Lates, 2020 https://www.organonachip.tk/news/4629/the-organ-on-a-chip-sh...
Life on a Chip, Ingenia (2022) https://www.ingenia.org.uk/ingenia/issue-90/life-on-a-chip