Holloway Group: Microfluidic Neurological Models (MNM)
The Oxford MNM group focuses on developing in vitro models for neurological disease. Employing micro-fabrication techniques to define channels and features in cell culture devices at the scale of the cell and below, opens up the opportunity to shape cellular microenvironments to better reflect those found in the body. Our work uses these techniques and induced pluripotent stem cell (iPSC) technologies to create human cell culture models of the brain with the aim of enabling new possibilities to study neurovascular disease and improve drug discovery.
By “reprogramming” cells from a patient biopsy into stem cells, we can then use developmental cues to turn these cells into neurons, enabling investigations to be made into the function of human neurons. However typically these cells are grown on standard flat plastic culture dishes which leads to a random entanglement of connected cells. This does not replicate the ordered circuits found in the brain. Furthermore in stroke and neurodegenerative diseases like Alzheimer’s and Parkinson’s, the disease or injury often starts out localised to a specific brain region but may spread through these neuronal circuits. Our work uses microfabrication techniques adopted from the computer microchip industry to create miniature cell culture devices with subcellular sized channels that can guide living neurons to connect in defined paths. We are now using these models to localise injuries that mimic stroke and study how damage can spread through circuits and identify methods to stop it.
The brain is more than just neurons. Blood vessels interact with brain support cells called astrocytes and are ensheathed by cells called pericytes which are embedded in a complex matrix called the basement membrane. Together these cells form the Glio-vascular unit (GVU). These cellular interactions help maintain the unique microenvironment of the brain, however in stroke this functional unit is disrupted. Most cell culture methods typically fail to replicate the 3D, dynamic and multi-cellular nature of the GVU that is so important to brain health and function. Our lab is developing microfluidic techniques to recreate the GVU using human cells to enable the study of stroke and diseases that affect blood vessels of the brain. With Prof Yvonne Couch, Dr Alessandro Granata (Cambridge) and the Oxford biotech EVOX, we are using these models to investigate a novel therapeutic approach to treat COL4A disease (a form of cerebral small vessel disease that causes early onset stroke).