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A novel human 3D in vitro dynamic model with integrated sensors for studying neurovasculature inflammation


Project Description

The brain microvasculature is composed of endothelial cells, pericytes and astrocytes. The endothelium forms the barrier between the blood and the brain cells (i.e “blood-brain barrier “, BBB). Inflammation has been shown to disrupt the stability of the BBB and to initiate the atherosclerosis, neurodegenerative diseases, such as Alzheimer’s disease (AD). AD is associated with cognitive decline and accumulation of amyloid beta peptides (Aβ) in the brain. The BBB maintains the brain homeostasis. Aβ plays significant roles in the BBB dysfunction. Conversely, BBB dysfunction leads to faulty Aβ clearance from the brain and increased influx of peripheral Aβ across the BBB (Sagare et al.,2012). Thus, it is imperative to study the mechanisms of BBB dysfunction in a physiologically relevant model for developing better therapeutic strategy targeting BBB integrity for this devastating disease. At present, most studies on BBB use complex in vivo models in mice and dogs. In vitro models are primarily based on 2D constructs, use animal cells and lack the shear stress produced by blood flow. Organs-on-a-chip platforms are often intricate, laborious and do not allow to visualize cell-cell interaction across the BBB (Brown&Pensabene, 2015). Collaborating with Kirkstall Ltd and Queen Mary University of London, supported by BBSRC/Innovate UK, we recently optimised human primary cell densities, flow rate for individual cell types and conditioned-medium for growing BBB cell types together using Quasi-Vivo system (QVS). We thus showed that Aβ produces differential effects on BBB cells under static and dynamic conditions (Miranda-Azpiazu et al.,2018). Novelty: This PhD project aims to develop a reliable microphysiological system (MPS) or Organ-on-a-chip (OOAC) system recreating the hematoencephalic barrier to clarify the role of endothelial inflammation, the effects of Aβ and other pro-inflammatory cytokines on individual and co-cultured human cells to understand the downstream mechanisms of these proteins on BBB under dynamic condition. By integrating laser, nanoparticles for selective imaging and nanofluidic sensors in the microfluidic system, it will be possible for the first time to directly and non-invasively monitor the cell behaviour and response to a therapeutic treatment.

Funding Notes

UK/EU/International  – School of Electronic & Electrical Engineering Scholarship Award paying Academic Fees at Home/EU fee rate of £4,600 in Session 2020/21 or International fee rate of £23,750 in Session 2020/21 and Maintenance matching EPSRC rates (currently £15,009 in Session 2019/20) per year for 3 years.  Funding is awarded on a competitive basis.

How good is research at University of Leeds in General Engineering?

FTE Category A staff submitted: 44.80

Research output data provided by the Research Excellence Framework (REF)

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