4-year PhD Studentship: Using advanced 3D bioprinting techniques to assemble complex models of the blood-brain barrier at University of Bristol on FindAPhD.com

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Dr James Armstrong, Dr S Miners, Dr Liliang Ouyang, Dr AW Perriman No more applications being accepted Self-Funded PhD Students Only

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Bristol United Kingdom Biomedical Engineering Medicine Tissue Engineering

About the Project

The blood-brain barrier (BBB) is a complex multicellular structure that selectively regulates transport between the circulating blood and the extracellular fluid of the central nervous system. This permits the transport of essential hormones and nutrients, restricts the passage of immune factors and pathogens, and facilitates the removal of metabolites and disease-associated proteins from the brain.[1] The anatomical inaccessibility of the BBB has restricted most studies to animal models, an approach that poses both ethical and technical limitations. This has led to immense interest in the development of cell models that can recreate the BBB in vitro, however, it remains a major tissue-engineering challenge to spatially organize the three key cell types (endothelial cells, pericytes, astrocytes) within their natural configuration. However, we have recently developed two state-of-the-art bioprinting methods that enable the fabrication of complex vascular networks and 3D astrocyte cultures; advances that we will leverage in this project to assemble BBB tricultures structured within perfusable microvascular networks. This will provide a tractable in vitro model to interrogate the structure-function relationships of barrier transport in health and disease,[2] and test therapeutic strategies (e.g., nanomaterials, focussed ultrasound) that aim to bypass or disrupt the BBB to aid neurological drug uptake.[3-4]

Aims and Objectives

To use two advanced bioprinting technologies to engineer the first perfusable model of the BBB containing the three major cell components assembled within their native configuration.
To fully characterize the engineered BBB in terms of tissue structure, cell organization, cell connectivity, and selective barrier function, providing a benchmark for objectives 3-4.
To interrogate how genetic perturbations relevant to monogenic diseases (e.g., slc2a1, mfsd2a) affect the multicellular interactions and selective barrier function of the BBB.
To interrogate how therapeutic interventions (e.g., ultrasound, nanomaterial vectors) affect the multicellular interactions and selective barrier function of the BBB.

Methodology

This interdisciplinary, internationally collaborative PhD project will be supervised between the University of Bristol and Tsinghua University, institutions that are ranked 9th in UK and 1st in China, respectively (QS World University Rankings 2021). The supervisory team has extensive experience in developing bioprinting strategies for engineering complex tissues[5-10] and will employ two state-of-the-art methods recently pioneered by Dr Ouyang and Dr Armstrong. Void-free 3D bioprinting[5] will be used to fabricate gelatin methacryloyl hydrogels containing perfusable vasculature of endothelial cells and pericytes, with astrocytes incorporated into the matrix using complementary network bioinks.[6] The engineered BBB will be optimized and benchmarked against human tissue biopsies, systematically perturbed through targeted gene editing, and exposed to both focused ultrasound stimulation and nanomaterial drug vectors. The resulting effects will be characterized by immunofluorescence staining, live-cell confocal fluorescence microscopy, electron microscopy, and barrier transport assays. The student will use advanced bioprinting facilities at both Tsinghua University (via Dr Ouyang) and the Bristol Centre for Bioprinting (directed by Prof. Perriman), and benefit from leading expertise in BBB pathology (Dr Miners),[11-12] tissue engineering, hydrogel, ultrasound, nanomaterials, bioimaging, and biological characterization (Dr Armstrong). Full training will be provided for all methods.

Keywords

Blood-brain barrier, bioprinting, tissue engineering, in vitro model

How to apply for this project

This project will be based in Bristol Medical School - Translational Health Sciences in the Faculty of Health Sciences at the University of Bristol.

Please visit the Faculty of Health Sciences website for details of how to apply

Funding Notes

This project is open for University of Bristol PGR scholarship applications (closing date 25th February 2022)
The University of Bristol PGR scholarship pays tuition fees and a maintenance stipend (at the minimum UKRI rate) for the duration of a PhD (typically three years but can be up to four years).

References

[1] Pandit et al. Advanced Drug Delivery Reviews (2020).
[2] Sweeney et al. Nature Reviews Neurology (2018).
[3] Lipsman et al. Nature Communications (2018).
[4] Terstappen et al. Nature Reviews Drug Discovery (2021).
[5] Ouyang, Armstrong et al. Advanced Functional Materials (2020).
[6] Ouyang, Armstrong et al. Science Advances (2020).
[7] Ouyang, Armstrong et al. Advanced Functional Materials (2020).
[8] Correia Carreira et al. Advanced Healthcare Materials (2020).
[9] Ouyang et al. Advanced Materials (2017).
[10] Armstrong et al. Advanced Healthcare Materials (2016).
[11] Tayler et al. Brain Pathology (2021).
[12] Miners et al. Brain Pathology (2016).