PhD Study : Development and optimisation of a human in vitro blood brain barrier model for high throughput screening of drug delivery vehicles

Summary

Successful delivery of drugs across the blood brain barrier (BBB) is essential for the treatment of numerous neurological conditions. In vitro BBB models are useful for the assessment of drug transport studies as a precursor to preclinical work - due to in part to lower costs, the ability to directly quantify the uptake of compounds and to gain information on their mechanism of action. It is also beneficial to detect potential negative impacts on BBB integrity at an early stage of drug development before commencing in vivo studies. However, the in vitro models developed so far have used animal cell lines and/or cell combinations that do not accurately reflect the architecture of the human BBB in vivo. Recently, we have generated preliminary results on the construction of a human 3D in vitro BBB model which more accurately reflects the in vivo cell architecture. This model shows promise but requires substantial optimisation to produce a robust, reliable assay that may be used for high throughput screening assays. Our pilot studies also suggest that the model can be utilised for the evaluation and quantification of encapsulated drug cargoes across the model.

Underlying aim

To develop and optimise a human cell 3D in vitro BBB assay for the high throughput screening of drug delivery vehicles.

Specific objectives/Methodology

To achieve the underlying aim, the project will be based on the following objectives (OB):

OB1 – develop the preliminary human cell 3D in vitro BBB assay using different human brain cell types including endothelial cells, astocytes and pericytes.

OB2 – optimise the BBB assay using a range of techniques including TEER measurement, SDS PAGE and westen blotting, confocal microscopy and SEM.

OB3 – enhance the BBB assay for high throughput use using a variety 3D scaffolds.

OB4 – develop a range of drug delivery formuations, containing model drugs, based on pegulated polymersomes. Characterisation of these formulations will include size, PDI, zeta potential, encapsulation efficiency and release and stability profiles.

OB5 – testing of these novel drug delivery formualtions on the high throughput BBB assay.

This project will highlight a paradigm shift in the way 3D BBB models are constrcuted, with scope for worldwide implementation and business.

References

Huey, R., O’Hagan, B., McCarron, P. and Hawthorne, S. (2017). International Journal of Pharmaceutics, 525(1), 12-20.

Huey, R., Rathbone, D., McCarron, P. and Hawthorne, S. (2019). Journal of Drug Targeting, 27(9), 959-970.

Aibani N, Nesbitt H, Marino N, Jurek J, O’Neill C, Martin C, Di Bari I, Sheng Y, Logan K, Hawthorne S, McHAle AP, Callan JF and Callan B. (2018) Acta Biomaterialia 80, 327-340.

Martin, C., Marino, N., Curran, C., McHale, A.P., Callan, J.F., Callan, B. (2016). International  Journal of Pharmaceutics. 511, 570 – 579.

Additional Requirements

Desirable experience: nanoparticle formulation and characterization, cell culture, SDS PAGE and western blotting.

Essential criteria

Applicants should hold, or expect to obtain, a First or Upper Second Class Honours Degree in a subject relevant to the proposed area of study.

We may also consider applications from those who hold equivalent qualifications, for example, a Lower Second Class Honours Degree plus a Master’s Degree with Distinction.

In exceptional circumstances, the University may consider a portfolio of evidence from applicants who have appropriate professional experience which is equivalent to the learning outcomes of an Honours degree in lieu of academic qualifications.

• Sound understanding of subject area as evidenced by a comprehensive research proposal

Desirable Criteria

If the University receives a large number of applicants for the project, the following desirable criteria may be applied to shortlist applicants for interview.

• Completion of Masters at a level equivalent to commendation or distinction at Ulster
• Experience using research methods or other approaches relevant to the subject domain
• Work experience relevant to the proposed project
• Publications - peer-reviewed
• Publications record appropriate to career stage
• Experience of presentation of research findings
• A comprehensive and articulate personal statement
• Use of personal initiative as evidenced by record of work above that normally expected at career stage.
• Relevant professional qualification and/or a Degree in a Health or Health related area

Funding and eligibility

The University offers the following levels of support:

Vice Chancellors Research Studentship (VCRS)

The following scholarship options are available to applicants worldwide:

• Full Award: (full-time tuition fees + £19,000 (tbc))
• Part Award: (full-time tuition fees + £9,500)
• Fees Only Award: (full-time tuition fees)

These scholarships will cover full-time PhD tuition fees for three years (subject to satisfactory academic performance) and will provide a £900 per annum research training support grant (RTSG) to help support the PhD researcher.

Applicants who already hold a doctoral degree or who have been registered on a programme of research leading to the award of a doctoral degree on a full-time basis for more than one year (or part-time equivalent) are NOT eligible to apply for an award.

Please note: you will automatically be entered into the competition for the Full Award, unless you state otherwise in your application.

Department for the Economy (DFE)

The scholarship will cover tuition fees at the Home rate and a maintenance allowance of £19,000 (tbc) per annum for three years (subject to satisfactory academic performance).

This scholarship also comes with £900 per annum for three years as a research training support grant (RTSG) allocation to help support the PhD researcher.

• Candidates with pre-settled or settled status under the EU Settlement Scheme, who also satisfy a three year residency requirement in the UK prior to the start of the course for which a Studentship is held MAY receive a Studentship covering fees and maintenance.
• Republic of Ireland (ROI) nationals who satisfy three years’ residency in the UK prior to the start of the course MAY receive a Studentship covering fees and maintenance (ROI nationals don’t need to have pre-settled or settled status under the EU Settlement Scheme to qualify).
• Other non-ROI EU applicants are ‘International’ are not eligible for this source of funding.
• Applicants who already hold a doctoral degree or who have been registered on a programme of research leading to the award of a doctoral degree on a full-time basis for more than one year (or part-time equivalent) are NOT eligible to apply for an award.

Due consideration should be given to financing your studies. Further information on cost of living