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Acoustic holography for precise drug delivery into the brain

Subject areas:

Biomedical and life sciences. Engineering. Physics. Computer science. Chemistry. Pharmacology.

Funding type:

Tuition fee. Stipend.

Awarding body:

The Engineering and Physical Sciences Research Council (EPSRC).



Fully funded 3 years 4 months full-time PhD studentship (including home tuition fees, annual stipend and consumables) starting on 1st June 2022.

Award details

Aim of the project

The aim of this project is to develop non-invasive and personalized brain therapies using the exciting concept of acoustic holography.

Focused ultrasound in combination with circulating microbubbles is currently the only method that allows non-invasive, localised and reversible opening of the blood-brain barrier (BBB), for targeted drug delivery into the brain. However, current methods allow treatment of a single area at a time. This is limiting its application for diseases that have multiple sites in the brain.

Acoustic holography is an approach which can circumvent this limitation using 3D-printed acoustic lenses. These lenses bend the acoustic field into desired shapes, to cover arbitrary brain volumes. In this project, we will develop lenses tailored to specific species and subjects, aiming at personalized and precise drug delivery into the brain. Fluorescence and gadolinium contrast agents within liposomal carriers will be delivered in vivo to enhance diagnosis, delineation and treatment of brain tumours.

Project description:

One of the main limiting factors in drug delivery into the brain is the presence of the blood-brain barrier (BBB). The BBB protects the brain from pathogens, but at the same time blocks most of therapeutics for the treatment of neurodegenerative diseases and brain tumours. Focused ultrasound (FUS) in combination with circulating microbubbles is a non-invasive method to overcome the BBB in a localized and reversible manner. FUS is typically generated with a single-element transducer with a defined focal volume, imposed by wavelength-imposed restrictions. Acoustic holography is a new technology that permits shaping of the focal area into arbitrary volumes. In this project, we will design species-specific and subject-specific acoustic lenses to perform personalized delivery of therapeutics into the brain.

The first part of the project will include performing numerical simulations of transcranial ultrasound propagation. CT scans of different species (e.g. mice and humans) will be used to derive the density and speed of sound within the skull. Time-reversal propagation from arbitrary volumes within the brain (e.g. hippocampus, substantia nigra, or tumours) will provide the phase delay distributions that need to be applied on the transducer surface. Based on this information, acoustic lenses will be 3D-printed and then tested in benchtop experiments. The developed lenses will be tested in free field and with ex vivo skulls. The student will identify the precision of this technology and the limits for each target and each species. 

The second part of the project will involve characterization of the model therapeutic in vitro. The student will prepare liposomes and will determine their size distribution and stability. The liposomes will have fluorescence and gadolinium markers as surrogates of drugs. Drug release profiles will be estimated in vitro, both in the absence and presence of an ultrasound field and/or microbubbles. Ultrasound-triggered release will be investigated as a potential mechanism for enhancing the localization of drug delivery ,assessed by fluorescence or inductively coupled plasma mass spectrometry (ICP-MS).

The final part of this project will pursue hologram-assisted BBB opening and liposome delivery in vivo. Targeted delivery will be performed in wild-type mice, followed by tumour-bearing mice. We will attempt holographic focusing in different parts of the brain, either in one or in both hemispheres at the same time. BBB opening will be confirmed with contrast-enhancedT1-weighting MRIand near infrared fluorescence imaging. BBB closing timeline will be established with serial MRI scans. Drug delivery distribution will be confirmed post-mortem through immunohistochemistry and mass spectrometry. The overall aim of the in vivo experiments will be to improve the diagnosis, delineation and treatment of brain tumours, by precisely targeting their entire volume and delivering theranostic agents.

By the end of the project, the student will have acquired mastery in a wide spectrum of technologies, including therapeutic ultrasound, acoustic holography, numerical simulations, 3D printing, benchtop experiments, chemical synthesis and characterization ,biomedical imaging (i.e., CT, MRI, and fluorescence imaging),as well as in vivo experiments and techniques for tissue processing.

Informal email enquiries from interested students to the supervisor are encouraged (contact details below).

Dr Antonios Pouliopoulos -  antonios.pouliopoulos@kcl.ac.uk

Award value

Each studentship is fully funded for 3 years 4 months. This includes home tuition fees, stipend and generous project consumables.

Stipend: Students will receive a tax-free stipend at the UKRI rate of ca £17,000 per year as a living allowance.

Research Training Support Grant (RTSG): A generous project allowance will be provided for research consumables and for attending UK and international conferences.

Eligibility criteria

Eligibility criteria:

Candidates who meet the eligibility requirements for Home Fee status will be eligible to apply for this project. Home students will be eligible for a full UKRI award, including fees and stipend, if they satisfy the UKRI criteria below, including residency requirements. To be classed as a Home student, candidates must meet the following criteria: 

  • be a UK National (meeting residency requirements), or 
  • have settled status, or 
  • have pre-settled status (meeting residency requirements), or 
  • have indefinite leave to remain or enter.

Applicable level of study: Postgraduate research 

Prospective candidates should have a 1st or 2:1 M-level qualification in Bioengineering, Biomedical Engineering, Physics, Engineering, Computer Science, Chemistry, Biology, Pharmacology, or a related programme.

Preference will be given to candidates with a background conducive to multidisciplinary research and preferably strong programming skills.

We welcome eligible applicants from any personal background, who are pleased to join diverse and friendly research groups.

 

Application process

Please submit an application for the Biomedical Engineering and Imaging Science Research MPhil/PhD (Full-time) programme using the King’s Apply system. Please include the following with your application:

  • A PDF copy of your CV should be uploaded to the Employment History section.
  • A 500-word personal statement outlining your motivation for undertaking postgraduate research should be uploaded to the Supporting statement section.
  • Funding information: Please choose Option 5 “I am applying for a funding award or scholarship administered by King’s College London” and under “Award Scheme Code or Name” enter BMEIS_DTP. Failing to include this code might result in you not being considered for this funding.

Closing date: 11th April 2022 (please note that the applications can be closed early if a suitable candidate is found)

 
 

Academic year:

2021-22

Study mode:

Postgraduate research

Application closing date:

11 April 2022