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Ultrasound and microbubble-mediated blood brain barrier opening for targeted drug delivery
The blood-brain barrier (BBB) poses a substantial challenge for effectively treating brain diseases with drugs. Utilising focused ultrasound in conjunction with microbubbles offers a promising approach to selectively and temporarily breach the BBB. This presents a potential avenue for enhancing drug delivery from the bloodstream into the brain. The proposed project seeks to explore the opening of the BBB using ultrasound and microbubble mediation with unprecedented precision.
The blood-brain barrier (BBB) poses a substantial challenge for effectively treating brain diseases with drugs. Utilising focused ultrasound in conjunction with microbubbles offers a promising approach to selectively and temporarily breach the BBB. This presents a potential avenue for enhancing drug delivery from the bloodstream into the brain. The bubbles employed in clinical applications have a diameter of less than 10 μm to avoid flow blockages in capillary vessels, and hence, are referred to as microbubbles.
Upon harmonic acoustic driving, the microbubbles undergo a periodic succession of expansion and compression phases, which leads to the generation of mechanical stress on the surrounding cell/tissues which eventually enhance their permeability to drugs [Sierra et al. JCBFM 2017]. Despite the significant progress made in recent studies, achieving a comprehensive mechanistic understanding of the entire process remains a formidable challenge owing to the wide range of spatial and temporal scales involved and the challenges associated with directly observing this phenomenon. The proposed project seeks to explore the opening of the BBB using ultrasound and microbubble mediation with unprecedented precision. This will be achieved by employing a novel human-cell-based BBB in-vitro platform developed in house [Wei et al. Adv Sci 2023], alongside existing ultra-high-speed and fluorescence imaging. The objective is to temporally analyse the individual microbubble response to ultrasound stimulation and establish correlations with the BBB opening.
The blood-brain barrier (BBB) poses a substantial challenge for effectively treating brain diseases with drugs. Utilising focused ultrasound in conjunction with microbubbles offers a promising approach to selectively and temporarily breach the BBB. This presents a potential avenue for enhancing drug delivery from the bloodstream into the brain. The bubbles employed in clinical applications have a diameter of less than 10 μm to avoid flow blockages in capillary vessels, and hence, are referred to as microbubbles. Upon harmonic acoustic driving, the microbubbles undergo a periodic succession of expansion and compression phases, which leads to the generation of mechanical stress on the surrounding cell/tissues which eventually enhance their permeability to drugs [Sierra et al. JCBFM 2017]. Despite the significant progress made in recent studies, achieving a comprehensive mechanistic understanding of the entire process remains a formidable challenge owing to the wide range of spatial and temporal scales involved and the challenges associated with directly observing this phenomenon. The proposed project seeks to explore the opening of the BBB using ultrasound and microbubble mediation with unprecedented precision. This will be achieved by employing a novel human-cell-based BBB in-vitro platform developed in house [Wei et al. Adv Sci 2023], alongside existing ultra-high-speed and fluorescence imaging. The objective is to temporally analyse the individual microbubble response to ultrasound stimulation and establish correlations with the BBB opening.
The main research goals are:
i) to adapt the existing BBB platform to ensure compatibility with imaging facilities,
ii) to visualize the response of bubbles to ultrasound and evaluating the opening of the BBB.
The project is composed of the following steps:
1. Learn about the topic:
a. Following publications: Shakya et al. ADDR 2024, Wei et al. Adv Sci 2023, Cattaneo & Supponen Soft Matter 2023, Cattaneo et al. IEEE IUS 2023, Beekers et al. JCR 2020
b. Perform independent literature search.
2. Familiarise with the existing BBB platform and the high-speed and fluorescence videomicroscopy facilities.
3. Adapt and customise the BBB platform using soft photolithography and 3D printing.
4. Cultivate human cerebral cells in the customised BBB platform.
5. Perform experiments with the customised BBB platform. Record the bubble response with ultra high speed imaging (10 Mfps) and evaluate the BBB opening with a fluorescent model drug and/or barrier electrical resistance.
6. Document the work writing a report, creating a poster and presenting your work.
The main research goals are: i) to adapt the existing BBB platform to ensure compatibility with imaging facilities, ii) to visualize the response of bubbles to ultrasound and evaluating the opening of the BBB.
The project is composed of the following steps: 1. Learn about the topic: a. Following publications: Shakya et al. ADDR 2024, Wei et al. Adv Sci 2023, Cattaneo & Supponen Soft Matter 2023, Cattaneo et al. IEEE IUS 2023, Beekers et al. JCR 2020 b. Perform independent literature search. 2. Familiarise with the existing BBB platform and the high-speed and fluorescence videomicroscopy facilities. 3. Adapt and customise the BBB platform using soft photolithography and 3D printing. 4. Cultivate human cerebral cells in the customised BBB platform. 5. Perform experiments with the customised BBB platform. Record the bubble response with ultra high speed imaging (10 Mfps) and evaluate the BBB opening with a fluorescent model drug and/or barrier electrical resistance. 6. Document the work writing a report, creating a poster and presenting your work.
For additional information, the candidates can contact Marco Cattaneo via email (mcattaneo at
ethz.ch)
For additional information, the candidates can contact Marco Cattaneo via email (mcattaneo at ethz.ch)