Missions

The main objectives of the project are as follows:
1. To use microfluidics technology to create nanodroplets that are uniform in size.
2. To identify the perfect composition of droplets, which includes perfluorocarbon and/or surfactant that will result in an ultrasonic vaporization pressure below 0.6 MPa.
3. To observe the opening of an artificial BBB model on a chip provided by a collaborator, using a microscope.
4. To optimize the experimental setup that will be used in the experiments.

Activities

The main objectives of the project are as follows:
1. To use microfluidics technology to create nanodroplets that are uniform in size.
2. To identify the perfect composition of droplets, which includes perfluorocarbon and/or surfactant that will result in an ultrasonic vaporization pressure below 0.6 MPa.
3. To observe the opening of an artificial BBB model on a chip provided by a collaborator, using a microscope.
4. To optimize the experimental setup that will be used in the experiments.

Skills

Ultrasound
Microfluidics
Knowledge of MATLAB and the “Python” programming language will be appreciated but not essential

Work Context

The proposed research will take place at LPENS, a laboratory situated in the center of Paris that is directed by Prof. Wladimir Urbach (https://orcid.org/0000-0002-1673-6923). The research will be carried out in close collaboration with Dr. Nicolas Taulier (https://www.lib.upmc.fr/~ntaulier/).
The project will also involve working with
- Ayako Yamada, who specializes in the in situ formation and micro vascularization of human cerebral organoids on an artificial substrate integrated into a microfluidic chip,
- Christine Contino-Pépin, who synthesizes fluorinated surfactants for the project;
- Experiments involving ultrasound will be partly conducted at the "Laboratoire d'Imagerie Biomédicale", which is a 15-minute walk away from LPENS. LIB has a team of specialists in therapeutic ultrasound, led by Nicolas Taulier.
All the necessary microfluidics instruments are available at LPENS.

Additional Information

NANODROPLETS FOR BLOOD BRAIN BARRIER OPENING
2-YEARS POSTDOC POSITION

Laboratoire de Physique de l'Ecole Normale Supérieure v

State of the art. Brain Tumors, trauma, vascular injury or neurodegenerative and neuropsychiatric diseases, or epilepsy, affect today one out of three people worldwide, which represents a serious public health problem that needs to be addressed by active principles that have to pass the Blood Brain Barrier (BBB) to reach their target. Although the integrity of the BBB is compromised during the progress of most by these pathologies, crossing this barrier remains a key challenge to overcome for the treatment of brain diseases. Focused ultrasound (FUS) has emerged as a very promising approach to overcome the BBB obstacle by using the interaction between the acoustic pressure field and intravenously injected microbubbles (MBs) to cause the transient opening of the BBB. For now, today most pre-clinical and clinical studies use commercial ultrasound contrast agents. These MBs are injected intravenously and circulate in the vascular system. Stimulated by ultrasonic pressure, the stable oscillation of MBs induces mechanical stress and transient down-expression of proteins which proteins that maintain the tight junction between endothelial cells ensuring the impermeability of BBB. Associated with magnetic resonance guidance, FUS appears as a new non-invasive modality allowing a safe and transient BBB opening with a high degree of spatial (sub-millimetric precision) and temporal accuracy and specificity (the normal barrier function is restored after a few hours).
There are two major drawbacks with MBs. The first one is their fast disappearance (within 15 minutes), as the gas encapsulated in bubble core is rapidly dissolved into the plasma. The second is their size polydispersity The acoustic field is chosen so that the MBs having a given diameter (generally equal to the average of all the MBs) oscillate in volume. But then MBs with a much larger diameter risk imploding causing hemorrhage. That why none of these commercial ultrasound contrast agents have been authorized, and will probably never be, by medical agencies (FDA or EMA) to be used as openers of BBB and they may never be authorized due to these undesirable side effects linked to their size polydispersity.

Project goal. As a better and safer alternative to commercial ultrasound contrast agents to open the BBB, we propose to use perfluorocarbon nanodroplets. These nanodroplets will be produced by microfluidics to ensure a monodisperse size. At a given pressure of FUS these nanodroplets will be transformed into monodisperse microbubbles
The 3 goals of the project will be:
-Produce nanodroplets of monodisperse size using microfluidics,
- Find the optimal droplet composition (perfluorocarbon and/or surfactant) for vaporization ultrasound pressure lower than 0.6 MPa.
-Study, under a microscope, the opening of an artificial model of BBB on a chip, provided by a collaborator.
- These experiments will use a dedicated setup that will have to be optimized

Facilities. The proposed research will be hosted at LPENS, a laboratory in the center of Paris under the supervision of Pr. Wladimir Urbach (https://orcid.org/0000-0002-1673-6923) and Dr. Nicolas Taulier (https://www.lib.upmc.fr/~ntaulier/).
The project will be carried out in close collaboration with:
-Ayako Yamada is working on the in-situ formation and micro vascularization of human brain organoids on an artificial substrate integrated into a microfluidic chip.
- Christine Contino-Pépin synthesizes for us fluorinated surfactants. All microfluidics instruments are available at LPENS.
Experiments involving ultrasound will be performed at LIB, in a team specialized in therapeutic ultrasound.
Expected profile. The applicant should have a Ph.D. and is expected to have experience in ultrasound and microfluidic.
How to apply. The postdoc should start no later than Fall 2024, but the exact starting date is flexible.
5 recent relevant references.
1. “Acoustic droplet vaporization of perfluorohexane emulsions at an ultrasonic frequency of 1.1 MHz.”
Langmuir 39 (2023) 15716-15729.(doi:10.1021/acs.langmuir.3c02272)
2. “Perfluorocarbon Nanodroplets as Potential Nanocarriers for Brain Delivery Assisted by Focused Ultrasound-Mediated Blood–Brain Barrier Disruption”. Pharmaceutics 14 (2022) 1498 (doi:10.3390/pharmaceutics14071498)
3. “In vitro evaluation of polymeric nanoparticles with a fluorine core for drug delivery triggered by focused ultrasound.
Colloids Surf”. B 200 (2021) 111561 (doi:10.1016/j.colsurfb.2021.111561)
4. “Molecular study of ultrasound-triggered release of fluorescein from liposomes. “
Langmuir 37 (2021) 3868-3881 (doi:10.1021/acs.langmuir.0c03444)
5. “Ultrasound-triggered delivery of paclitaxel encapsulated in emulsion at low acoustic pressures. “
J. Mat. Chem. B 8 (2020) 1640-1648 (doi:10.1039/c9tb02493j)