PhD in UPtoPARIS MSCA programme : Combinatorial drug screening with droplet microfluidics

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Lieu de travail :

Paris - Ile-de-France - France

Intitulé du sujet :

Combinatorial drug screening with droplet microfluidics

Champs scientifiques :



Imaging in depth biological tissues with Light for medical diagnosis in a major issue, e.g. early tumors detection, since acoustical and optical contrasts deliver complementary information.

Due to multiple scattering processes, a conventional optical imaging is limited beyond the mm range, corresponding to a transport mean free path (l*). The coupling between Light and Ultrasound (US) opens access to a local optical information (absorption, scattering) localized by the ultrasound, ballistic for frequencies beneath 20MHz. Typically, we perform images with 500 microns-resolution or less through scattering objects of several cm.

We have developed at Institut Langevin a coherent technique - Ultrasound Optical Tomography (UOT) - based on the acousto-optic effect : light crossing the US is partly shifted from the US frequency (so called the tagged-photons). UOT consists in counting the tagged-photons – a few in thick biological tissues : if the US locates in an optical absorber, their amount is reduced (light is absorbed), thus a scan of the US over the volume images the OPTICAL properties of the sample, LOCALIZED by the US. Detection of the tagged-photons is quite complex, since one has to compose with a speckle character at the output of the sample. We have developed adaptive holography techniques in real time (two-wave mixing) using non-linear materials (e.g. photorefractive crystals) sensitive within the diagnosis optical window (650-1100nm). The technique uses a US imaging device, meaning that we are able to recover an ultrasound and an optical image (bi-modal technique). Until recently, the US system performed a focused excitation, not optimized in terms of acquisition speed, and sensitivity. This is partly solved in exciting the US under plane waves with multi-angle incidences (international patent deposited), improving the acquisition speed by a factor of 30 [1], though with a loss of transverse resolution. We plan to recover this resolution still with a US structured plane waves excitation (2 patents have been recently deposited).

The development of those techniques will be an important point during the PhD (software, experimental development),in particular in designing custom UOT-probes (combination of US probes and optical input/output fibers), in the aim to push the method in-vivo on small animals with the help of biologist colleagues (collaborations are under progress). The concept will be used with an adaptive holographic [2] setup, but also with a more recent version that directly selects the tagged-photons using an ultra-narrow filter (10^-6nm) created within a rare-earth doped inorganic crystal at Helium temperature (spectral holeburning mechanism).

[1] Ultrafast acousto-optic imaging with ultrasonic plane waves,
Laudereau et al., Vol. 24, No. 4 | OPT. EXP. 2016
[2] Two-color interpolation of the absorption response for quantitative acousto-optic imaging,
M. Bocoum, Opt. Lett. 43, 399-402, 2018
3i Aspect of the proposal

The photonics project we plan to develop is potentially applicable in biotechnology, but some developments need to be performed further in laboratory in order to be mature. Once demonstrated in vivo (under progress), the different techniques we develop can have an important impact in biomedical imaging. In particular, a multi-wavelength UOT measurement can lead to important information on intrinsic markers as haemoglobin/oxy-haemoglobin (oxygen saturation ratio measurement), encountered in many pathologies. Our team has regular contacts with Thalès Research and Technology (TRT), where close problematics occur in ultrafast Radio-Frequency detection with an optical carrier, and LIDAR technologies.
This experimental project is at the crossroad of many fields, since it involves the monitoring of specific acoustic waves, optical methods of non-conventional wavefront adaptive holographic techniques using non-linear photosensitive crystals. From a technological point, the integration of optics and acoustics is an important aspect in the aim to realize a compact UOT probe, e.g. using optical fibers. At term, the optical detection could be implemented within a commercial ultrasound imaging device, in order to obtain a bi-modal imaging system. In a first step the project will be tested on calibrated scattering phantoms ; at present, we are launching a process in order to be able to perform measurements on small animals and biopsies with biologist colleagues we are collaborating with.
The project is part of a national fundings (Inserm – Plan cancer) we have obtained last year, with four laboratories from the Paris Area, with whom we are in close contact for many years. Though without official fundings yet, our team is in close contact with European labs working on the subject (University College London - UK, Nottingham University – UK, DTU Fotonik Roskilde- Denmark, University of Lund – Sweden, Tyndall University Cork - Ireland). François Ramaz has spent two weeks at the University of Lund in november 2017 as an invited professor, in the group of Dr Stefan Kröll.

3i aspect of the project

By combining cutting-edge microtechnology and biotechnology, this project will push the current frontier in drug discovery, by introducing a 100 to 1000 fold increase in measurement throughput compared to conventional microtiter plate robotic systems. The considerable throughput improvement proposed in this project is made possible by the combination of droplet microfluidics, molecular bar-coding, Next Generation Sequencing and bioinformatics. The combination of these technologies is critical to cross the required throughput barrier, as they altogether provide a consistent scaling up from sample preparation to data interpretation. The project will be led in collaboration with Sander Tans. Pr Tans is the PI of the Biophysics Lab at AMOLF (ND) and professor at Delft University. These visits of the PhD in the AMOLF lab will be aimed at characterizing and modelling bacteria strains showing differential response to antibiotic combinations, notably evolve experimentally antibiotic resistant, but non-pathogenic, strains.

Nature du financement

Financement public/privé
Précisions sur le financement

Présentation établissement et labo d’accueil

The Hosting Lab

This project will be led in the UMR Chemistry Biology Innovation (CBI) 8231 (dir. Jérôme Bibette). CBI comprises teams with expertise ranging from microbial evolution, to biochemistry, physico-chemistry, microfluidics and analytical techniques.
Philippe Nghe and Andrew Griffiths are members of the Laboratory of Biochemistry (LBC), which develops droplets microfluidics technology to performed very high-throughput (1000 Hz) biochemical operations, with applications in single cell analysis (phenotyping and genotyping) and drug screening.
Jérôme Bibette is an expert in emulsion physico-chemistry, the LCMD having developed a number of droplet systems with well controlled exchange properties.

Name of the supervisor : Philippe Nghe
Name of the co-supervisor : Andrew Griffiths

Site web :

Profil du candidat

Given the highly interdisciplinary character of the project, the PhD candidate could either :

- have a strong engineering background, including a Master degree in physics or chemistry, and be highly motivated to learn the microbiology and molecular biology aspects of the project.

- have a background in biology, with an emphasis on systems biology and quantitative approaches, and be highly motivated for engineering challenges.

An experience in droplet-based microfluidics is not required.
Flexibility, autonomy, ability to work in a highly multidisciplinary team and good interpersonal skills are essential. Sense of entrepreneurship and a motivation for industrial challenges are a highly valued.

Date limite de candidature

> 25 et < 35 K€ brut annuel

Applications must be submitted on the UPtoPARIS website :
More information is available in the "How to apply" section of the website


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