Design of 4D printable and biocompatible polysaccharide hydrogels for biomedical applications.

The 3D printing of stimuli-responsive materials is called “4D printing” and is of great interest for the development of innovative medical devices (dynamic synthetic tissues, soft robotic actuators, controlled drug release systems etc.). Reported examples of these printable smart materials are programmed to autonomously change their shape in response to specific stimuli (e.g. temperature, light, magnetic field, pH, etc.) but are almost exclusively based on synthetic polymers.
To transpose this concept to biomedical application, this PhD project aims at designing 3D printable, biocompatible and stimuli-responsive polysaccharide hydrogels. In particular, the targeted hydrogels will be able to deform under two different stimuli: (i) a temperature variation or (ii) the application of a near-infrared (NIR) beam for the material activation without deterioration of biological tissues. These will be achieved by combining (i) polysaccharide chains functionalized with thermoresponsive groups and (ii) photothermal nanoparticles capable of converting NIR light into heat.
This interdisciplinary project is at the interface between Chemistry (polymer chemistry, nanoparticle synthesis), Physical Chemistry (formulation and characterization of hydrogels), Materials Science (3D printing studies, mechanical tests) and Biology (cytocompatibility studies). An additional originality is that the experimental data collected by the PhD candidate will be fed into artificial intelligence tools which, in turn, should provide guidelines to accelerate the discovery of the targeted materials.

Geometric deep learning applied to medical applications

The PhD subject deals with geometric deep learning and its use in several medical applications.
The merging of these two domains (geometry and artificial intelligence) is at the core of the phD with the conception of SPDnet neural networks that combine both end-to-end training of frequency and spatial parameters with mathematical operations on the variety of symmetric definite-positive (SPD) matrices.
The design of such methods both from a mathematical and software point of view are part of the phD’s objectives as well as their application on public medical datasets like in electroencephalography-based brain-computer interface (BCI).
The expected results consist first in demonstrating the superiority of these geometric approaches over state-of-the-art methods used in BCI and second to identify the best architectures in different medical applications ranging from multi-array data to medical image processing.

Design of a new light-sheet microscope for the temporal monitoring of organoids-on-chip

The subject of the thesis is the development of a fluorescence light-sheet microscope for the optical characterization of organoids-on-chips and 3D organoids. The thesis will focus on the conception of a compact multi-color 3D system, to allow time-lapse imaging of multi-scattering 3D samples directly in a cell culture incubator. The work will begin with a clear understanding of the miniaturization process on the quality of the images. The excitation will be correctly model to avoid optical artefacts and to allow the deepest penetration into the biological tissue. The candidate will be responsible to test different optical strategies as well as different excitation wavelengths. As a final step, the system will be characterized in a cell culture incubator for the morphological and functional monitoring of organs-on-a-chip and 3D organoids using specific fluorescent markers. If needed, novel modifications of the microfluidic chamber with integrated optical functions will be proposed. The research program will mainly focus on the morphological and functional monitoring of two samples: pancreatic organoids on a microfluidic chip and 3D brain organoids.

Wavefront shaping for photobiomodulation - Application to neurodegenerative diseases

Photobiomodulation consists in using light, in the visible/near infrared range, to treat or slow down the evolution of a pathology. In the case of Parkinson’s disease, a neurodegenerative disease without any curative treatment so far, the brain region responsible for symptoms is located in the midbrain area, deep in the brain, which requires neurosurgery to position the optical implant. At Clinatec, 3 patients have been implanted with such an active implantable medical device so far, following years of preclinical research that showed the potential of the technique. At the moment the photon propagation in brain is mostly driven by scattering; therefore scattered photons reach regions of the brain that should not be stimulated and that also limits the yield. In this context, the PhD goal will be to develop wavefront shaping for a clinical use to restrain scattering to go towards a clinical use.
The technique has been published in 2007 by Vellekoop and consists in acting on the amplitude and phase of a coherent light source to compensate for scattering and therefore focus light in tissue. The final goal is to illuminate exclusively the desired brain region. The PhD work will include experimental and fundamental developments in optics, particularly for the feedback control (photoacoustics signal generated by the light pulse), but also in numerical simulation. The PhD will be located between Clinatec and Optics and Photonics lab of CEA LETI, and directed by LiPhy at UGA.

Multi-target capture strategy for micro total analysis systems

The concentration of biomarkers and pathogens in biological samples is generally limited by the preparation of these samples after their collection. In addition, their detection, when based on an antibody-antigen capture reaction, can be difficult to optimize within biosensors. If the approach which consists of functionalizing a wall to capture molecules or particles flowing in a micro channel seems simple at first glance, the results are often below expectations. On the one hand, the capture of molecules is a convection-diffusion problem; on the other hand, capturing particles must also take into account the pressure distributions on them. Thus the proposed thesis subject is part of a project to optimize the capture and concentration of all types of biological and biochemical targets within fluidic microsystems.

The thesis project will begin by the exploration of models dedicated to the capture of biochemical and biological targets within a microchannel. The objective of this task is to specify the optimal and common conditions for capturing all targets of interest. Among all possible configurations, maintaining functionalized beads dispersed in volume by an adequate field will be favored because it is expected to be optimal. This configuration will be a subject of particular attention, especially as it offers an original microfluidic implementation, particularly in the study of organoids on chips to capture, concentrate and monitor their secretions.

For this project, the laboratory is looking for a student motivated by experimental work in microfluidics with a detailed understanding of the involved physical phenomena. In addition, knowledge of classic molecular biology tests will be appreciated. Skills in numerical simulation are also an asset when applying for the proposed thesis.

Optimization of gamma radiation detectors for medical imaging. Time-of-flight positron emission tomography

Positron emission tomography (PET) is a nuclear medical imaging technique widely used in oncology and neurobiology. The decay of the radioactive tracer emits positrons, which annihilate into two photons of 511 keV. These photons are detected in coincidence and used to reconstruct the distribution of tracer activity in the patient's body.
We are offering you the opportunity to contribute to the development of an ambitious, patented technology: ClearMind.
You will work in an advanced instrumentation laboratory in a particle physics environment.
Your first task will be to optimize the "components" of ClearMind detectors, in order to achieve nominal performance.
We'll be working on scintillating crystals, optical interfaces, photo-electric layers and associated fast photo-detectors, readout electronics.
We will then characterize the performance of the prototype detectors on our measurement benches, which are under continuous development. The data acquired will be interpreted using in-house analysis software written in C++ and/or Python.
Finally, the physics of our detectors will be modeled using Monté-Carlo simulation (Geant4/Gate software), and we will compare our simulations with our results on measurement benches. A special effort will be devoted to the development of ultra-fast scintillating crystals in the context of a European collaboration.

Porous materials integrated into devices for glycomic analysis in hospitals.

Glycomics involves identifying oligosaccharides (OS) present in a biological fluid as a source of biomarkers for diagnosing various pathologies (cancers, Alzheimer's disease, etc.). To study these OS, sample preparation involves 2 key phases, enzymatic cleavage (breaking the bond between OS and proteins) followed by purification and extraction (separation of OS and proteins). However, the materials currently used in the protocols impose numerous manual and time-consuming steps, incompatible with high-throughput analysis.

In this context, the LEDNA laboratory specialized in materials science has recently developed a sol-gel process for the manufacture of Hierarchical Porosity Monoliths (HPMs) in miniaturized devices. These materials have provided a proof of concept demonstrating their value for the second stage of glycomic analysis, i.e. the purification and extraction of oligosaccharides. The LEDNA is now looking to improve the first step, corresponding to enzymatic cleavage, which has become a limiting factor in the glycomics analysis process. Functionalization of porous materials, in particular HPMs, with enzyme would enable simple sample preparation in just a few hours with a single step.

The aim of this thesis is therefore to show that the use of porous materials with a dual function - catalytic and filtration - applied to the preparation of samples for glycomic analysis is a relevant means of simplifying and accelerating glycomic analysis, as well as employing them in hospital-related studies to identify new biomarkers of pathologies.

The research project will involve developing a device incorporating porous materials with catalytic and filtration functions. Several aspects will be addressed, ranging from the synthesis and shaping of these materials to characterization of their textural and physico-chemical properties. Particular emphasis will be placed on enzyme immobilization. The most promising prototype(s) will be evaluated in a glycomic analysis protocol, verifying the oligosaccharide profiles obtained from human biofluids (plasma, milk). Physico-chemical characterization will involve a variety of techniques (SEM, TEM, etc.), as well as characterization of porosity parameters (nitrogen adsorption, Hg porosimeter). Oligosaccharides will be analyzed by high-resolution mass spectrometry (mainly MALDI-TOF).

For this multidisciplinary thesis project, we are looking for a student chemist or physical chemist, interested in materials chemistry and motivated by the applications of fundamental research in the field of new technologies for health. The thesis will be carried out in two laboratories, LEDNA for the materials part and LI-MS for the use of materials in glycomics analysis. The research activity will be carried out at the Saclay research center (91).

Development of dense and fluidized granular beds in microfluidic channels for healthcare applications

The major public health problem of sepsis requires breakthrough technologies for ultra-fast diagnosis. Dense, fluidized granular beds are ideal systems for liquid-solid or gas-solid exchange processes. They are widely used in industry thanks to their high surface-to-volume ratio. Over the past decade, microfluidics and lab-on-a-chip have enabled numerous advances, particularly in biological sample preparation. We propose to develop a versatile microfluidic platform that will enable the creation of such dense, fluidized beds. We will first work on the incorporation of membranes into microchannels, drawing on the patented know-how developed in the laboratory. We will then study and characterize the granular beds, and finally test them for the detection of bacteria in biological samples. This work will be carried out in collaboration with our physicists (LEDNA) and biologist (LERI) partners at CEA Saclay.

Aptamer-based molecular fingerprinting for the diagnosis of neurodegenerative diseases.

The PhD project consists of developing a novel diagnostic capable of detecting the signature of a pathological forms of protein intimately associated to neurodegenerative diseases. The aim is to improve the diagnosis of patients suffering from neurodegenerative proteinopathies due to the aggregation of the proteins alpha-synuclein and tau, e.g. Parkinson’s and Alzheimer’s diseases. This project builds on our team's expertise in aptamer technology (nucleic acid-based ligands) and the production of structurally distinct aggregates of alpha-synuclein and tau that we demonstrated to trigger distinct synucleinopathies and tauopathies. During this work, different aptamer libraries will be evaluated against different polymorphs of protein fibers found in different diseases. These aptamers will then be used to design a diagnostic test using a recently patented method (AptaFOOT-Seq). The student should have a strong interest in biomedical research, particularly the molecular aspects of biology. This thesis will provide in-depth training in RNA and protein synthesis and purification, directed molecular evolution, quantitative PCR (qPCR and droplet PCR), high-throughput sequencing, bioinformatics analysis and structural biochemistry. The aim of the thesis is to obtain results that can be exploited in terms of intellectual property and to enable the student to envisage a career in an academic or industrial environment.