Characterization of motor recovery in stroke patients during a BCI-guided rehabilitation
This thesis will explore the use of implanted brain-computer interfaces (BCIs) for motor rehabilitation in stroke patients. The project leverages Clinatec's WIMAGINE technology, which measures brain activity through electrocorticography (ECoG) to accurately decode patients' motor intentions. Integrating this technology into a rehabilitation protocol is expected to enhance residual motor abilities through neural plasticity. In this context, the thesis aims to implement the rehabilitation protocol with Clinatec's technical and clinical teams and to characterize motor recovery in patients during training sessions, both behaviorally and neurally. The study will include a review of current BCI-assisted rehabilitation approaches, the development of tools to monitor motor progress and measure neural plasticity indicators, as well as the optimization of rehabilitation sessions based on patients' motor performance. Motor and neural progression will be studied longitudinally over nine months, with an extended two-year follow-up to assess the durability of the benefits. Supported by the French Ministry of Research and the EU, this project offers a unique opportunity to establish the foundations of a new post-stroke rehabilitation paradigm using implanted BCIs.
The development of surfaces that limit microbial proliferation is a crucial public health issue. In the context of manned flights to remote destinations such as low Earth orbit, the Moon and possibly Mars, biological contamination represents a significant threat to crew health and the preservation of space equipment. The microflora carried by the crew in enclosed habitats constitutes an unavoidable risk, accentuated by prolonged periods of isolation and dependence on closed environment life support systems. In addition to the risks to astronauts' health, biocontamination is known to damage critical equipment on board spacecraft. Furthermore, micro-organisms exposed to the space environment can develop resistance and mutate, transforming benign microbes into pathogens. To mitigate these risks, effective measures, such as filtration systems and self-decontaminating surfaces that limit bacterial proliferation, need to be put in place. The MATISS experiment (2016-2025), in which the SyMMES and PRISM laboratories were involved, explored the use of hydrophobic coatings to reduce biocontamination on board the ISS, but further improvements are needed, in particular to find alternative solutions to perfluorinated agents and antibiotics, but also applicable to a wide range of materials. Such advances could have a wide range of applications beyond space, including food safety (packaging), implantable materials, drinking water treatment, public transport hygiene, etc. The aim of this collaborative thesis between SyMMES and CEA-Leti in Grenoble is to develop sustainable antimicrobial coatings free from harmful substances, by exploring different functionalization methods, such as the formation of self-assembled monolayers, electropolymerization on conductive materials, and in a highly original way by implementing a new cold atmospheric plasma deposition method, suitable for large surfaces, and above all applicable to a wide range of different materials.
Embedded systems for natural acoustic signals analysis while preserving privacy
The PhD topic aims at developping Embedded systems to record and analyze natural acoustic signals. When targeting city deployement, the privacy issue is raised: how can we keep a satisfactory analysis level while never record or transmit human voices?
Hyperpolarized Xenon NMR to probe the functionality of biological barriers
Optical pumping of xenon, giving rise to an intense NMR signal, is a specialty of the LSDRM team. Xenon, which is soluble in biological media, has a wide range of chemical shifts, which we use here to study the properties of cell barriers. Numerous pathologies stem from an alteration of these barriers.
In this thesis, we aim to develop a specific methodology using hyperpolarized xenon to study the functionality (integrity, permeability, selectivity) of biological barriers, using in vitro and in vivo spectroscopy and imaging. The thesis will be divided into two parts: in vitro, the aim will be to develop a device and NMR protocols for studying model cell assemblies; in vivo, studies on rodents will enable us to assess xenon's ability to reach organs more or less close to the lungs while maintaining its polarization, and to measure kinetics across barriers. This topic will enable major instrumental and methodological advances, as well as a deepening of our knowledge of selective transport processes at different biological barriers.
Development of a Multilayer Encapsulation System for the Production of Core-Shell Microcapsules Suitable for Organoid Growth
Every year, 20 million people worldwide are diagnosed with cancer, with 9.7 million succumbing to the disease (Kocarnik et al., 2021). Personalized treatment could significantly reduce the number of deaths. This thesis addresses this challenge by proposing the development of organoids derived from patient biopsies to optimize treatments.
The bioproduction of encapsulated cells in biopolymers is a rapidly growing field, with applications in personalized medicine, research, drug screening, cell therapies, and bioengineering. This thesis aims to contribute to these fields by focusing on the multilayer encapsulation of cells in biopolymers with a wide range of viscosities.
The inner layer (core) provides an optimal environment for the maturation and survival of cells or organoids, while the outer layer (shell) ensures mechanical protection and acts as a filtering barrier against pathogens.
This new thesis aims to design, develop, and study—both analytically and numerically—the architecture of a dual-compartment nozzle for the high-frequency production of monodisperse core-shell capsules. It builds upon a previous thesis completed in 2023, which focused on the detailed characterization and development of a predictive model for the generation of single-layer microcapsules using centrifugal force alone.
The formation and ejection mechanisms of multilayer capsules are complex, involving the rheological properties of biopolymers, centrifugal force, surface tension, and interfacial dynamics. The nozzle architecture must account for these properties.
The first part of this thesis will focus on understanding the multilayer formation and ejection mechanisms of microcapsules as a function of nozzle geometry. This will allow the prediction and control of capsule formation based on the rheological properties of the biopolymers. The second part will involve developing an automated system for the aseptic production of capsules. Finally, biological validation will assess the functionality and reliability of the developed technology.
To achieve the objectives of this study, the candidate will first conduct analytical and numerical studies, design the ejection nozzles, and leverage the laboratory's expertise for their fabrication. Fluidic tests on prototypes will help optimize the design, leading to the development and testing of a fully operational microcapsule production system.
The ideal candidate will have a background in physics, engineering, and fluid mechanics, with a strong inclination for experimental approaches. Prior experience in microfluidics or biology would be a valuable asset.
New rapid diagnostic tool for sepsis: microfluidic biochip for multi-target detection by isothermal amplification
Sepsis is among the main cause of death across the world, and is caused by severe bacterial infection but can also originate from viruses, fungi or even parasites. In order to drastically increase survival rates, a rapid diagnostic and appropriate treatment is of paramount importance. The commercially available tools for nucleic acid detection by qPCR are able to sense multiple targets. However, these multiplexed analyses arise from the accumulation of analysis channels or reaction chambers where only one target can be detected. The original sample has to be divided, resulting in a loss of sensibility since a smaller amount of targets is available in channels or chambers.
In order to tackle the question of “How to detect multiple targets without a loss in sensibility?”, the PhD candidate will have to develop a multiplexed detection in a single reaction chamber by localized immobilization of LAMP primers (Loop-mediated isothermal amplification) on a solid substrate like COC or glass.
The expected outcome is a biochip allowing for real-time and fast (minutes) detection of several molecular DNA targets including: primers design and selection, primers immobilization on surface, integration of the biochip into a microfluidic cartridge and data collection and management for fluorescence detection of targets.
This innovative work will provide the PhD candidate with strong skills in diverse scientific domains such as molecular biology, surface functionalization, modelling and simulation, in a very multidisciplinary working environment.
On-line monitoring of bioproduction processes using 3D holographic imaging
The culture of adherent cells on microcarriers (MCs) is a promising approach for various bioproduction applications, such as drug manufacturing and delivery, regenerative medicine, and tracking of cellular differentiation. However, the analysis of single cell morphology and behavior without affecting the substrate integrity remains a major challenge. Lens-free holographic imaging is emerging as a promising solution for real-time, non-invasive monitoring of cellular processes. This technique captures wide field of view images without requiring exogenous labeling or sample manipulation, thus preserving the integrity of the cellular environment.
This thesis proposes the development of a 3D lens-free imaging system to monitor cells on MCs in near real-time. The microscope will be coupled with advanced algorithms for data reconstruction and analysis in on-line bioreactors. The use of deep learning techniques will allow for real-time segmentation and analysis of single cells, facilitating the tracking of cellular dynamics. This innovative project paves the way to a non-invasive monitoring of 3D multicellular samples, with potential applications on organ-on-chip and more complex organoids systems.
Sperm 3D - Male infertility diagnostic tool using holography for imaging and 3D tracking
Infertility is a growing problem in all developed countries. The standard methods for the diagnostic of male infertility examine the concentration, motility and morphological anomalies of individual sperm cells. However, one in five male infertility cases remain unexplained with the standard diagnostic tools.
In this thesis, we will explore the possibility to determine the male infertility causes from the detailed analysis of 3D trajectories and morphology of sperms swimming freely in the environment mimicking the conditions in the female reproductive tract. For this challenging task, we will develop a dedicated microscope based on holography for fast imaging and tracking of individual sperm cells. Along with classical numerical methods, we will use up-to date artificial intelligence algorithms for improving the imaging quality as well as for analysis of multi-dimensional data.
Throughout the project we will closely collaborate with medical research institute (CHU/IAB) specialized in Assisted Reproductive Technologies (ART). We will be examining real patient samples in order to develop a new tool for male infertility diagnosis.
Ultra-wide-field smart microscope for the detection of egg parasite (SCREENER)
In most parasitic cycles, the free phase passes through an egg stage, which is released by the host into the environment via a complex faecal matrix, which has highly variable and often low egg concentrations. The classical detection method relies on microscopic observation of these eggs, which implies a tedious and time-consuming preparation of the sample to concentrate the eggs, with highly variable sensitivity values. This detection is crucial because, once dispersed, the eggs contaminate the environment and food, leading to cases of parasitic zoonoses in humans.
Detection in environmental and food matrices is even more complex than for faeces because of the very low number of eggs present : 1 to 10 per sample in the vast majority of cases. The thesis aims at developing a lensless wide-field imaging system that will allow the counting and identification of parasite eggs in complex matrices, while increasing sensitivity. This will make it possible to automate detection, thus opening up the possibility of investigating more samples for better health surveillance.
Early diagnosis of sepsis using a GMR sensor-based biochip
Sepsis, an extreme and deregulated immune response to an infection that then spreads through the bloodstream, can lead to organ dysfunction and death (11 million deaths worldwide every year). The patented GMR (Giant MagnetoResistance) sensor-based biochip we have developed has real potential for the early detection of pathogens involved in sepsis or biomarkers of the disease, present in very small quantities in the blood, without the need for a culture step. The innovative approach we are proposing is cross-disciplinary, since it is based on the use of magnetic nanoparticles (NPM), functionalized by monoclonal antibodies produced in the LERI laboratory, directed against target biological objects (cells, bacteria, yeasts, etc.) which are detected dynamically and simultaneously one by one by GMR sensors arranged on either side of a microfluidic channel in which they flow. Proof of concept for this biochip was obtained on a murine myeloma cell model.We were able to achieve a sensitivity and specificity with this model that makes our technique highly competitive with existing Point-of-Care tests. However, we still need to validate these results on pathogens.
During the course of the thesis, two objectives will be defined. Following on from the current thesis, the first objective of the student at the LNO will be to adapt the biochip (sensors, microfluidics and signal processing) so that it is sensitive and rapid for the detection of bacteria and yeasts involved in sepsis in blood samples. At LERI, he will optimize the magnetic labeling of bacteria and yeasts in this clinical matrix using commercial NPM functionalized with one or more antibodies directed against the target. This stage of the thesis will be carried out in close collaboration with the Service de Bactériologie et Hygiène at Hôpital Béclère (also a member of the IHU), which will recommend and supply relevant bacterial and yeast strains for detection, as well as clinical samples.One of the GMR biochips will be installed at Hôpital Béclère for measurements under real-life conditions. The second objective will be to use the GMR biochip to quantify the reduction in monocyte expression of mHLA-DR molecules, which is an indicator of the immunosuppressed state of sepsis associated with increased infectious risk and mortality.