Architecture of small animal single photon emission tomograph.
Medical imaging, a source of major innovations, presents remarkable potential for meeting new challenges with the growing demand for precision medicine, which requires cutting-edge diagnostic and therapeutic approaches personalized for each patient.
In this context, CEA-Leti proposes a PhD internship to develop a dedicated preclinical SPECT (Single Photon Emission Tomography) imager that will provide the performance (spectral information, high resolution, and high sensitivity) needed by researchers developing new radiopharmaceuticals.
The laboratory has a recognized expertise on CZT (Cadmium Zinc Telluride) semiconductor imagers enabling better spatial and energy resolution than scintillators used by most systems. They open new opportunities for emission imaging like easier Compton imaging, multi-isotope imaging and better contrast.
The candidate will have to handle the following tasks:
1. Study the state of the art of small animal SPECT imagers to participate with the team to the choice of system specification and choice of a draft architecture.
2. Simulate this architecture by using Monte-Carlo codes and optimize free parameters.
3. Design and manufacture the prototype system, with the help of the team including system engineers.
4. Test and validate the imaging capabilities, using reconstruction algorithms provided by the team.
The PhD will be conducted inside an instrumentation laboratory with access to acquisition electronics, detectors, motorized mechanics, gamma-ray sources and processing/simulation software. The candidate will also work in collaboration with a clinical and preclinical centre (at Orsay’s hospital) for conducting imaging test on phantoms and animals.
Non-invasively exploring the cerebellum microstructure with magnetic resonance
To better diagnose and monitor brain diseases, we need “non-invasive biopsies” to access the tissue cell-type composition and state without opening the skull. Magnetic resonance imaging (MRI) research efforts attempt to tackle the challenge but often lack cellular specificity because of the ubiquitous nature of water. Diffusion-weighted magnetic resonance imaging (dMRS) measures diffusion of intracellular and partly cell specific molecules in a region of interest, and forms a solid basis for resolving cell-types non-invasively. Among challenges, resolving signal contributions from the different cerebellar neurons could help monitor and understand neurodevelopmental and ataxic disorders. The cerebellum is a brain region representing 10% of the brain volume but containing more than half of the brain neurons, with the very large and complex Purkinje cells and the very small and round granule cells, both having very different functions and metabolism. The PhD project aims to disentangle these cells with complementary strategies: a classical dMRS approach and a quantum dMRS approach confronted to the state-of-the-art microstructure MRI methods.
Fluctuations microscopy for functional imaging of organoids
Phase contrast microscopy and fluorescence microscopy are the two pillars of modern biological imaging. Phase contrast reveals the morphology of the sample, while fluorescent labeling provides specificity to the process of interest. In both cases, the image is the average value of the measured signal. In this thesis, we propose to focus not on the average value, but on the fluctuations observed in phase contrast. This new contrast will be called Fluctuations Imaging. The fluctuations arise from the active and passive transport phenomena that characterize cellular machinery, and it can be assumed that the level of fluctuations is correlated with cellular activity. The objective of the thesis is to detect phase contrast fluctuations, quantify them, and link them to a process of interest using machine learning methods. The object of study will be lymphocyte activation, which is a critical parameter for monitoring rejection in certain patients with type 1 diabetes who have undergone islet transplantation. Fluctuations Imaging would enable tracking without labeling, simplifying the monitoring protocol. The expected work is (i) optimizing a phase contrast microscope to detect fluctuations, (ii) analyzing image sequences to quantify them, and (iii) implementing the developed method on various biological models, some of which will be pancreas-on-a-chip organs. This thesis, at the intersection of instrumentation, biophysics, and biology, is intended for a student with a background in optics, physics, or equivalent, with a good knowledge of image processing and a strong interest in applications in biology and health.
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, 40% of 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.
Image sensor-based differential phase contrast imaging
Biopharmaceutical production is booming and consists of using cells to produce molecules of interest. To achieve this, monitoring the culture and the state of the cells is essential. Quantitative phase imaging by holography is a label-free optical method that has already demonstrated its ability to measure the concentration and viability of cultured cells. However, implementing this technique in a bioreactor faces several challenges related to the high cell density. It is therefore necessary to develop new quantitative phase imaging methods, such as differential phase contrast imaging.
The objective of the PhD is to develop this technique using a specific image sensor for which a prototype has been designed at CEA-LETI. The PhD candidate will use this new sensor and develop the reconstruction and image-processing algorithms. They will also identify the limitations of the current prototype and define the specifications for a second prototype that will be developed at CEA-LETI. Finally, they will consider the design of an inline probe to be immersed in the bioreactor.
Magnetic Tunnel Junctions at Boundaries
Spin electronics, thanks to the additional degree of freedom provided by electron spin, enables the deployment of a rich physics of magnetism on a small scale, but also provides breakthrough technological solutions in the field of microelectronics (storage, memory, logic, etc.) as well as for magnetic field measurement.
In the field of life sciences and health, giant magnetoresistance (GMR) devices have demonstrated the possibility of measuring the very weak fields produced by excitable cells on a local scale (Caruso et al, Neuron 2017, Klein et al, Journal of Neurophysiology 2025).
Measuring the information contained in the magnetic component associated with neural currents (or magnetophysiology) can, in principle, provide a description of the dynamic, directional and differentiating neural landscape. It could pave the way for new types of implants, thanks to their immunity to gliosis and their longevity.
The current bottleneck is the very small amplitude of the signal produced (<1nT), which requires averaging the signal in order to detect it.
Tunnel magnetoresistances (TMR), in which a spin-polarised tunnel current is measured, offer sensitivity performance that is more than an order of magnitude higher than GMR. However, they currently have too high a level of low-frequency noise to be fully beneficial, particularly in the context of measuring biological signals.
The aim of this thesis is to push back the current limits of TMRs by reducing low-frequency noise, positioning them as break sensors for measuring very weak signals and exploiting their potential as amplifiers for small signals.
To achieve this objective, an initial approach based on exploring the materials composing the tunnel junction, in particular those of the so-called free magnetic layer, or on improving the crystallinity of the tunnel barrier, will be deployed. A second approach, consisting of studying the intrinsic properties of low-frequency noise, particularly in previously unexplored limits, at very low temperatures where intrinsic mechanisms are reached, will guide the most promising solutions.
Finally, the most advanced structures and approaches at the state of the art thus obtained will be integrated into devices that will provide the building blocks for going beyond the state of the art and offering new possibilities for spin electronics applications. These elements will also be integrated into systems for 2D (or even 3D) mapping of the activity of a global biological system (neural network) and for evaluating capabilities for clinical cases (such as epilepsy or motor rehabilitation).
It should be noted that these improved TMRs may have other applications in the fields of physical instrumentation, non-destructive testing, and magnetic imaging.
Development of an integrated solid state nanopore analysis system
The identification of biological material (DNA, RNA, proteins,…) is generally done thanks to cumbersome lab equipment and/or rely on ultra-specific and proprietary sensitive reagents. We aim to develop a new platform based on the solid-state nanopore technology which could produce label-free results on field.
One way to pierce a nanopore in an ultra-fine dielectric membrane is to use an electron beam. An ion current is obtained when placing this pierced membrane in-between two insulated reservoirs filled with electrolytes and applying a low voltage. A particle going through the pore modifies this ionic current giving us information on its size, charge or conformation.
For this technique to yield the best results we need control over each bit of the platform: the dielectric assembly and nanopore within; the high speed and precision electronic apparatus to measure ionic current; the fluidic integration and even the algorithm responsible for deciphering the current trace. Starting from the simplest setup possible, the PhD candidate will have to push forward every aspect of this ambitious project, aiming for protein sequencing, relying on the multiple expertise of the Leti and the Lambe laboratory.
Development of a bifunctionnal zwitterionic nano-coating for aptasensors - a new linker for biological probes that hinders non-specific adsorptions
The field of biosensor development frequently encounters the issue of non-specific signals. These signals often limits the performance of biosensors and complicates industrial transfers. The functionalization steps for biosensors design generally include three steps: i) functionalization of the transducer with a linker molecule, ii) immobilization of a biological probe (antibodies, aptamers, oligonucleotides...) using the linker, iii) treatment with an entity to block non-specific interactions. The literature is full of solutions that highlight the blocking of these non-specific interactions with different types of chemical or biological entities: proteins (BSA, casein...), polymers (PEG, PVP) or small molecules (ethanolamine, hexylamine...).
However, an alternative functionalization approach with a linker that offers both the ability to immobilize biological probes while ensuring the blocking of non-specific interactions represents an innovative path for the development of biosensors.
This PhD project aims to explore the design and surface functionalization with a bifunctional nano-coating responding to this approach. Regarding the blocking, zwitterionic polymers will be at the heart of the development. Indeed, numerous studies demonstrate their ability to drastically reduce the interactions of complex biological environments with surfaces that are functionalized with them. Furthermore, it is possible to exploit the chemical functions of certain types of zwitterions to immobilize biological probes on demand. After optimizing their activity in homogeneous phase, aptamers will be immobilized on silicon transducers (QCM-d and photonic chip) via the bifunctional zwitterionic nano-coating. The objective of the thesis is to obtain a proof of concept of a biosensor functionalized with this new linker that ensures the reduction of non-specific signals while ensuring the specific detection of the target considered (Tyrosinamide model) in model and complex environments derived from biomedical sector, such as serum or plasma.
Optical intradermal sensing via instrumented microneedles
Cortisol plays a central role in regulating the circadian cycle and in many essential physiological processes such as energy metabolism and immune response. Conventional monitoring of cortisol relies on single blood or saliva samples, which do not accurately reflect the temporal dynamics of its secretion. It is therefore necessary to develop innovative approaches that enable continuous, minimally invasive, and reliable measurement of cortisol concentration in patients.
The doctoral project aims to develop an original optical instrumentation system coupled with microneedles functionalized with fluorescent aptamers for continuous, minimally invasive intradermal monitoring of cortisol without the need for sampling. Within this framework, the PhD candidate will be responsible for designing and sizing the future optical microneedles intended for cortisol detection. They will set up the experimental systems required to characterize the optical microneedles fabricated within the department and test their performance in a representative environment. Finally, the PhD candidate will develop a comprehensive data processing and analysis methodology to identify the key parameters that establish a quantitative relationship between the collected signals and cortisol concentration. Altogether, this work will contribute to the development of an innovative measurement device based on cutting-edge optical emission and detection technologies available at CEA Leti, combining precision, sensitivity, compactness, and thus compatibility with in situ use.
On-line monitoring of bioproduction processes using 3D holographic imaging
The culture of adherent 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 adherents cells in near real-time. The microscope will be coupled with advanced algorithms for data reconstruction and analysis and tested on different cell models. 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.