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.
From angstroms to microns: a nuclear fuel microstructure evolution model whose parameters are calculated at the atomic scale
Controlling the behavior of fission gases in nuclear fuel (uranium oxide) is an important industrial issue, as fission gas release or precipitation limit the use of fuels at extended burn-ups. The gas behavior is strongly influenced by the material’s microstructure evolution due to the aggregation of irradiation-induced defects (gas bubbles, dislocation loops and lines). Cluster dynamics (CD) (a kind of rate theory model) is relevant for modelling the nucleation/growth of the defect clusters, there gas content and the gas release. The current model has been parameterized following a multiscale approach, based on atomistic calculations (ab initio or empirical potentials). This model has been successfully applied to annealing experiments of UO2 samples implanted with rare gas atoms and has emphasized the impact of the irradiation damage on gas release. The aim of this PhD thesis is now to improve the model, particularly the damage parameterization, and to extend its validation domain through in depth comparison of simulation with a large set of recently obtained experimental results, such as gas release measurement by annealing of sample implanted in ion beam accelerator, bubble and loop observation by transmission electrons microscopy, and positron annihilation spectroscopy. This global analysis will finally yield an improved parameterization of the CD model.
The research subject combines a “theoretical” dimension (improving the model) with an “experimental” one (interpreting existing experiments or designing some new ones). The variety of techniques will introduce the candidate into the experimental world and thus broaden his scientific skills. The candidate will also have to manage collaborations for the experiments analysis, for the model development and for the specification of additional atomistic calculations. He will be at the interface of atomistic techniques, large-scale simulation and various experimental techniques. Therefore, he will develop a broad view of irradiation effects in materials and of multi-scale modelling in solids in general.
This project is an opportunity to contribute to the overall development of numerical physics applied to multi-scale modeling of materials, occupying a pivotal position and adopting a global viewpoint. This will allow experiencing oneself the way computed fundamental microscopic data finally helps solving complex practical issues.
Further readings:
Skorek et al. (2012). Modelling Fission Gas Bubble Distribution in UO2. Defect and Diffusion Forum, 323–325, 209.
Bertolus et al. (2015). Linking atomic and mesoscopic scales for the modelling of the transport properties of uranium dioxide under irradiation. Journal of Nuclear Materials, 462, 475–495.
Assisted generation of complex computational kernels in solid mechanics
The behavior laws used in numerical simulations describe the physical characteristics of simulated materials. As our understanding of these materials evolves, the complexity of these laws increases. Integrating these laws is a critical step for the performance and robustness of scientific computations. Therefore, this step can lead to intrusive and complex developments in the code.
Many digital platforms, such as FEniCS, FireDrake, FreeFEM, and Comsol, offer Just-In-Time (JIT) code generation techniques to handle various physics. This JIT approach significantly reduces the time required to implement new simulations, providing great versatility to the user. Additionally, it allows for optimization specific to the cases being treated and facilitates porting to various architectures (CPU or GPU). Finally, this approach hides implementation details; any changes in these details are invisible to the user and absorbed by the code generation layer.
However, these techniques are generally limited to the assembly steps of the linear systems to be solved and do not include the crucial step of integrating behavior laws.
Inspired by the successful experience of the open-source project mgis.fenics [1], this thesis aims to develop a Just-In-Time code generation solution dedicated to the next-generation structural mechanics code Manta [2], developed by CEA. The objective is to enable strong coupling with behavior laws generated by MFront [3], thereby improving the flexibility, performance, and robustness of numerical simulations.
The doctoral student will benefit from guidance from the developers of MFront and Manta (CEA), as well as the developers of the A-Set code (a collaboration between Mines-Paris Tech, Onera, and Safran). This collaboration within a multidisciplinary team will provide a stimulating and enriching environment for the candidate.
Furthermore, the thesis work will be enhanced by the opportunity to participate in conferences and publish articles in peer-reviewed scientific journals, offering national and international visibility to the thesis results.
The PhD will take place at CEA Cadarache, in south-eastern France, in the Nuclear Fuel Studies Department of the IRESNE Institute [4]. The host laboratory is the LMPC, whose role is to contribute to the development of the physical components of the PLEIADES digital platform [5], co-developed by CEA and EDF.
[1] https://thelfer.github.io/mgis/web/mgis_fenics.html
[2] MANTA : un code HPC généraliste pour la simulation de problèmes complexes en mécanique. https://hal.science/hal-03688160
[3] https://thelfer.github.io/tfel/web/index.html
[4] https://www.cea.fr/energies/iresne/Pages/Accueil.aspx
[5] PLEIADES: A numerical framework dedicated to the multiphysics and multiscale nuclear fuel behavior simulation https://www.sciencedirect.com/science/article/pii/S0306454924002408
Optimizing the estimation of the mass of the nuclear material by advanced statistical methods
In order to comply with safety and security standards for nuclear waste storage and non-proliferation treaties, producers of waste containing uranium or plutonium often need to measure the amount of nuclear materials in their radioactive waste. The radiological characterization of nuclear materials by passive and active neutron measurement is one of the historical research activities of the Nuclear Measurement Laboratory (LMN) of the CEA/IRESNE Institute.
Proportional counters filled with 3He or covered with boron are the reference detectors used for these techniques, which are reference tools for measuring plutonium or uranium. In passive measurement, neutron coincidence makes it possible to discriminate spontaneous fission events associated in particular with 240Pu from neutrons resulting from (a, n) reactions. In active measurement, the active neutron interrogation technique (DDT) provides information on the amount of fissile isotopes inside a waste package.
In order to reduce the sensitivity of neutron measurement techniques to matrix attenuation and contaminant localization effects, one of the objectives of the thesis is to study the coupling of different types of measurements, such as channel-by-channel measurement, emission tomography or high-energy X-ray radiography, within a framework of advanced statistical methods. The thesis also aims to evaluate the contribution of advanced statistical methods, such as regression algorithms, Bayesian approaches (among which the Gaussian process), and neural networks, to reduce the uncertainty associated with the plutonium mass.
Particular attention will be paid to the treatment of heterogeneities in the matrix and the distribution of the radioactive contaminant. The influence of these heterogeneities can be particularly difficult to quantify, requiring not only the use of advanced statistical methods, but also an in-depth experimental study using the SYMETRIC neutron measurement station of the CEA/IRESNE Institute.
The thesis work will be carried out at the CEA site of Cadarache Nuclear Measurement Laboratory, which is a professional laboratory, expert in non-destructive methods of radiological, elementary and physical characterization of objects whether radioactive or not. It is equipped with leading technological platforms, located in the TOTEM facility (neutron and gamma measurements) and the INB Chicade (SYMETRIC platforms for neutron measurement and CINPHONIE for high-energy RX imaging). Finally, the doctoral student will work in a collaborative environment where the different teams interact closely with each other.
Simplified modelling of calcination in a rotating tube
As part of the reprocessing of uranium oxide spent fuel, the final high-level liquid waste is packaged in glass using a two-stage process, calcination followed by vitrification. Calcination gradually transforms the liquid waste into a dry residue, which is mixed with preformed glass in a melting furnace. The calciner consists of a rotating tube heated by a resistance furnace. The calcined solutions consist of nitric acid and compounds in their nitrate form or insolubles in the form of metal alloys. In order to improve control of the calciner, it is proposed to model it.
The modelling will consist of creating and then coupling three models:
- A thermodynamic model to represent the transformations undergone by the material. This part will almost certainly involve ATD and ATG measurements, coupled with a design of experiments type approach (1st year).
- A material flow model. The literature already contains very simplified principles for representing the flow in a rotating tube calciner, but we will have to be innovative, in particular by defining tests to characterise the flow of the material during the calcination process (2nd year).
A thermal model that will take into account exchanges between the furnace and the calciner tube as well as exchanges between the material and the tube. The exchange coefficients will have to be characterised (1st year).
Combining these three models (3rd year) will give rise to an initial simplified calcination model. This model will be used to help control the calcination stage and also to train operators to control this apparatus.
You will be working in the LDPV, a multidisciplinary team (process, chemistry, fluid mechanics, modelling, mechanics, induction) comprising 16 engineers and technicians. A team with 30 years' experience in vitrification processes, recognised both nationally and internationally.
Towards a high spatial resolution pixel detector for particle identification: new detectors contribution to physics
Future experiments on linear colliders (e+e-) with low hadronic background require improvements in the spatial resolution of pixel vertex detectors to the micron range, in order to determine precisely the primary and secondary vertices for particles with a high transverse momentum. This kind of detector is set closest to the interaction point. This will provide the opportunity to make precision lifetime measurements of short-lived charged particles. We need to develop pixels arrays with a pixel dimension below the micron squared. The proposed technologies (DOTPIX: Quantum Dot Pixels) should give a significant advance in particle tracking and vertexing. Although the principle of these new devices has been already been studied in IRFU (see reference), this doctoral work should focus on the study of real devices which should then be fabricated using nanotechnologies in collaboration with other Institutes. This should require the use of simulation codes and the fabrication of test structures. Applications outside basics physics are X ray imaging and optimum resolution sensors for visible light holographic cameras.
Development of thin film negative electrodes for Li-free all-solid-state batteries
The aim of this work is to develop 'Li-free' negative electrodes for new generations of high energy density all-solid-state lithium batteries. The function of this type of electrode is to provide a significant gain in energy density in the battery, to facilitate its manufacture by eliminating the need to handle lithium metal and, most importantly, to enable the formation of a homogeneous, dendrite-free lithium film when the battery is charged.
These electrodes will be based on the functionalisation of a metal collector with thin-film materials comprising at least one lithiophilic material (typically a compound that can be alloyed with lithium) and an inorganic ionic conductor. These electrodes are prepared by physical vacuum deposition processes such as sputtering or thermal evaporation. It will therefore be necessary to study the influence of the composition and structure of the lithiophilic layer on the nucleation and growth mechanism of the lithium film and on the evolution of the electrode during charge/discharge cycles. The role of chemical/mechanical interactions with the ionic conducting layer will also be investigated.
This work, which is part of a national CEA/CNRS joint project, will be carried out at the CEA Tech site in Pessac, which has a full range of vacuum deposition and thin film characterisation equipment, in close collaboration with ICMCB CNRS in Bordeaux. It will benefit from the many characterisation resources (confocal optical microscopy, SEM/cryo FIB, ToF-SIMS, SS-NMR, µ-XRD, AFM,...) available in the various partner laboratories involved in the project.
Sub-10nm CMOS performances assessment by co-optimization of lithography and design
While developing and introducing new technologies (ex. FDSOI 10nm CMOS), design rules (DRM) are the guidelines used to ensure that a chip design can be reliably fabricated. These rules govern the physical dimensions and spacing of various features used by the designer in the chip layout. They translate both device electrical constraints and manufacturing processes constraints. Among them, lithography and patterning processes are critical step in defining the intricate structures and features on a semiconductor wafer. The most efficient design rules can only be obtained from a co-optimization merging design and lithography constraints.
The objective of this research work is to demonstrate that the use of a digital lithography twin can improve the performance of CMOS by co-optimization of design and lithography (DTCO).
Starting from specific use cases for FDSOI 10nm CMOS technologies, and using advanced lithography simulation tools, the candidate would :
- Develop novel characterization methods to assess lithography process capabilities (hotspot prediction).
- Assess design rules with respect to the lithography process capabilities.
- Quantify, though design rules, lithography impact on device performances.
- Identify significant both process and design limitations and propose paths to challenge them.
As PhD student of CEA-Leti, you will join a technology research institute dedicated to micro and nanotechnologies, within a dynamic and international research environment. You will join the Computational Patterning Laboratory with strong connections with integrated circuit design experts of CEA-Leti. You will benefit from the exceptional facilities of the institute's 300mm clean room and from state-of-the art lithography software tools.
You will be encouraged to publish your work and participate to international conferences and workshops.
CCA-secure constructions for FHE
Fully Homomorphic Encryption (FHE) is a corpus of cryptographic techniques that allow to compute directly over encrypted data. Since its inception around 15 years ago, FHE has been the subject of a lot of research towards more efficiency and better practicality. From a security perspective, however, FHE still raises a number of questions and challenges. In particular, all the FHE used in practice, mainly BFV, BGV, CKKS and TFHE, achieve only CPA-security, which is sometimes referred to as security against passive adversaries.
Over the last few years, a number of works have investigated the security of FHE in the beyond-CPA regime with new security notions (CPAD, FuncCPA, vCCA, vCCAD, and others) being proposed and studied, leading to new attacks and constructions and, overall, a better understanding of FHE security in that regime.
With respect to CCA security, recent works (2024) have defined new security notions, which are stronger than CCA1 and shown to be achievable by both exact and approximate FHE schemes. Leveraging on these advances, the present thesis will aim to design practical FHE-style malleable schemes enforcing CCA security properties, at least for specific applications.
Water at the hydrophilic direct bonding interface
The microelectronics industry is making increasing use of hydrophilic direct bonding technology to produce innovative substrates and components. CEA LETI's teams have been leaders in this field for over 20 years, offering scientific and technological studies on the subject.
The key role of water at the bonding interface can be newly understood thanks to a characterization technique developed at CEA LETI. The aim of this thesis is to confirm or refute the physico-chemical mechanisms at play at the bonding interface, depending on the surface preparations and materials in contact.
A large part of this work will be carried out on our cleanroom tools. The characterization of surface hydration using this original technique will be complemented by standard characterizations such as adhesion and adherence energy measurements, FTIR-MIR and SIMS analyses, and X-ray reflectivity at ESRF.