Development of new antidote formulations based on chitosan-coated bilosome with active targeting, against intoxications by organophosphorus neurotoxins for nasal administration

The aim of this innovative project is to develop and validate the biological efficacy of new formulations including original and patented reactivators (CNRS/IRBA). These molecules present a large spectrum of action against acetylcholinesterase (AChE) inhibited by Organophosphorus Neurotoxins (NOPs), hence the interest in developing centrally effective antidotes for nose-to-brain administration. The novel bilosome-based formulations designed at CEA will be administered via the non-invasive nasal route, which could enable delivery to the brain either after passage into the systemic circulation, or by absorption through the olfactory nerves which provides direct access to cerebrospinal fluid and brain parenchyma, bypassing the blood-brain barrier (BBB). The approval by health authorities of Nyxoïd (naloxone) and Valtoco (diazepam) demonstrates the relevance of nasal therapeutic approaches to emergency situations (e.g. overdose, epilepsy) in subjects who may be unconscious or in respiratory distress. The project's innovations could ultimately interest the recently-created french company OPGS Pharmaceuticals, for the valorization of the work with the preclinical development (toxicity, selectivity...) and a possible industrialization of this medical countermeasures.
The thesis will take place in TOULOUSE.

Robustness of thick metallizations made on 3D ceramic substrates.

A robust and high quality metallization of 3D ceramic substrates is a key element of the success of this project and a necessity for a future industrial development of the research work that will be carried out during these two theses.
The work in progress on the material platform of the CEA of Toulouse already provides interesting results which allow to consider the first subject proposed here. However, during this work, we could highlight that a joint work between the material and power teams allows to improve the quality of the results by integrating the design for reliability aspect to the material. This is why, this second subject aims to treat in detail the realization of 3D metallized ceramic parts, in order to understand the evolution of the performances of the parts made according to the ceramics used, the metallization techniques, the nature of the metals, the designs, the processes... used.
Also, this thesis work will begin with the realization of flat ceramic structures on which will be carried out tests of metallization by using various techniques such as brazing of tracks, the deposit of layers of adhesion followed by electroplating, ...
These different techniques and interfaces will be subjected to aging and mechanical tests. In addition, morphological characterizations will be performed. The quality of the interfaces can also be evaluated by means of dielectric characterizations (measurement of dielectric rigidity, dielectric losses, I(V)).
Specimens will also be made to verify the mechanical, dielectric and thermal characteristics of the ceramic, which will provide the first thesis topic with material data.
Moreover, during the whole thesis, test vehicles will be realized in order to define the design rules to be used for the dimensioning of the power module.
Finally, 3D metallized ceramic parts will be realized and characterized in order to allow the realization of the power module defined in the first subject of thesis.

Electrothermal optimization of Wide band gap power modules by functionalization of 3D ceramic substrates made by 3D ceramic printing (Al2O3/AlN)

In order to take advantage of Wide band gap components (GaN and SiC), it has been demonstrated that it is necessary to reduce the parasitic elements in the switching cells and therefore in the power modules. The 'trivial' solution is to make the power modules more compact to solve this problem of parasitic elements. However, this is often done at the expense of thermal performance. The subject proposed here has therefore the ambition to not neglect any of these aspects by taking advantage of the new freedoms offered by ceramic 3D printing in terms of design and performance.
Also, this thesis will start with a study of current wide band gap power modules, which will allow the PhD student to complete his knowledge and to understand the limits of these architectures: parasitic elements, parallelizations, signal integrity, thermal management, partial discharges ...
From this first assessment, which is intended to be as exhaustive as possible, we propose to use 3D FEM simulation to find a set of topologies that can be produced by 3D ceramic printing and that will be able to respond to the problems identified.
Based on these results, a new high voltage power module (800V-400A) can then be designed and built.

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