Olfactory technology (Qi - Wei): Chinese inspiration for ecotechnology

The specificity of Chinese technological thought has been the subject of recurrent philosophical debate since the early 20th century. This discussion highlights the originality of the sensory relationship with nature expressed in Chinese writing and culture. “Olfactory technology (Qi - Wei): a Chinese inspiration for ecotechnology” explores the hypothesis that a philosophy of technology, inspired by China but open to other cultures, can renew thinking on technology in its relationship to the environment, based on the paradigm of olfaction (Wei).
This approach is based on an analysis of traditional Chinese thought developed by contemporary Chinese philosophers, in particular Gong Huanan, and shows its influence on current Chinese technological thought. It also draws on the work of specialists in olfaction, as well as Western philosophers of technology, science and the imaginary (such as Gilbert Simondon, Gaston Bachelard and Dominique Lestel).
The primary scientific challenge is to restore the olfactory paradigm of Chinese technological thought in order to examine its relationship to the environment, and then to develop a transcultural ecotechnological reflection. In the light of these analyses, we will then reconsider the imaginaries of robotic and digital technologies in order to explore new avenues of innovation. Finally, from a science fiction prototyping perspective, speculative fictions will extend the analysis by examining the impact of imaginable technologies based on the olfactory paradigm.

Multilayer encapsulation of cells by a centrifugation device

Cell encapsulation in bio-polymers is a rapidly expanding field in bioproduction, encompassing organoid or spheroid maturation, drug screening, cellular therapies, and bioengineering. This thesis contributes to these applications through the multilayer encapsulation of cells in bio-polymers with a wide viscosity range. The inner layer (core) provides a more favorable environment for the maturation and survival of cells or organoids, while the outer layer ensures mechanical protection (shell) and acts as a filtering barrier against pathogens. Laden with selected biological agents, it allows controlled interaction with the core cells of the capsule.

The objective of this thesis is to develop an innovative ejection nozzle for forming high-frequency multilayer microcapsules using centrifugal force in a laboratory centrifuge. This new thesis builds upon a completed thesis in 2023 that studied, detailed, and developed a predictive model for generating single-layer microcapsules solely through centrifugal force.

The mechanisms of formation and ejection of multilayer capsules are complex, involving the rheological properties of bio-polymers, centrifugal force, surface tension, and interfaces. The design of the ejection nozzle must consider these properties. The first part of this thesis aims to better understand the multilayer formation and ejection mechanisms of microcapsules based on the selected ejection nozzle's geometry. This understanding will enable the prediction and control of formation based on the rheological properties of the bio-polymer(s). The second part involves developing an automated system for aseptic capsule production. Finally, biological validation will confirm the developed technology.

To achieve the study objectives, the candidate must initially conduct an analytical and numerical study, design ejection nozzles, and leverage the laboratory's expertise to manufacture them. Fluidic tests will be performed on models, and the design will be optimized to create and test a microcapsule formation prototype. The candidate should have a background in physics, engineering, and fluid mechanics, with a particular talent for experimental approaches. Prior experience in microfluidics/biology would be advantageous.

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.

Development of x-ray phase contrast and dark field imaging numerical model

Since 2013, CEA List (Université Paris Saclay) has been developing phase contrast X-ray imaging methods, in particular using multi-lateral shearing interferometry. In addition to absorption information, the phase shift of X-rays provides additional contrast and sensitivity on the image, particularly for materials with low atomic numbers or low density.
Various techniques have been developed to generate a phase contrast, based in particular on the addition of a random or regular intensity modulator (sandpaper or grid). In addition, dark field imaging has emerged as a valuable complementary signal to phase contrast imaging. The dark field signal comes from the small-angle scattering of fine structures in the sample. In particular, the dark field signal has proven it sensibility to reveal features of the sample that remain invisible by conventional means. It can, for example, reveal the microstructural properties of the lung in cases of chronic obstructive pulmonary diseases.
The continuation of these developments requires the implementation of a numerical model producing sufficiently accurate images that are representative of an experimental system.
The aim of the thesis is to develop a numerical model that takes into account the phenomena of phase contrast and scattering, in particularby refraining from a classic modelling hypothesis, which is the consideration of an thin object (projected thickness hypotheseis). Failure to take this assumption into account will have to be dealt with in order to move towards phase imaging on a thick object (e.g. a thorax).
As a general rule, phase contrast is represented using models based on wave propagation. In contrast, scattering phenomena are usually simulated using a particle-based approach, often using Monte Carlo techniques. In this study, a combined approach will be developed with experimental validation.
The thesis will be carried out in CEA List with people who have solid numerical and experimental skills.

In vitro fertilization technology: microfluidic platform for non-invasive embryo reception and characterization

Infertility affects 17.5% of couples of childbearing age. Assisted reproductive technologies (ART), such as in vitro fertilization (IVF), are costly and complex procedures requiring advanced equipments and a highly skilled workforce. Successive embryo manipulations are a source of stress that can impact on embryo quality and viability. But developmental abnormalities and miscarriages are mainly caused by chromosomal number anomalies or aneuploidies. These can be detected by pre-implantation diagnosis of aneuploidies (PGD-A) followed by high-throughput sequencing (NGS). However, PGD-A remains complex and invasive, with embryo biopsy potentially having implications for embryo development.
The question the PhD student will have to answer is: can we design a technological alternative that enables both automated culture of in vitro fertilization (IVF) embryos and their selection by non-invasive methods? The project will focus on automating embryo handling, while minimizing mechanical stress, and on extracting the extra-embryonic medium for circulating DNA analysis.
Expected results include an automated microfluidic platform for handling embryos without human intervention, extraction of extra-embryonic medium for aneuploidy analysis by sequencing, and building the program basis for microfluidic technologies applied to IVF.

Protection by self-decontaminating coatings against biocontamination of surfaces

The proposed PROBIO-ES project falls within the scope of the priority defense theme « biologie, santé, NRBC », and in particular the sub-themes of protection and decontamination. Its aim is to develop self-decontaminating surfaces for a number of terrestrial and space applications. The project has been shortlisted by CNES for the award of a 1/2 thesis grant. In the context of manned spaceflights to distant destinations such as low Earth orbit, the Moon, and potentially Mars, biological contamination poses a significant threat to the health of the crew and the preservation of space equipment. The microflora carried by the crew in enclosed habitats is an unavoidable concern, heightened by prolonged periods of isolation and dependence on closed-loop life support systems. Beyond risks to astronaut health, biocontamination can damage critical equipment aboard spacecraft. Microorganisms 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 limiting bacterial proliferation must be implemented. The MATISS experiment (2016-2024) explored the use of hydrophobic coatings to reduce biocontamination aboard the ISS, but improvements are needed. This collaborative thesis between SyMMES and CEA-Leti in Grenoble aims to develop durable antimicrobial layers without harmful substances, using a new method of deposition through cold atmospheric plasma, suitable for large surfaces. The PROBIO-ES project is therefore fully in line with the « biologie, santé, NRBC » thematic priorities of AID 2024 call for projects.

Transcutaneous sampling of gaseous biomarkers

The development of wearable medical devices is a fundamental and essential in order to promote ambulatory medicine. Exhaled gases as transcutaneous gases (gases that diffuse through the skin) are known to carry molecules ("biomarkers") representative of pathologies or degradation of the physiological state, the ambulatory monitoring of which would be a real diagnostic and monitoring tool. However, the personal equipment associated to the continuous monitoring of exhaled gases is inappropriate for intensive sports activities, unlike the transcutaneous gases monitoring which could be carried out without losing mobility and discreetly (social impact), for example with a device placed on the forearm. Apart from oxygen and carbon dioxide, most of the biomarkers present are in very low concentrations and are therefore difficult to detect. One way of getting around this low concentration is to carry out a pre-concentration step, i.e. to accumulate over time, and therefore to concentrate enough molecules so that they are more easily detectable and measurable.
The objective of this thesis is therefore to develop and optimise a transcutaneous gas collector and pre-concentrator. The work will consist in particular in modelling the gas exchanges between the skin and the device in order to optimize the efficiency of the pre-concentration. The model will be compared with experimental results on a gas test bench for validation with two biomarkers of interest.
This subject requires a highly motivated person with skills in modelling and instrumentation. Skills in mechanical design of medical devices would be a plus.

Hollow microneedle and capillary microfluidic system for InterStitial Fluide (ISF) monitoring

Interstitial fluid (ISF) is the fluid that occupies the space between blood capillaries and cells. ISF consists mainly of water, salts, sugars, hormones, neurotransmitters, CO2 and fatty acids. It is particularly interesting as it is described as a filtrate of plasma, but more accessible than blood for continuous monitoring. Continuous monitoring of ISF is targeted, for example, for cortisol (a marker of stress, whose circadian rhythm makes continuous monitoring very interesting), sex hormones (PMA) and other biomarkers for monitoring a patient's state of health. The aim of this thesis is to develop a wearable device for ISF sampling, which co-integrates biocompatible or even resorbable hollow microneedles and a capillary microfluidic part. Eventually, this type of system will be combinable with various types of sensors at the fluidic outlet for various applications such as circadian cortisol monitoring for stress and post-traumatic stress. Three main issues will need to be addressed in this thesis: (a) One is the management of very low flow rates in passive microfluidics (flow rates in the nL/min range). (b) Technologically, the manufacturing process for resorbable hollow microneedles with fine management of the surface finish of the channel interior (to promote capillarity) will also be an important focus of the study. (c) Finally, the process will be evaluated and improved in terms of eco-circularity.

Development of innovative medical devices from new bacterial polyhydroxyalkanoates (PHA) derivatives.

To address the future challenges of wearable or implanted medical devices (MDs), which are less invasive and increasingly personalized and effective, it is necessary to have a broad range of biocompatible materials with diverse mechanical properties. Preferably, these biomaterials should be of biological origin and employed under mild conditions (preferably in water) to reduce the risk of releasing toxic by-products. Material biodegradability is another key characteristic to master for the development of prostheses and devices with a lifespan adapted to their use. In this context, the ANR PHAMOUS aims to demonstrate the high potential of bacterial polyhydroxyalkanoates (PHA) for designing innovative MDs.
In this framework, the doctoral candidate will initially be responsible for the chemical modification of various PHAs to enhance their water solubility (e.g., pendant PEG groups), introduce photo-crosslinkable groups (e.g., methacrylates), and incorporate specific functions (peptides) to enhance cellular adhesion and antimicrobial properties. The doctoral candidate will then use the different functionalized PHAs to develop two demonstrators implemented through two different processes. Photo-crosslinkable and solvent-soluble PHAs will be formulated to manufacture a prototype of a bronchial stent using "vat polymerization" 3D printing processes. Simultaneously, electrospinning of PHAs will be used to develop micro-structured and porous membranes.

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.

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