The current biopsy procedure is to introduce a needle inside the patient towards a given target using echography imaging for control of the position. Reaching the target at the right position is a real issue for diagnosis, therapy and also prognosis, for example concerning tumors or abscess. The NOCT project aims at developing two apparatus, one for imaging and one for navigation, integrated in a complete clinical application of real-time echography navigated biopsy, which would be the first of its kind in the world. We will build an optical imaging system with a needle-like probe that could perform virtual “optical biopsy” prior to the excision of the sample by revealing in vivo the fine microstructures of the tissue. Full-Field OCT is the best-suited technique for this purpose. This technology is now commercialized in a microscope for ex vivo imaging, and we plan on adapting it in a system with a thin rigid probe, with emphasize on ergonomic constraints such as the diameter and length of the needle. We will create a precise surgical navigation system that will be adapted to the clinical ambulatory context, so that it would become in the next decade a reference system for computer assisted medical interventions. This project is a translational research between physics, informatics and medicine, where a key point is to adapt novel technologic apparatus to specific clinical needs. With the aim of the future clinical application we will characterize the preclinical and clinical performance and pay attention on risk management and authorization from the CPP, ANSM and HAS. We will meet these challenges as a consortium of five partners: two laboratories specialized in optics and in computer assisted medical interventions, Institut Langevin-ESPCI and TIMC-IMAG, one clinical investigation center specialized in interventional radiology and computer assisted medical interventions, CIC-IT, and two private companies that will industrialize the final resulting systems, LLTech and Surgiqual Institute.

The Dynametafluid Project aims at developing a microfluidic device for real time and clonal evaluation of metabolic and energetic balance shifts in engineered microbes within controllable and adjustable microenvironments. Each microorganism is encapsulated into a growth medium droplet that acts as an individual micro-bioreactor. For osmotic reasons, evolution of the size of the droplets is directly related to cell energetics. Hence, growth of a single cell into a population and its metabolism are tracked at the same time. Subpopulations of growing cells will be differentially submitted to metabolic perturbations resulting either from light or temperature-induced recombinant gene expression, changes in oxygen or carbon dioxide concentrations, or chemical stresses and their physiological response dynamically analyzed. Based on real time windowed multi-parametric analysis, individual droplets will be selected and recovered to allow complementary genomic and transcriptomic analyses down to single cell level. Genotype, metabolic and transcriptional status of pseudo-clones will be compared in high throughput conditions allowing the establishement of genotype-phenotype relationships at the level of subpopulations of variable sizes. Following a careful validation phase of the hardware involving simple models of recombinant microorganisms (yeast and E. coli), microbial models more representative of metabolic engineering of industrial interest will be designed and analyzed. Among basic questions, consequences of stochastic events affecting single or multistep metabolic engineering directed by episomal vectors will be addressed in relation to the type of vectors and mode of metabolic coupling (intra- or inter-cells) under positive, negative and triggered selections. A focus will be performed on different types of short term (copy number, transcriptional) and long term (genetic drift) adaptive mechanisms that will be characterized both at phenotype, genotype and transcriptome levels. In the last phase of the project, the validated technology will be transferred onto the site of biologist partners for out-of-project use in basic and industrial projects. The project involves three internationally recognized complementary partners specialized in microfluidic, omics and genetic engineering respectively and takes place in close vicinity and interaction with the industry oriented TWB transfer structure.

Recycled plastics typically exhibit poor physical properties because they consist of blends of incompatible polymers with poor interfacial adhesion. Although many approaches have been reported to strengthen such interfaces, all suffer from drawbacks in terms of performance, cost-effectiveness, or modularity. In this research program, I will explore unconventional strategies to mechanically interlock incompatible semi-crystalline polymers together. The key innovation will be compatibilizers that feature molecular anchors, which are functional groups that are designed to become mechanically trapped in targeted crystalline phases. This project is oriented at improving the properties of polyolefin blends, but these principles will be applicable to semi-crystalline polymers in general. We envision that this strategy will also unlock new methods for surface functionalization and adhesion.

Sparing our natural resources is very important for tyre industry, on both the society side and the economical side. Optimal design - lighter tyres but even safer and with longer life – is a real challenge that can only be addressed with a thorough understanding of crack growth mechanisms. In the specific case of filled elastomers, representing most of the tyre composition, fatigue crack growth approach is very empirical and potential progress on material design is limited. We want to open new areas of innovation and optimization of filled elastomers, by developing a new understanding approach of the damaging phenomena in the crack tip area (from using new experimental and simulation techniques to predicting tools for guiding new material design). This way, we hope to understand the first order effects of micro-structural parameters on intrinsic crack growth resistance properties. Today, influencing mechanisms are rather poorly understood and much discussed. Among other difficulties is the key issue of coupling various phenomena at different scales: large strain constitutive law, including softening and self-heating, mechanical and thermal fields evolution through geometric modification of the crack tip, and so on … Our project consists in a multi-scale approach linking the physico-chemical scale (material structure, from a few nanometers to some micrometers), the crack tip scale (hundreds of micrometers) and the scale of the structure (a few centimeters). This approach must link physico-chemics, physical damage and continuum mechanics. It includes proposing a new constitutive law for filled elastomers, taking into account its fatigue evolution, and a damaging model at the crack tip based on the understanding of local mechanisms. These models shall be included in a finite element crack simulation. Digital image correlation technique will be used for comparing experimental displacement fields near the crack tip with simulated fields. Then simulation shall be upgraded, in several experimental/simulation loops. The first model difficulties lie in the fact that it is compulsory to have a good coherence between the small scale field and the far field at the scale of the whole structure. The project is also very ambitious in trying to put together several aspects which are individually poorly mastered in the case of filled elastomers. On one hand, physico-chemical damage origin at the crack tip is still unknown, partly because measurements are very tricky near this crack tip. On the other hand, constitutive laws for filled elastomers are difficult to measure and to simulate, due to high non linearities and to their strong sensitivity to loading history. Finally, existing damage simulation principles, developed for other materials, and displacement field measurements, by digital image correlation, have both never been applied to elastomers. Thus, the global project approach mixes several analysis scales (from micro-stuctural physico-chemics of the material to continuum mechanics). Each of these analysis hits strong difficulties and their coupling is in itself very tricky. Common work between so many specialists joining their expertises together on the same problem and on the same experimental setup has yet never been tried. We think that complementarity of gathered expertises is the only way to reach significant progress in understanding crack propagation in filled elastomers and in identifying innovative tracks for proposing more resistant materials.

The nucleus, far from solely being the repository of genomic information, is increasingly viewed as a complex physical entity, mechanically and chemically coupled to its cellular environment. It is now clear that the three-dimensional architecture and the physical properties of the genome play a central role in its genomic and non-genomic functions. In recent years, novel approaches based on chromatin conformation capture techniques, complementing genome-wide assays and fixed-cell imaging tools have revealed multiple layers of conformational organization closely linked to genome function, including gene regulation, DNA replication, chromosome segregation, differentiation and others. Yet, despite the rapid evolution in our understanding of genome architecture in the past years, several roadblocks remain, that critically hold up progress in genome biology. First, experiments are predominantly performed on population of cells or in fixed conditions and there is a clear need to carry out measurements at the level of single living cells in order to address the conformational dynamics of chromatin at all scales, from the formation of loops to that of domains, compartments and territories. Second, most experiments (notably imaging measurements) are based on the passive observation of chromatin, possibly combined with global alterations such as gene knock-down. As a result, it is often difficult to distinguish between correlation and causality. Third, the dynamics and conformation of chromatin is governed by many energy-driven processes, and understanding the properties of chromatin as active matter is essential. Finally, chromosomes are mechanical objects with a conformation that can be dynamically modified as a function of the mechanical stresses exerted on the nucleus. Overall there is a clear need for a comprehensive description of the genome that account for the physical properties of chromosomes, notably including the out-of-equilibrium and mechanical processes that contribute to their organisation and dynamics in the nucleus. To address this challenge, we propose a novel approach that consists in mechanically perturbing the genome architecture, at the single chromosome level and with genomic specificity, and directly assessing the associated effects on nuclear organization and genomic functions. To do so, we will leverage our consortium’s unique expertise in cell biophysics, genome editing and nanoprobe chemistry to design an innovative nanotoolbox for chromosome imaging and manipulation. Specifically, we will develop a highly versatile and scalable strategy to decorate genomic loci in live cells with fluorescent quantum dots or magnetic nanoparticles via specific targeting using recombinant catalytically inactive CRISPR/Cas9 proteins, complexed with synthetic gRNAs. These novel functionalized nanoprobes will allow us to image and physically manipulate individual chromosomes at specific genomic sites in mammalian cells and to record the effect of these mechanical perturbations (in the pN range) on chromosomal conformations and functions. By doing so, we will directly assess: (i) the rheological and elastic properties of individual chromosomes in interphase and the role of out-of-equilibrium processes in their multiscale conformations, (ii) how mechanical forces affect transcriptional activity. Our approach, which goes well beyond the state-of-the art in genome research, will contribute to bridge the gap between population biochemical assays and the biophysical models of chromatin. Thereby, we will achieve a more integrative understanding of nuclear organization and dynamics and we will open many prospects for the study of a variety of scientific questions on different genome functions (transcription, repair, replication) and on the alteration of genome organization during processes as diverse as development, differentiation, disease or ageing.