Chronic respiratory diseases represent a major public health issue in both industrialised and emerging countries. Objective and quantitative markers for their diagnosis and/or monitoring are, however, incomplete which prevents the development of efficient therapies. The LabCom project MUCUS (MUlti-sCale analysis of hUman Sputum), bringing together the Laboratoire Rhéologie et Procédés (LRP, CNRS/Grenoble INP/Univ. Grenoble-Alpes, UMR 5520) and Rheonova, focuses on the development of biophysical tools to fulfil this need. Rheonova proposed and realised a first and functional device dedicated to the rheological analysis of sputum, clinically validated and commercialised since 2018. However, the correlation between mucus rheology and the clinical condition of patients remains essentially empirical. MUCUS is expected to shed new light on the mechanisms related to the existing biophysical markers, develop new biophysical markers, and improve the future clinical practices that will rely on these markers. The quadruple objective of the programme is (i) to validate the rheological approach, (ii) to define sample manipulation protocols, (iii) to refine and improve the relevant biomarkers, and (iv) to identify third therapeutic approaches to which rheology could be generalised. These objectives will respectively translate into four major research directions: 1. Understand, from in vitro models, the interactions between pathogens, structure, and transport properties of the mucus; 2. Quantify, from microstructural analyses, the impact of sample manipulations on the rheology of mucus and on the associated biomarkers; 3. Explore the rheology of mucus in regimes (large shear, high frequency) and at scales not exploited so far, and develop the associated instruments; 4. Understand the transport of agents (therapeutic vectors) within the mucus, and the transport of mucus within the lower airways. These investigations should improve the use of devices currently offered by Rheonova and eventually to broaden its innovation portfolio towards new markets (point-of-care, then point-of-need devices) and other pathologies.

Biological surfactants are a family of natural molecules obtained from the microbial digestion of fatty acids and sugars. These compounds are developed the low impact of the synthesis process (industrial biotechnology), low toxicity and high biodegradability. Sophorolipids, glucolipids or cellobioselipids are some of the most important molecules. Historically developed as biodegradable detergents to replace petrochemicals, their high cost/benefit ratio stimulates their use for other high-end applications. Recent work demonstrates their self-assembly properties into fibers and bilayers, which show the formation of shear-thinning stimuli-responsive hydrogels. This class of soft materials is an interesting alternative to known matrices for tissue engineering, a field in continuous seek for new biomaterials due to problems of contamination, purity, cell adhesion and cost. The goal of SELFAMPHI is to use biocompatible amphiphiles to develop new injectable and printable hydrogels to test in tissue engineering (spinal disc repair and skin fillers) applications.

We recently developed, patented, and successfully transferred a technology for DNA purification, enrichment, and separation. This technology coined µLAS involves an electric field and a counter hydrodynamic flow in viscoelastic liquids, in which transverse forces oriented toward the walls occur. These forces increase with DNA molecular weight (MW) and hence induce a progressive reduction in DNA migration speed that triggers size separation in microfluidic channels as well as in capillaries. Therefore with conventional microfluidic control systems of pressure and electric field, the transport of DNA can be finely controlled. More specifically using commercial Capillary Electrophroresis, this technology allows us to perform DNA separation in the 0.1-5 kbp with unrivalled sensitivity of 20 pg/mL with an operation time of ~10 minutes. In this proposal we aim to bring this technology one step ahead and perform the operations of separation, enrichment and purification for virtually every DNA molecular weight. We target academic and industrial needs in third generation sequencing, bacteriology, epidemiology, and cancer diagnostics. For this we will optimize the separation mechanism according to rational rules determined by specific physics models of flows in microchannels. More specifically, we intend to perform original experimental and theoretical researches on visco-elastic lift forces using different families of polymer solutions (WP2). Our goal is the development of a predictive platform to reach µLAS optimal performances. We will then confirm or invalidate the predictions of our platform by running separation experiments with DNA molecules of increasing molecular weight (WP3), and obtain optimal separation performances for the different DNA size ranges targeted in this project. We then wish to investigate whether enhanced separation performances for high molecular weight molecules can be reached with temporal modulations of the electric field (WP4). Note that WP3 and WP4 are mutually reinforcing: both aim to gradually improve the features of µLAS for DNA separation. The final task of this project (WP5) is devoted to the specification of a prototype for strain typing and/or quality control of bioprocesses, such as third generation DNA sequencing. Our project will be accomplished by LAAS and LRP, which are two laboratories expert in DNA separation in microfluidic systems and complex fluids hydrodynamics, respectively. Developments will be transferred to an SME company Picometrics for industrial prototyping.

This multidisciplinary project focuses on the development of new scaffolds dedicated to the regeneration of soft tissues. In order to optimize the development of new implantable medical devices, the objective of this project is to promote and validate a methodological approach to forecast the evolution of the mechanical properties of the biocomposite "scaffold/growing cells" during the antagonistic effects of the biodegradation of the scaffold and cell colonization. For this purpose, new biocompatible and biodegradable block copolymers having hyper elastic behavior close to that of soft tissues will be synthesized. These materials will be processed by electrospinning to produce biomimetic structures favoring the cellular growth. The mechanical properties of the scaffolds will be characterized at various stages of degradation in the presence of growing cells. Simulation methods, from the cellular scale up to that of the scaffolds will integrate the experimental results to characterize and finally forecast mechanical behavior of scaffolds according to these intrinsic properties.

The gastrointestinal tract involves many biological, chemical and physical phenomena to secure the absorption of nutrients from our food. Also, specific sites of the digestive mucosa are gateways to our immunologic system which pave the way for the development of innovative oral therapeutic strategies. These strategies are based on the encapsulation of drugs in nano- or micro- particles or the administration of bacteria, which would target these sites in order to induce an immune response. However, a major scientific barrier is to be able to predict the flow of these "micro-particles" and thus control the dose absorbed by our body. The objective of TransportGut is to develop a predictive and comprehensive modelling of the transport of microparticles in the gastrointestinal system. The challenge of such a model is to account for the different specificities of the physical environment of the digestive tract on the phenomena of transport and mixing. On the one hand, transport and mixing are controlled by the mechanical activity of the smooth muscles of the intestinal mucosa, on both macroscopic and microscopic scales. On the other hand, this activity varies according to the time scales considered. Several scales are thus relevant: the microstructures of the mucosa, the isolated organ and along the digestive system. Mixing at large scales are probably controlled by mixing at small scales. There is currently no particle transport model that takes into account these different scales. TransportGut is an integrated and interdisciplinary project that draws on the complementary expertise of three teams in biorheology, theoretical biophysics and physiology. The team of the Laboratoire Rhéologie et Procédés (LRP) has significant experience in the development of experiments in complex fluid mechanics at macroscopic and microscopic scales, as well as in numerical modeling of flows in the gastrointestinal tract. The team of the Laboratoire Jean Perrin (LJP) has expertise in theoretical modeling of the transport of bacteria and their interactions with the immune system of the digestive tract. Finally, the team from Techniques de l’Ingénierie Médicale et de la Complexité (TIMC-IMAG) develops experimental systems and original technologies for understanding the physiology of smooth muscles. Based on experiments at the interface of physiology and fluid mechanics and numerical simulations of flows, we propose to develop an analytical model of transport connecting these different scales. We will develop experiments on animal models to study the transport of particles along the digestive system and in the vicinity of microstructures of the intestinal mucosa. These experiments will be used to simulate numerically the coupling between flows at microscopic and macroscopic scales in order to understand the role of active and microstructured interfaces on the transport and mixing of microparticles. All of these data from experiments and numerical simulations will make it possible to build analytical and simplified models of the transport and mixture of particles at different spatial and temporal scales. This model would predict the spatiotemporal dispersion of particles in order to be a decision-making tool for the pharmaceutical industry, but also to understand the fundamental mechanisms that govern the spatial structure of the intestinal microbiota.