Osteoarthritis (OA) is the most frequent joint disease in adult. It is responsible for disability and increased mortality. There is no efficient treatment and OA leads to cartilage degradation and joint destruction. Cartilage calcification favors cartilage degradation and worsens OA disease. It is composed of calcium orthophosphate, mainly as carbonated apatite, and calcium pyrophosphate dihydrates (CPPD) crystals. These crystals stimulate the production of catabolic mediators and proteolytic enzymes by joint cells. How these crystals activate cells remains unclear, especially their interactions with cell membrane and intracellular outcomes. Moreover, their individual role in OA is unknown since current imaging techniques possess low capacity to discriminate apatite from CPPD crystals. OASIS project aims: 1/ in fundamental studies to decipher calcium crystal-cell membrane interactions, crystal internalization and intracellular crystal outcomes and ; 2/ in applied issues to optimize spectral multi-energy computerized tomography (SPCCT) acquisition and analysis procedures allowing discrimination between apatite and CPP crystals in OA patients. OASIS project involves a consortium of 5 multidisciplinary academic partners (physicians, chemists, cell biologists, physicists and computer scientists) and an industrial partner (Canon Medical System), well-renowned as CT constructor. This consortium possesses complementary skills including a unique know-how in the synthesis of pure phase apatite, CPPD crystals and fluorescent organic nanoparticles (FON), a mastery of cellular and physico-chemical analysis techniques (Raman spectroscopy, X-ray diffraction, atomic force microscopy (AFM)), deep knowledge of scanner procedures and the access of cohort of well-phenotyped patients and the last spectral CT prototype (AQUILION PRISM). We achieved for the first time to obtain stable FON-coupled calcium phosphate crystals which will allow their internalization and intracellular follow-up. In addition, first tests showed the ability of the spectral CT AQUILION PRISM to differentiate CPPD crystals contained in quadriceps muscle from apatite contained in the femur. These preliminary results guarantee the success of this project. This project will include nanoscale characterization, cellular and animal studies and end with application in patient care. FON-coupled crystals will serve to study their cell membrane interactions and intracellular outcomes using AFM and confocal microscopy in artificial membrane, macrophage and in vivo models. Blocks of apatite or CPPD crystals with different size and mass, grafted in mouse quadriceps and then embedded in resin, will permit ex-vivo identification of SPCCT optimal parameters that discriminate apatite from CPPD crystals. These parameters will be applied in OA patients who will undergo total knee joint replacement surgery. SPCCT results will be compared to ex vivo analysis performed on surgical samples. The capacity to differentiate apatite from CPPD crystals will be a major step in the understanding of OA pathogenesis and allow a better disease management. OASIS project possesses high valorization potential in fundamental and applied issues. Identification of cellular activation mechanisms will open new therapeutic targets and understanding of calcium phosphates crystal internalization mechanisms can be generalized to other inorganic particles. Similarly, the SPCCT diagnosis procedures that permit discrimination between apatite and CPPD crystals can be applied to other calcification tissues and fields including kidney stones, vessel calcification, tumor calcification, etc… These procedures will be integrated in software of future CT.

Discrete oligomers with a very long π-conjugated path are of major interests for both fundamental and applicative reasons, as they can be used in countless areas ranging from energy and imaging to sensing and advanced optoelectronics. Numerous attempts have been made to achieve a full control of the p-electronic length (1D). In contrast to random and self-organization preparations, the stepwise synthesis of oligomers appears to be the unique efficient method allowing a full control over the chain length. Controlling the width is even more challenging but highly alluring because such two dimensional (2D) variants can be seen as graphene nanoribbons (GNRs), that have been the subject of manifold works during the last decade. If 1D and 2D oligomers could be prepared by classical approaches based on the use of standard C-C coupling reactions to form extensively fused π-conjugated (hetero)aromatic compounds, these approaches clearly suffer from drawbacks in line with the C-C bond formation (purification, side reactions, cost). Developing a new stepwise strategy to access such oligomers with full delocalization of the electrons is therefore extremely appealing. CONDOR wishes to address this fundamental chemical issue by exploiting the long-known but overlooked π-d conjugation phenomenon (delocalization of electrons over both the metal and the ligand). This strategy will allow the first easy and low-cost entry to conjugated oligomers with a perfect dimensional control [both length (1D) and width (2D)], that should give rise to (new) controlled electronic features. This control of the extension of the electrons delocalization is objectively an appealing approach to tune the HOMO-LUMO gap (HLG) and to redshift the absorption bands up to the near infra-red (NIR) region, a remarkable window for many technological sectors.

UNICORN aims at developing cutting-edge Nuclear Magnetic Resonance (NMR)-based metabolomic approaches to offer unprecedented prognostic and diagnostic solutions for personalized medicine, with an application to one of the major causes of death worldwide, cardiovascular diseases (CVD). This project, at the interface of chemistry and biology, will thus answer a key societal health-related question. The originality of UNICORN is to apply for the first time novel NMR-based methods to an ambitious biological question, by deciphering the biological mechanisms sustaining athero-protection and identifying a broad spectrum of biomarkers. Thanks to a well-chosen study design, the project will provide a wider picture of CVD-related phenotypes and innovative insights for the implementation of precision medicine in the most at-risk patients. The characterization of a specific athero-protection signature should also enable the identification of new therapeutic targets to reduce the risk of CVD. In terms of methodology, the project will open new horizons to NMR-based metabolomics by offering highly resolved and sensitive analytical strategies that represent many advantages in clinical settings, namely intrinsic quantitation, and the possibility of doing longitudinal studies over a long-term period of recruitment and with minimal sample preparation. UNICORN will allow the scientific coordinator of the project to set up her own impactful and independent research team at the interface of NMR-based metabolomics and clinical research.

Protactinium, a radioelement with unknown chemistry, is a key element : first actinide for which the 5f orbitals can be involved in chemical bonding, it is also naturally ocurring in envrionment, in the nuclear fuel cycle and also appear in the synthesis of innovative isotopes for medicine. Understanding the chemical behaviour of Pa in these compartments constitutes a great challenge especially since the basic chemistry of this element remains quite blurred ! In this project, we propose to switch to a new paradigm: "predict then experiment". Two main types of properties will be scrutinized, reactivity in terms of equilibrium constants between a set of ligands and protactinium(IV/V) and spectroscopy of protactium compounds. After an extensive methodological study and state-of-the-art theoretical predictions, we will set up prime electromigration, solvent extraction and spectroscopy (high-resolution XANES and laser spectrofluorimetry) experiments aiming at validating/improving the theoretical models and revealing this rare chemistry.

The recent rise of high-resolution and depth imaging techniques like photoacoustic microscopy (PA) stimulates novel research areas in biology. In vivo tracking of immune cells, signaling inflammation and severe pathologies thereof, is one of them and attracts great interest. The AZOTICS project thus aims at addressing the current PA microscopy limitations by fabricating innovative biocompatible elastomeric nanolabels relying on azo photochromes. Photostimulated actuation mechanisms will help amplify the PA contrast based on thermal expansion. The photoinduced mechanical deformations of single nano-objects will be assessed at the nanoscale using atomic force microscopy in order to propose a rationale for the performance of photoacoustic probes beyond their sole optical absorption ability. Their PA imaging capability will be validated through an in vitro, in cellulo and in vivo continuum of studies involving macrophage staining, microfluidic systems mimicking microvasculature, and models of acute inflammatory activated in mice. The interdisciplinary AZOTICS consortium gathers experts in chemistry, physics and optics from Nantes and Grenoble, having already tightly worked together and being keen to share their knowledge in order not only to address unexplored fundamental questions but also to propose innovative photoacoustic systems for in vivo imaging.