The importance of oligonucleotides (ON) pushed chemists to develop powerful syntheses to build them. Currently, the access to natural ON has become an efficient automated process. Nevertheless, the natural link is rapidly hydrolyzed in physiological media. Unnatural ON were thus explored to reach more stability, specificity, etc. and lower toxicity. Particularly, unnatural ON having mimic C-C links are of primary interest due to their stability and their similarity compared to natural ON. However, the elaboration of a C-C link between two nucleosides remains challenging. The goal of this project is to offer an innovative alternative to build unnatural bonds in position 3’ of nucleosides from easily accessible structures and to extend the structural scope of nucleosides. The strategy is based on the use of metal-catalyzed cross-coupling reactions (MCC) on glycal-type nucleosides (NuG), very scarce in the literature. For the past few years, we have been acquiring expertise in the synthesis of C-glycoanalogues via MCC. This project tends to capitalize on our expertise and the expertise of Prof. Lecouvey in the synthesis of complex phosphorus-containing molecules. The first objective will be the set-up of the MCC methodology. The second objective will consist in applying this reactivity to the synthesis of small oligomers. The third objective will aim to extend this reactivity to various complex phosphorylated reagents. The project will involve a PhD in co-supervision, a post-doctoral position and two Master 2 internships. The proposal will also include missions for the consortium and will pay the global working.

The project deals with the design of new Ti/polymer(P)/Ti and P/Ti/P sheets for biomedical applications, controlling their interface and adjusting their mechanical properties and shaping behaviour. Elaboration, process development, analysis of the properties, and their forming limits will be performed in synergy between three partners with the goals: 1. Developing strategies to design P/Ti interfaces in sandwich sheets (SMs) to employ surface-confined, resin free compatible polymer layers as adhesives for a strong bond between P and Ti for final shaping without delamination. “Grafting from” and “Grafting to” methods will be used, allowing a larger choice of monomers. “Grafting from” to produce Ti/P/Ti SMs with modulated properties in polymer by designing the glass transition temperature of the selected polymer. A polymerization initiator will be grafted at NaOH modified-Ti surface via a phosphonate anchor. Linear polymer chains of various molar masses, as homopolymers or copolymers types will be grown from the initiator using a controlled radical polymerization process. The monomers used will be as methyl methacrylate (MMA), n-butyl methacrylate (nBMA) and methyl acrylate (MA). A mixture of monomers will be used for the synthesis of random copolymers.. Grafting to” for bioactive thick polymer layers on Ti of homo and copolymers of sodium 4-styrenesulfonate (NaSS) and MA. A readily accessible anchor incorporating both an anchoring group (catechol), capable of forming a robust, stable monolayer, and a clickable function allowing the modular and efficient post-functionalization of the Ti surface will be used. In parallel, polymers or copolymers bearing thiol end groups will be attached using thiolene click reaction onto the monolayer. Linear polymer chains of various molar masses, as homo-polymers or co-polymers types will be synthetized by a controlled radical polymerization to give thiol-ends. In order to obtain thiol end polymers or copolymers, addition-fragmentation transfer polymerization will be chosen. The monomers used will be NaSS and/or MMA and a mixture of monomers to synthetize statistical copolymers. 2. Fabricating Ti/P/Ti or P/Ti/P SMs, SMs will be processed at IMET by bonding modified Ti sheets to commercially or in laboratory made polymer foils of defined thicknesses (e.g. PMMA or PMMA-co-PBMA foils or PMMA-co-PNaSS foil). The feasibility of the “Grafting from” method was stated in DFG project PA 837/44-1 3. Tailoring the mechanical properties close to the bones’ ones. Mechanical and shaping properties will be studied and controlled by modulating the molecular and structural parameters of the polymers or the ratio of the layer thicknesses. 4. Stability and cytocompatibility of the SMs will be conducted. The advantages of these systems usable for cranioplasty and mandible surgery will be lightweight SMs with mechanical properties designable in the range of bones’ ones and improved thermal and acoustic properties compared to Ti.

For the last decades, the seas and the oceans have become of first ecological and socio economical interests. The detection and assay of traces of chemicals is the keystone of many oceanographic problematics such as environmental monitoring or the study and forecast of spreading of chemicals in complex ecosystems (such as PAH-Polycyclic Aromatic Hydrocarbon- or pesticides). It is now well-established that the development of compact portable sensors and analyzers can be of great help to alleviate the inherent limitations of laboratory techniques in terms of both spatial and temporal resolutions. However, the conversion of bench-top systems to on field apparatus requires integrated micro-components capable of performing accurate measurement in harsh environment. The ability to quickly detect, identify and monitor (bio)-chemical species by means of integrated optical platforms of small dimension is also a major challenge in the field of Health where the development of early diagnostic tools in medicine has become an issue of great importance. Consequently in a context of growing demand for integrated sensors for environmental and biological applications, the aim of LOUISE project is to design, assess and implement an infrared (IR) micro-component sensor based on evanescent wave spectroscopy with surface enhanced IR absorption effect (SEIRA-EWS). To achieve this innovative micro-sensor, the LOUISE project will be focused on chalcogenide glasses for their technological flexibility: integrated platform with propagation in middle-IR, compatibility with CMOS technology and suitability for mass production. An important feature of this project lies in the gold plasmonic nanoantennas that will enhanced the IR absorption of targeted molecules (PAHs and biomarkers) deposited on the surface of the chalcogenide waveguide which propagates the MIR evanescent wave. Gold nanostructures in the form of an array of nanowires will be deposited on the chalcogenide waveguide to improve the IR absorption and thus the detection of the targeted molecules. Modeling will enable us to optimize the coupling between the MIR evanescent waves at the chalcogenide waveguide surface and the plasmon modes of the gold nanoantennas in order to increase the sensitivity and the resolution of the sensor. Then, the gold nanoantennas will be functionalized with a layer of polymer or antibodies to further increase the sensitivity and the specificity of the detection. The micro-component will be integrated into a portable instrument system and will be assessed for hydrocarbon and disease biomarkers/proteins detection during validation campaigns. Two compounds will be dealt with: fluoranthen, a PAH, and toluene. At the end of the project, the micro-component is expected to detect them at concentration as low as 0.1µg/L and 70µg/L respectively. For the biological compounds, we will focus on proteins that are known to be disease biomarkers such as the manganese superoxide dismutase involved in cardiovascular injury or liver cancer. Using SEIRA techniques integrated to IR micro-sensor as proposed by this project, we expect to reach some very low detection -limit of the order of 10-12 mol/L- in body fluids (plasma, saliva…), to develop a highly sensitive biosensor and to speed-up implementation. The LOUISE project offers the opportunity to a multidisciplinary French consortium to develop MIR sensors with sensitivity enhanced by advanced technology.

The Protéobios joint laboratory project is to create a structure for the pooling of knowledge and skills of the Laboratoire de Biomatériaux Pour la Santé (LBPS - CNRS UMR 724 and of the company Ost-Developpement. To elaborate bone substitutes that are as close as possible to autograft (the reference solution), natural bone from a human donor (allogenic substitute) or animal (xenogenic substitute), both treated with various physical and chemical treatments to obtain a high level of microbiological safety, are used. This is the area of expertise of OST Development company that produces such bone substitutes for twenty years in its Clermont Ferrand facilities. The physico-chemical treatments implemented are primarily intended to protect the patient against the risk of transmission of a pathogen, such as bacteria, virus or non-conventional pathogens. The use of such chemical agents inevitably impact the naturally protein composition of bone tissue and we now know that these protein play a role in the process osseointegration and remodeling bone substitute implanted. Proteobios proposes the implementation of the technologies for studying the relationship between the physico-chemical treatments applied to bone biomaterials such as those produced by OST Development of 1) the quantity and quality of protein in bone substitutes, 2 ) biomechanical properties and 3) the osteoconductive and osteoinductive capacity of these biomaterials This Labcom program on bone substitutes is the first step in a program to develop innovative approaches to: - industrial production of even more effective bone substitutes whose biological safety is achieved without compromising the essential biological functions of bone tissue starting in a type approach "tissue engineering". - Development of natural bone matrices could be effectively combined with stem cells to deliver customized therapeutic solutions.

This project addresses the issue of investigating, both theoretically and experimentally, and taking advantage of the unique optical properties of gold nanostructures for the design of new photonics and more precisely plasmonics devices. Indeed, such nanostructures, after proper biofunctionalization into biochips, will be inserted into an optical instrument for the purpose of enhanced sensor systems. In order to increase the performances of such a platform and make a breakthrough in this technology, the project proposes to demonstrate that it is possible to take advantage simultaneously, in a bimodal optical instrument, of both the sensitivity enhancement than can be obtained for surface plasmonic resonance imaging (SPRI) as well as surface enhanced Raman scattering (SERS) systems. In such an instrument, the biochip would be analysed both: -by SPRI whose parallel imaging capability will provide label-free detection and quantification of bio-target binding in real-time and with high throughput, -by SERS which will be used to analyse only those areas of interest as directed by the SPRI data and whose spectral signatures will provide unambiguous identification of the captured bio-targets. Modelling of the electromagnetic field in the complex metallo-dielectric structures will be performed using efficient in-laboratory made codes, providing accurate and optimized nanostructures, while being reasonable in calculation time and computer requirements. These calculations will be conducted in order to optimize the SPRI sensing capabilities as well as the SERS spectroscopic analysis by modelling the electromagnetic field enhancement provided by the nanostructures, taking progressively into account the details of the real structures. Using optimised optical properties and geometrical parameters (size, shape and in-plane arrangement) of the nanostructures, we will be able to design a highly sensitive nanosensor. The real structures will be produced firstly through e-beam lithography, to experimentally demonstrate the structural properties on micronic to millimetric scales, and secondly using nano-imprint techniques, to demonstrate the feasibility of the production of these nanostructures on a large surface, from millimetric to centimetric scales, and at low cost and yet reasonable quality as required for routine usage. Chemical functionalization will address the issue of transforming these structured substrates into biochips. Taking advantage of the efficient structures in terms of sensing will require precise localization of the biomolecular probes, in particular either using orthogonal chemistries onto SiO2 masked Au substrates or using self-assembled monolayer density changes around the structure angular areas. A bimodal instrument prototype including SPRI and SERS detection will be industrially developed. Demonstration of the capability of this new nano-enhanced bimodal optical instrument will be done on important societal and market applications ranging from medical diagnosis to food safety. Model cases will include protein biochips for cancer early diagnosis and biological and environmental food contaminants. To achieve such objectives, a well-balanced academic, industrial and end-users consortium has been brought together. It is composed of the (Nano-)BioPhotonics groups from Institut d’Optique, Palaiseau, and from the “Chemistry Structures and Properties of Biomaterials and Therapeutic Agents” of “University Paris Nord”, as well as the Institut d’Electronique Fondamentale of Université Paris Sud and Institut des NanoTechnologies de Lyon – all four academics being CNRS laboratories. The industrial partner, Horiba Jobin Yvon, is a world key player in analytical systems. The validation of the envisioned bimodal instrumental system, providing both plasmon imaging and Raman analysis, will be demonstrated by an end-user club, involving many public hospitals (APHPs and CHUs) as well as French agri-food pole of excellence AgroParisTech.