SiBio aims to develop and study the biodegradation potential of customized carbonated hydroxyapatite (CHA) based bioceramics with optimized surface curvature porous network for the treatment of critical-sized bone defects. Specific architecture containing gyroïd-like geometries, known to promote the rapid development of mature bone, will be studied. The elaboration of CHA implants requires a sintering atmosphere rich in CO2 to stabilize the phase up to a temperature allowing its densification. Sintering is therefore a crucial step to guarantee the composition, the final mechanical quality of the parts and, consequently, their biological properties. The core of SiBio consists in an in depth study of the reactive sintering of CHA parts under mixed atmosphere to be able to controlled the final microstructure and chemistry. After powder preparation by wet precipitation (WP1), the first objective is to produce non-macrostructured CHA ceramics with controlled carbonate amount and microstructure (WP2). This will be achieved thanks to a sinterability study where multiple parameters, including procedure (e.g., two-step sintering), heating rate, temperature, atmosphere (e.g., PCO2 and PH2O partial pressures) and initial composition will be screened to identify the best sintering protocols with respect to the final composition, microporosity range and mechanical properties. The second objective of SiBio is to thoroughly evaluate the degradation behaviour of macro-structured CHA ceramics. To achieve this, CHA ceramics with controlled composition and gyroïd-like geometries will be manufactured thanks to additive manufacturing technologies (WP3). Then dynamic acellular and cellular in vitro tests will be set up to investigate their biodegradation (WP4). Specific attention will be paid to thoroughly characterized the ceramic at a macro- (e.g., shape, macro-porosity, bulk chemical composition) and micro-scale (e.g., micro-porosity, chemical homogeneity) to study the interplay between ceramic features and its bioactivity. In addition, the questions raised in terms of implant design will be addressed through an outreach action for lay public (WP5) and will make it possible to disseminate the scientific culture of this multidisciplinary research field in a participatory form. The knowledge acquired thanks to SiBio will allow envisaging personalised treatments according to the bone defect to be reconstructed and the characteristics of the patient.

Nacre is a natural composite that has the ability to stimulate bone formation via osteoblasts and to reduce bone resorption mediated by osteoclasts. The exact composition of nacre remains until now unknown and the structure and nature of the active components are partially known. This project will be divided in three parts: 1. We will continue the identification and synthesis of the active peptides of nacre. 2. We will specify how nacre molecules act on osteoblastic stimulation and osteoclastic inhibition. First, we will screen the activity of the nacre molecules identified in step 1, then we will analyse the signaling pathways activated in osteoblasts and osteoclasts. 3. Finally, we will determine the ability of nacre and its compounds to limit bone loss in the hindlimb unloaded and ovariectomized mice models. The results will represent a decisive breakthrough allowing new developments in therapeutics to reverse osteoporosis bone imbalance.

This proposal aims at obtaining a support from MRSEI for preparing a project proposal for the EU call FETPROACT-EIC-07-2020 which closes on 22nd April 2020. We have already reached advanced discussions with a European consortium for preparing a proposal to this call. Here is an abstract of the project we plan to achieve. Today, more than ever, we understand what causes blood vessels and heart to age and how the aging cardiovascular system leads to cardiovascular disease. In addition, we have pinpointed risk factors that increase the odds a person will develop cardiovascular disease. In the future, interventions or treatments that slow accelerated aging of the arteries in young and middle-aged people who seem to be healthy could prevent or delay the onset of cardiovascular disorders in later life. Drug treatments or gene therapies can target specific cellular changes and could potentially be a way to intervene in the aging process. However, every individual is different as the changes that take place in cells and molecules during aging are very patient-specific, which renders drug design extremely challenging when one wants to target those changes. Through mechanotransduction, which is the process by which a cell translates mechanical stresses or strains into a biochemical signal to activate downstream responses, Vascular smooth muscle cells (VSMCs), which are found in the medial layer of blood vessel walls, regulate various aspects of vessel homeostasis, including contraction, dilation, and matrix remodeling. However, due to specific genetic conditions which can be inherited or acquired with aging, mechanotransduction may be altered and VSMCs may lose their regulating ability, which may cause life-threatening conditions such as aneurysms or dissections in the aorta. In this proposal, we assume that potential mechanotransductive impairment would manifest through the disactivation of one or several of the mechanotransduction pathways (a comprehensive model of these pathways will be developed as part of this project using homogenization, physics informed models and machine learning), and this could be detected through the gene expression profile of VSMCs. By characterizing the gene expression profile of VSMCs and also using detailed molecular analyses of time-dependent molecular changes (transcriptomics and proteomics), it is also possible to analyze the drug response patterns to 100+ drugs and select the ones that would possibly repair mechanotransductive function. Building on this assumption, we propose to establish the digital twin of every cardiovascular patient based on a comprehensive multiscale & multiphysics mathematical and numerical model. The virtual patient will be used to evaluate how aging, drug treatment, or surgery is going to affect their cardiovascular system and estimate the probability of cardiovascular failure, as for instance aneurysm with rupture or dissection in the aorta. Digital twins, which rely on simulation tools, are now commonly used in many industries and areas (health in particular) to optimize, through virtual testing, the operation of existing devices or systems on which data are captured. Developing the digital twin of every cardiovascular patient, which is a completely new concept, is the scientific goal of our proposal. Establishing the digital twin of aging cardiovascular system, including customized patient-specific conditions will permit to achieve a new technological paradigm for the design of biotechnologies in personalized cardiovascular medicine. As numerical simulation has now become commonplace in the design departments of automotive or aeronautics industries, future biotechnologies will also rely on virtual testing thanks to our digital twin, permitting a drastic reduction in vitro and clinical studies and of their tremendous costs.

During COVID-19 pandemia, the EFS contributes to the global effort of research to better understand this disease and to treat the most severe patients while decreasing the incidence and tension in hospitalisations. The CovidEP study (authorized by ANSM and CPP – HCL sponsor / Scientific coordination EFS Auvergne-Rhône-Alpes Dr O Hequet) pursues to remove cytokines in excess that induce inappropriate immune responses in patients in intensive care unit and to study the immune improvements. The aim of this study is to clarify whether this aproach leads to restore an appropriate and efficient immune response while overcoming a critical medical position in severe patients infected with COVID-19. In practice, this is performed by removing plasma (containing cytokines in excess) from patients with COVID-19 and replacing it by fresh frozen plasma form healthy donors during therapeutic plasma exchange sessions (TPE). The analysis of immune responses, mainly T lymphocyte immune responses and platelet activation after cytokine removing, will be compared to the reponses in patients without TPE. Currently the immune features are not evaluated during TPE for COVID-19. The current support concerns the physiopathological analysis of the complications observed in patients in intensive care unit and the immnological improvments induced by this TPE approach, while concentrating on inflammation, T lymphocyte immune response and platelet activation.

Osteoarthritis (OA) affects around 40 million people in Europe. OA causes a heavy socioeconomic burden. There is currently no cure for OA. Also, the development of therapies that can prevent joint damage associated with OA is thus urgently needed. OA is characterized by loss of joint cartilage, pathological change in the bone that lines the cartilage, and mild inflammation of the synovial membrane. The disappearance of cartilage results from an alteration in the functions of chondrocytes, the cells that compose cartilage. Notably, the chondrocytes become hypertrophic. This transformation is currently considered to be critical in the progression of OA. It could be the link between the disappearance of cartilage and its replacement with bone. In OA, the interface between the articular cartilage which is avascular and the bone is characterized by the development of blood vessels (angiogenesis). We believe that these blood vessels play a key role in replacing articular cartilage with bone and that their development is stimulated by hypertrophic chondrocytes. Our preliminary results show that articular chondrocytes rendered hypertrophic in culture acquire angiogenic activity. This property is inhibited by blocking CXCR4 on the surface of endothelial cells, the cells of blood vessels. CXCR4 is the CXCL12 receptor which is produced by hypertrophic chondrocytes. In the TARGET-OA project, we propose that the CXCL12 / CXCR4 axis has a crucial role in the dialogue between hypertrophic chondrocytes and endothelial cells in OA. Our objectives are to define the role of this axis in pathological communication between chondrocytes and endothelial cells and to demonstrate that its targeting has a clinical interest for the treatment of OA.