Hydro-chemo-mechanical (HCM) couplings within mucoid tissues (such as hyaline cartilage , bladder, stomach tissues...) are essential to bond micro- and macro-scale and explain interactions in between cell behavior and effective tissue response. In fact, mastering such couplings is a key element to understand biological tissues’ complex synergy and propose predictive tools on their bioactivity wherein local hydro mechanical and chemical states play a major role. Ever since, once applied to biological tissues, biomechanical modelings fail to explain the inter-location and inter-donor variability even though tissue compositions are similar. Biological tissues are complex materials due to their multiphysics but also bioactivities related to a memory through growth and remodeling. Large experimental data collections are consequently required to be able to set a sound numerical model with optimized parameters generating predictive simulations to improve mucoid tissue’s behavior insights and extend it to clinical applications. Therefore, HyCareMat’s main objective is to build a crosstalk between experiments, numerical simulations and modeling to investigate and predict HCM couplings in soft biological tissues, with a focus on mucoid matrices. As a first step, it requires a well known tunable biological material model to feed inverse method procedure and validate virtues of the ensued predictive tools. With respect to recent work of the HyCareMat consortium, Wharton’s Jelly (WJ) appears to be a suitable and tunable material exhibiting HCM interactions. Representing a valuable opportunity for the development of biological scaffolds, as they can be easily achieved both from a technical and an ethical point of view, WJ was extensively investigated by biologists but poorly by biomechanicists. As a second objective, the WJ and WJ-derived materials will be deeply investigated to master their HCM behavior and produce predictive numerical tools. Finally, switching from the passive biomechanical characterizations of the two previous objectives, the third objective focuses on the impact of bioactivity on the HCM behavior of this promising material by monitoring tissular integration and host’s biological response. Therefore, a murine animal model will be set to collect in vivo data on implanted WJ structures. This ultimate step will validate our tools to select the best WJ-derived material for medical applications based on biomechanical characteristics, pushing towards human applications. The main hypothesis consists to consider couplings between solid and fluid phases, as well the chemical components of both, more precisely GAGs combined to collagen and electrically charged physiological fluid ions. The fluid structure interaction will be modeled as a homogenized continuous medium within the framework of poro or hydro mechanics while the chemo-mechanical coupling will be generated by chemical potential balance through osmosis. Based on preliminary results, it is considered that tuning cross links and GAGs content, on geometrically controlled structures, is sufficient to modulate interaction phenomena. Finally, combining multimodal imaging techniques while performing HCM loads and monitoring animal’s response to material integration is expected to provide enough data in order to build predictive tools. Combining interdisciplinary resources of 4 partners, HyCareMat aims throughout 5 work packages to build and validate a HCM predictive tool to gain a deeper comprehension of mucoid matrices (i.e. loose biological matrices). In the same time, it will extend the current knowledge on the WJ, a promising waste of human tissue, used as exemplary material. Ultimately, the project will allow enhancing WJ multiphysical response for medical applications. Therefore, its technical readiness level is in between 1 and 3 but it could reach the level 4 depending on the forthcoming achievements.

Medical implants replace dysfunctional or missing body parts to maintain physiological functions. The associated market is growing by 4%/year. However, the key factor restraining the market is high implant costs. In this view, PEEK and CRF-PEEK due to biocompatibility, mechanical properties similar to that of bone and radiolucency, are increasingly used instead of metals. But, these biomaterials are bionert inducing a very limited osseointegration, which is THE expectation for bone implants. Another expected properties are wear resistance, angiogenic ability and bacterio resistance. Ca-PEEK project is aiming at developing the next generation of PEEK implants that will provide answers to these expectations. For that, the PEEK surface will be modified with an adherent functionalized biomimetic apatite deposited by cold spray. The challenges are adhesion of the coating, maintaining the bioactivity of biomimetic apatite as a coating, preserving the mechanical properties of PEEK, enhancing the whole durability of the implant, and achieving multifunctionalization of the coating.

Antibiotic resistance is a major threat to modern medicine and societies (WHO, 2020), especially with the finding that 80% of bacterial infections involve biofilm, which is a microbial community tolerant against all types of antimicrobial agents. In such a clinical context, we must consider developing adapted models, new strategies, and new molecules to treat acute and chronic infections due to biofilm. Our research hypothesis is that a dedicated in vitro model reproducing the major factors of the bone environment, which influence the biofilm structure during bone and prosthesis infection (BPI) will reveal peculiar features of these biofilms that could be identified as antibiofilm targets. Then, this in vitro model will allow the screening of different antibiofilm strategies helping to the identification of essential mechanisms of biofilm. The development of molecules specific to and efficient against bone infections will be facilitated. Our objective is to fight against BPI biofilm through 1) mid-to-high throughput observations of clinical collection of S. aureus strains to identify “specific” bone context biofilm features and to create a database gathering all potential antibiofilm targets; 2) to screen a bank of natural molecules, synthetic quinolones derivatives and antimicrobial peptides in this same model. Both objectives will lead to highlight molecules with a high affinity towards identified targets thanks to in silico molecular docking or MicroScale Thermophoresis (MST) approach and/or to improve existing molecules to prevent or treat BPI. Identification of antibiofilm targets or molecules in a suitable and reproducible BPI model developed as a screening tool will help the scientific community to better decipher biofilms in BPI and will facilitate the transfer from in vitro toward in vivo models. New therapeutic strategies will raise to decrease the infection risk occurring after orthopedic surgery.

The Plas'ster project concerns the sterilization of materials and biomaterials used in medical devices. In the medical field, the most commonly used methods for sterilization of implantable or non implantable devices are steam sterilization (autoclave), ionizing radiation (gamma radiation) and ethylene oxide. The evolution of medical techniques and technologies and the emergence of new materials have led to great advances in medicine. Medical devices are listed in four categories and represent a very heterogeneous set ranging from wheelchair, eye lenses, pacemakers, biological glues, to bone filling products ? Application fields are wide and include among other orthopedics, ophthalmology, dentistry, nephrology, general surgery ... However, the sterilization of some of these new devices presents some difficulty linked to their vunerability to sterilizing agents (physical or chemical). Thus, new ways of sterilization are studied at present. One of the most promising methods is the cold plasma sterilization. This technique is based on the ionisation of a gas or gas mixture. Many studies have demonstrated the efficacy of a plasma on microorganisms inactivation. However, the possibility for preservation of sterility through this technique was rarely studied, and, in addition, there are few studies on the effects of plasma on materials and/or biocompatibility in the case of implantable devices. The project is based on the development of a sterilization process by cold plasmas and conservation of the sterilization state of delicate medical devices, meaning sensitive to temperature, humidity or radiation. Conservation of the sterilization will be guarenteed by direct treatment inside the transport pouch. Based on the combined experience of CRITT-MDTS, EA " Biomaterials and Inflammation in Bone Site" (EA 4691, ex INSERM UMR-S 926) and GREMI, this project will allow a multi-disciplinary approach. This will cover different aspects: the compliance with standards for sterilization of medical devices; conservation and integrity of the characteristics of devices subject to the plasmas, the integration of organic devices by checking the absence of toxicity or inflammatory reaction generated by the sterilization, the characterization of plasma species. Validating key data and conceptualization of an apparatus able to reach the main objective meaning sterilization and conservation of sterile condition, this project will lead to the industrialization of the plasma sterilization process for applications in hospitals or production sites while satisfying the regulations from health authorities.

With population ageing worldwide, there is a constant increase in need for bone filling material in order to treat critical bone defect. Actually long bone defects are particularly challenging for regenerative medicine. To date, no adequate scaffold able to promote tissue ingrowth within such a context is available. The current synthetic bone substitutes have a weak capacity to stimulate the neo-tissue formation, to limit the risk of infection and can induce an inflammation deleterious for the durability of the implant. Moreover, ceramic substitutes are naturally brittle with limited ergonomics, which make them difficult to use in certain conditions (anatomical sites present variable access, geometry and mechanical stress). The ionic doping of porous bioceramics based on calcium phosphates (CaP) could be used to overcome the first difficulties mentioned, using strontium (Sr2+), copper (Cu2+) and zinc (Zn2+) respectively, while the use of an interlocking or breakable ceramic scaffold, as well as biobased shape memory composite could make it possible to overcome the second limitation. Thus, our PIMyBone program aims to develop, to characterize (physically, chemically and mechanically), and to evaluate biologically (in vitro and in vivo) two therapeutic solutions via macroporous scaffolds either ceramics or hybrid ceramics/shape memory composite. These three-dimensional structures will be shaped by the same optimized PIM (Powder Injection Moulding) process using additive manufacturing tools, in order to obtain complex custom geometries with multiple porosity levels, to allow use in any indication and regardless of the geometry of the bone defect.