FunModuLAR

Bone defects require a surgical management involving implantation of synthetic bone substitutes associated with oral antibiotic treatment to prevent nosocomial infection. However, current results obtained with these substitutes are not sufficient and the oral administration of antibiotics cause side effects and antibiotic resistance. Improvement of these bone substitutes is therefore necessary in order to improve bone tissue regeneration and to effectively fight, locally, against infections, thus limiting the development of side effects. The FunModuLAR project intends to develop 3D bone ceramic substitutes made of calcium phosphate-based ceramics produced by additive manufacturing with a complex architecture and controlled multi-scale porosity. This manufacturing process will allow the shaping of a micro-macroporous material used as a support for bone regeneration. These bioceramics will be, after consolidation, dually functionalized by molecules of interest: (i) cytokines, molecules recently identified as participating in osteoimmunomodulation and (ii) an antibiotic in order to fight locally against infections. The functionalization techniques used will be adapted to the targeted release kinetics for both types of molecules. The objective is to control the functionalization and release kinetics of these molecules in order to obtain a burst release of cytokines and a local and extended release of antibiotic molecules. This functionalization will be fully characterized from a physico-chemical, pharmacotechnical and biological point of view under bone physiological conditions in a 3D perfusion bioreactor. This will initially allow the evaluation of the release kinetics of the molecules of interest and the degradation kinetics of the material. The modulation of these release kinetics will be possible by a constant feedback (i) on the porosity and specific surface area of the material and (ii) on the amount of cytokines and antibiotics present in the bioceramic. The biological evaluation of the dual-functionalized ceramic in the presence of cells from the bone environment will also be carried out in order (i) to evaluate the efficacy of the functionalized bioceramic in inducing bone regeneration and bacterial growth inhibition and (ii) to estimate the possible toxicity of the ceramic and the molecules of interest released on the different cell types. The development of this dual-functionalized bioceramic will open the way to new methods and perspectives for transdisciplinary research in line with the new European regulation of medical devices, which tends to move closer to the demanding regulation of medicines.