Design of smart scaffolds for the treatment and prevention of bone infection

Resumen

This thesis, entitled "Design of smart scaffolds for the treatment and prevention of bone infection", is focused on the development of smart organic-inorganic hybrid materials capable of perform controlled-delivery of drugs with biomedical purposes. In the first chapter, a general introduction about supramolecular chemistry, organic-inorganic hybrid materials and porous materials is given. The characterization and applications of porous materials are extensively explained, since those contents are highly related to the developing of this thesis. In the second chapter, three projects based on the design of gated devices are presented. In the first publication, two gated systems based on the use of a mesoporous silica material as an inorganic support, loaded and functionalised with organic molecules to achieve a controlled drug release are studied. The first molecular gate is composed by amino moieties and adenosine 5'-triphosphate (ATP), and the second one is composed by 3-(triethoxysilyl)propylisocyanate linked to ε-poly-L-lysine polymers. The two systems were characterized by solid state nuclear magnetic resonance (NMR) and Fourier transformed infrared spectroscopy (FTIR). The bioactivity capabilities of the materials were also studied. Then, both molecular gates have been implemented in loaded solids in order to demonstrate their controlled-release capabilities. In a first case, the mesoporous support was loaded with doxorubicin and capped with ATP molecules, and the system has been validated in a human osteosarcoma cell culture test. In a second case, the mesoporous support was loaded with levofloxacin and capped with the ε-poly-L-lysine molecular gates, and the system has been validated with E.coli bacteria. Once these two systems are described, a second project with the ATP molecular gates is presented. In this case, the mesoporous bioactive glass which acts as support has a composition of 80%SiO2-15%CaO-5%P2O5, and it has been loaded with levofloxacin with the purpose of killing bacteria. The solid has been characterized by corresponding techniques, and its bioactive properties have been studied. Finally, E.coli bacteria have been used to demonstrate that the solid is able to perform an antimicrobial activity only in the presence of acid phosphatase. The third project consists of a MCM-41 support loaded with a dye and capped with a peptide sequence. The trigger used in this case is the V8 protease, typical of the microorganism S. aureus. The system has been correspondingly characterized, and its drug release properties in vitro have been tested, demonstrating the efficiency of the design. In the third chapter, calcium phosphate microspheres and scaffolds have been functionalised with an essential-oil component derivative in order to achieve antibacterial properties. First, the vanillin-derivative has been synthesized and characterised, and in a second step, it has been attached to the surface of the calcium phosphate materials. Then, the antimicrobial properties of both materials have been tested against E.coli bacteria. Cytotoxicity assays with L929 fibroblast-like cells have been performed in order to demonstrate that the functionalized scaffolds did not perform a cytototxic effect. Finally, biocompatibility assays have been made with MG-63 human osteoblast-like cells, demonstrating that the functionalization of the scaffolds with vanillin do not affect their osteoregenerative properties. To sum up, it can be concluded that the results obtained in this thesis have contributed to the field of stimuli-responsive materials and antibacterial devices. The new designs could be key in the development of future applications in biotechology and biomedical research, particularly in bone infection and bone regeneration therapeutics.