SYNTHESIS AND CHARACTERIZATION OF BIOACTIVE GLASS-CERAMIC PARTICLES WITH ADVANCED ANTIBACTERIAL PROPERTIES FOR APPLICATIONS IN BONE REGENERATION

Bacterial infections are major surgical complications, which have worsened due to the continued evolution of drug-resistance. In coping with the decay of the antibiotic era, scientists eagerly search for alternative treatments. Multi-functional biomaterials capable of combating infections while triggering tissue regeneration are of great interest. For example, bioactive glasses have been regularly used to deliver drugs and regenerate tissue owed to their unique bone-bonding ability. Doping the bioactive glass structure with broad-spectrum biocide ions such as Ag+ confers advanced antibacterial properties. The release of Ag+ is controlled by the degradation process of the glass network, maintaining the dose within a therapeutic window that is not cytotoxic to eukaryotic cells. Despite the extensive research performed on Ag-doped bioactive glasses, their regenerative properties in bone tissues have been rarely investigated. This thesis presents promising interactions between Ag-doped bioactive glass (Ag-BG) microparticles and osteoprogenitor cells, providing evidence of the ability to support bone regeneration. Ag-BG’s degradation provoked cell proliferation and cell differentiation in vitro and demonstrated healing of critical calvaria defects in mice after one month of implantation, thanks to the release of Si and Ca ions. Additionally, Ag-BG was antibacterial against Staphylococcus aureus (S. aureus), the most common cause of bone-degenerative diseases like osteomyelitis, and demonstrated low proclivity to induce resistance. The antibacterial potential originated from the degradation by-products of the structure. The mechanism of inhibition was built upon four main sources from higher to lower contribution: Ag+ release, oxidative stress, mechanical damage by nano-sized debris, and osmotic effect. In addition, Ag-BG was capable of restoring ineffective antibiotics with cell-wall-related inhibitory mechanisms by simple combinatorial therapies, rendering them effective in clearing infections. This unprecedented functionality of Ag-BG was expanded with antibiotic depots, where Ag-BG served as a carrier for an ineffective drug. Bioactive glass nanoparticles (BGNs) have been proposed to advance biological and antibacterial properties compared to their micro-sized counterparts. However, the challenges of producing BGNs with multifold metallic ions in a reproducible manner have limited their use. Here, the Stöber method was comprehensively studied to understand the effect of process variables on BGNs’ composition, structure, and morphology. The use of methanol as solvent and the early addition of metallic ion reagents before catalysis helped improved their cation incorporation within the glass network. Extended stirring was key to achieving the targeted composition and controlling the particle size. Monodispersed 10 nm Ag-doped BGNs (Ag-BGNs) were achieved. These Ag-BGNs were stronger antimicrobial weapons, providing bacterial inhibition within hours of treatment. The biological properties were not significantly advanced in the Ag-BGNs compared to Ag-BG; however, cell proliferation, differentiation, and bone re-growth were still provoked. These Ag-BGNs were used as fillers in hydrogel nanocomposites with natural matrices consisting of collagen type I or extracellular matrix. Ag-BGNs distributed homogeneously along the polymer fibrils and allowed polymerization within hours at physiological conditions. These materials hold potential for injectable devices, designing minimally invasive single-step treatment for debilitating bone infections while promoting tissue recovery.