On targeting host-pathogen interaction to prevent biomaterial-associated infections on titanium implants

Abstract

The rising use of implants, driven by an ageing global population and conditions such as osteoporosis and osteoarthritis, highlights the urgent need to address implant-related complications. Despite high success rates, implant failures due to biomaterial-associated infections (BAI) remain a significant clinical challenge, posing the most feared and devastating complication for patients. The complexity of BAI pathology, marked by compromised immune responses and biofilm formation on implant surfaces, hampers effective diagnosis and treatment. Staphylococcus aureus and Pseudomonas aeruginosa are among the primary culprits, using biofilm-mediated defenses to evade host immune response and resist antibiotic treatment. The ongoing threat of antimicrobial resistance further accentuates the urgent need for preventive measures. This thesis investigates the influence of titanium-based biomaterials with surface modifications on the immune response and their effectiveness in combating bacterial infections. The research focuses on four main areas: I) Evaluating the competition for surface colonization between macrophages and S. aureus on modified titanium surfaces. Macrophages show improved phagocytic efficacy when they arrive to the surface before or simultaneously with S. aureus. However, if S. aureus forms a biofilm before the arrival of macrophages, they can evade the immune response, survive intracellularly, and increase macrophage cytotoxicity; II) Assessing the impact of quorum sensing inhibition on immunomodulation by P. aeruginosa. Sodium salicylate disrupts P. aeruginosa quorum sensing signals, which reduces virulence factor production, enhances immune cell migration, and limits pro-inflammatory cytokine secretion; III) Analyzing the antimicrobial and immunomodulatory properties of copper-electroplated titanium. Copper- electroplated titanium exhibits strong bactericidal and antibiofilm properties, enhancing macrophage phagocytosis of S. aureus. However, it reduces macrophage viability within the first 24 h; IV) Investigating macrophage-osteocyte paracrine crosstalk under simulated inflammation/infection conditions. Macrophages influence osteocyte behavior through paracrine signaling, with M1 phenotype macrophages attenuating bone formation and mineralization pathways. To effectively address BAI, it is essential to strike the right balance between effective antimicrobial activity and optimal cytocompatibility. The findings from this thesis enhance our understanding of the interactions between host immune cells bacteria, and biomaterials and represent an in vitro and in vivo proof-of-concept for the clinical translation of the evaluated antimicrobial mechanisms. In addition, it provides a comprehensive set of analytical methodologies for screening new biomaterials in terms of both immune response and antimicrobial activity.