Smart injectable nanoparticle-loaded hydrogel for synergic and targeted treatment of osteomyelitis (SinGel)

Osteomyelitis requires long-term antibacterial treatment, but poor vascularization around bone tissues hinders optimal drug delivery. The rapid development of antibacterial resistance, formation of biofilms, intracellular infections, and the need for two operations are urgent unanswered problems associated with osteomyelitis. We propose to provide a three-fold solution. Firstly, we aim to enhance the antibacterial and bone-affinity properties of four antibiotics (AB) - gentamicin, vancomycin, meropenem, ciprofloxacin - by synthesizing AB-bisphosphonate conjugates and testing synergy between AB and a panel of phenolic acids (PA) on both reference strains and clinical isolates. Besides their antibacterial and resistance-reversing properties, PA are known antioxidants and, therefore, could reduce the side effects associated with the treatment. Secondly, PLGA and PLGA-alendronate nanocarriers with co-encapsulated synergic combinations of AB and PA will be prepared to achieve sustained release of active agents. Thirdly, the nanocarrier system and free AB will be encapsulated in a thermo-sensitive, biodegradable, osteogenic hydrogel matrix. We hypothesize that a three-fold approach would lower the minimal effective concentration of the AB, en