Sustained release of vancomycin from polyurethane scaffolds inhibits infection of bone wounds in a rat femoral segmental defect model

Abstract

Infection is a common complication in open fractures that compromises the healing of bone and can result in loss of limb or life. Currently, the clinical standard of care for treating contaminated open fractures comprises a staged approach, wherein the wound is first treated with non-biodegradable antibiotic-laden poly(methyl methacrylate) (PMMA) beads to control the infection followed by bone grafting. Considering that tissue regeneration is associated with new blood vessel formation, which takes up to 6 weeks in segmental defects, a biodegradable bone graft with sustained release of an antibiotic is desired to prevent the implant from becoming infected, thus allowing the processes of both vascularization and new bone formation to occur unimpeded. In the present study, we utilized biodegradable porous polyurethane (PUR) scaffolds as the delivery vehicle for vancomycin. Hydrophobic vancomycin free base (V-FB) was obtained by precipitating the hydrophilic vancomycin hydrochloride (V-HCl) at pH 8. The decreased solubility of V-FB resulted in an extended vancomycin release profile in vitro, as evidenced by the fact that active vancomycin was released for up to 8 weeks at concentrations well above both the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC). Using PUR prepared from lysine triisocyanate (LTI) (PUR(LTI)), the extended in vitro release profile observed for V-FB translated to improved infection control in vivo compared to V-HCl in a contaminated critical-sized fat femoral segmental defect. The performance of PUR(LTI)/V-FB was comparable to PMMA/V-HCl beads in vivo. However, compared with PMMA, PUR is a biodegradable system which does not require the extra surgical removal step in clinical use. These results suggest that PUR scaffolds incorporating V-FB could be a potential clinical therapy for treatment of infected bone defects.