Infection is a common complication of severe open fractures and compromises bone healing. The present standard of care is a two-stage approach comprising of initial placement of antibiotic-impregnated PMMA beads to control infection followed later by bone grafting. Although the systemic antibiotics and PMMA/antibiotic beads control the infection initially, there are often residual bacteria within the wound. After grafting and definitive closure, the implanted graft is placed in an avascular defect and could function as a nidus for infection. Bioactive porous polyurethane (PUR) scaffolds have been shown to improve bone healing by delivering recombinant human bone morphogenetic protein-2 (BMP-2) and reduce infection by delivering antibiotics. The release kinetics of the BMP-2 were an initial burst to recruit cells and sustained release to induce the migrating cells. The Vancomycin (Vanc) release kinetics were designed to protect the graft from contamination until vascularisation by having an initial burst and then remaining over the MIC for Staph. aueus for two months. In this study, PUR+BMP-2+Vanc scaffolds were first tested in a non-infected critical size rat femoral segmental defect and was found to perform comparably to PUR+BMP-2, thus indicating that Vanc did not hinder bone healing. PUR+BMP-2+Vanc scaffolds were subsequently evaluated in an infected critical size rat femoral segmental defect. The dual delivery approach resulted in significantly more new bone formation and infection control than both PUR+BMP-2 and the collagen+BMP-2 treatments. These data indicate that the dual-delivery strategy effectively protects the graft from infection during wound healing and regenerates more bone in contaminated defects. This moderately osteoconductive bone graft is capable of being injected, provides a more sustained release of BMP-2 than the collagen sponge, and can release antibiotics for over 8 weeks. The dual-delivery approach may improve patient outcomes of open fractures by protecting the osteoinductive graft from colonization until vascularization occurs.

Introduction

Despite the routine use of irrigation, debridement and systemic antibiotics, there is a high incidence of infection in severe open fractures. The synergistic use of local and systemic antibiotics appreciably reduces infection rates although the time window within which this is effective is unknown. The aim was to determine if delaying treatment of wounds causes higher levels of infection.

Background: Despite aggressive debridement, thorough irrigation, systemic antibiotics, and staged treatment, many open fractures still become infected. A graft that can promote bone regeneration and prevent infection could decrease complications. Polyurethane (PUR) scaffolds have previously been shown in separate studies to be nontoxic, osteoconductive, can promote bone growth by delivering BMP, and prevent infection by the sustained release of an antibiotic. This scaffold can deliver both BMP and vancomycin simultaneously; the purpose of this study is to determine if the co-delivery of the antibiotic inhibits bone formation.

Methods: Using an established critical size defect rat femur model, the amount of bone formation created by PUR scaffolds containing low and high doses of rhBMP-2 (2.4 μg and 22.4 μg respectively) and 0.8 mg vancomycin (8% of graft by weight) were compared to scaffolds that contained rhBMP-2 without antibiotics. After 4 weeks, the femurs were harvested and bone growth was assessed using microCT.

Results: There was no significant difference in bone growth between the groups that had the high dose of rhBMP-2. Surprisingly, the scaffolds that had the low dose of rhBMP-2 and vancomycin promoted more bone formation than scaffolds that had rhBMP-2 and no antibiotics.

Conclusions: The addition and co-delivery of vancomycin to the scaffolds did not inhibit bone growth. The addition of vancomycin to the PUR scaffolds may have altered the release kinetics of the rhBMP-2; this may explain the increase of bone formation in this group. This study demonstrates that incorporation of a therapeutic and a clinically-relevant level of vancomycin does not inhibit bone formation. These results suggest that a dual delivery bone graft has potential to reducing complications associated with open fractures.