Abstract
Introduction Treatment of open fractures routinely involves multiple surgeries and delayed definitive fracture fixation because of concern for infection. If implants were made less susceptible to infection, a one-stage procedure with intramedullary nailing would be more feasible, which would reduce morbidity and improve outcomes. Methods In this study, a novel open fracture mouse model was developed using Staphylococcus aureus (S. aureus) and single-stage intramedullary fixation. The model was used to evaluate whether implants coated with a novel “smart” polymer coating containing vancomycin or tigecycline would be colonized by bacteria in an open fracture model infected with S. aureus. In vivo bioluminescence, ex vivo CFUs, and X-ray images were evaluated over a 42-day postoperative period. Results We found evidence of a markedly decreased bacterial burden with the local release of vancomycin and tigecycline from the PEG-PPS polymer compared to polymer alone. Vancomycin was released in a controlled fashion and maintained local drug concentrations above the minimum inhibition concentration for S. aureus for greater than 7 days postoperatively. Bacteria were reduced 139-fold from implants containing vancomycin and undetected from the bone and soft tissue. Tigecycline coatings led to a 5991-fold reduction in bacteria isolated from bone and soft tissue and 15-fold reduction on the implants compared to polymer alone. Antibiotic coatings also prevented osteomyelitis and implant loosening as observed on X-ray. Conclusion Vancomycin and tigecycline can be encapsulated in a polymer coating and released over time to maintain therapeutic levels during the perioperative period. Our results suggest that antibiotic coatings can be used to prevent implant infection and osteomyelitis in the setting of open fracture. This novel open fracture mouse model can be used as a powerful in vivo preclinical tool to evaluate and optimize the treatment of open fractures before further studies in humans.
Highlights
Treatment of open fractures routinely involves multiple surgeries and delayed definitive fracture fixation because of concern for infection
1% (v/v) (3-mercaptopropyl) trimethoxysilane was reacted with the K-wire in toluene at 90°C with stirring followed by sonication in chloroform (5 times), acetone (2 times), methanol (5 times), and milliQ water (5 times). e K-wire was heated at 50°C for at least 30 minutes to dry. e PEG-PPS polymer was dissolved in phosphate buffer saline (PBS) to make either a 3% or 6% (w/v) solution, which was used to dissolve either tigecycline or vancomycin at a concentration of 20 mg/ml
To confirm that the bioluminescence signals corresponded to the bacterial burden in vivo, the mice were euthanized following the last day of imaging, postoperative day (POD) 42, and the implant and surrounding tissue were cultured
Summary
Open fractures are often devastating injuries for patients. In addition to challenges of fracture healing in dramatically injured and denudated bone, exposure to the “outside world” results in osteomyelitis in up to 50% of cases [1, 2]. Vancomycin and gentamicin have been delivered locally in open fractures using polymethyl methacrylate (PMMA) cement beads, resulting in lower postoperative infection rates compared to intravenous antibiotics alone (4% versus 12%–16%) [16, 17]. These patients require a second operation to remove the residual cement, and the implant surface is not protected, leaving it susceptible to bacterial seeding and biofilm formation. Tigecycline is a newer antibiotic with increased antimicrobial activity against both MSSA and MRSA, especially against biofilm formation in both in vitro and in vivo settings [26, 27]. us, we incorporated vancomycin or tigecycline into a novel PEG-PPS polymer covalently linked to an intramedullary implant and evaluated the efficacy of these coatings against a local S. aureus infection
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