Locally delivered adjuvant biofilm‐penetrating antibiotics rescue impaired endochondral fracture healing caused by MRSA infection

Abstract

Infection is a devastating complication following an open fracture. We investigated whether local rifampin-loaded hydrogel can combat infection and improve healing in a murine model of methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis. A transverse fracture was made at the tibia midshaft of C57BL/6J mice aged 10-12 weeks and stabilized with an intramedullary pin. A total of 1 × 10 6 colony-forming units (CFU) of MRSA was inoculated. A collagen-based hydrogel containing low-dose (60 μg) and high-dose (300 μg) rifampin was applied before closure. Postoperative treatment response was assessed through bacterial CFU counts from tissue and hardware, tibial radiographs and microcomputed tomography (μCT), immunohistochemistry, and histological analyses. All untreated MRSA-infected fractures progressed to nonunion by 28 days with profuse MRSA colonization. Infected fractures demonstrated decreased soft callus formation on safranin O stain compared to controls. Areas of dense interleukin-1β stain were associated with poor callus formation. High-dose rifampin hydrogels reduced the average MRSA load in tissue (p < 0.0001) and implants (p = 0.041). Low-dose rifampin hydrogels reduced tissue bacterial load by 50% (p = 0.021). Among sterile models, 88% achieved union compared to 0% of those infected. Mean radiographic union scale in tibia scores improved from 6 to 8.7 with highdose rifampin hydrogel (p = 0.024) and to 10 with combination local/systemic rifampin therapy (p < 0.0001). μCT demonstrated reactive bone formation in MRSA infection. Histology demonstrated restored fracture healing with bacterial elimination. Rifampinloaded hydrogels suppressed osteomyelitis, prevented implant colonization, and improved healing. Systemic rifampin was more effective at eliminating infection and improving fracture healing. Further investigation into rifampin-loaded hydrogels is required to correlate these findings with clinical efficacy.

A Review on Hydrogels with Photothermal Effect in Wound Healing and Bone Tissue Engineering

“…Tumors [ 1 ], fractures [ 2 ], burns [ 3 ], diabetes [ 4 ], and other acute/chronic diseases seriously affect people’s health. These diseases are accompanied by severe infections or tissue defects.…”

Current osteomyelitis mouse models, a systematic review

“…All the studies using fixation plates apply surgical devices such as the "MouseFix" plate with 4 or 6 screw holes and/or surgical tools such as a Gigli saw to create a fracture size diameter of 0.22, 0.44 or 0.67 mm (RISystem, Davos, Switzerland). Alternatively, the studies that fix the fracture using an intramedullary nail, create the fracture first and then ream the bone pieces using a nail (Cahill et al, 2021;Johnson et al, 2018). 88 % of the studies analysed created the bone fracture in the femur, 6 % in the tibia and 6 % in the radius (Fig.…”

“…The studies that used fracture-related infection models encountered more complications. In the models with a fracture and an intramedullary nail the mortality was ranging between 5 and 10 % and it was related to surgical complications (Cahill et al, 2021;Andres García, personal communication, 2021). In the models with a fracture fixed using a fixation plate, the mortality was related to intraoperative complications (ranging between 2 and 29 %) such as implant misplacement (Sabaté Brescó et al, 2017), anaesthesia fatality (Oezel et al, 2019;Sabaté Brescó et al, 2017;Ceylan Windolf, personal communication, 2021;Fintan Moriarty, personal communication, 2021) or cardiopulmonary instability (Oezel et al, 2019).…”

Controlled and Local Delivery of Antibiotics by 3D Core/Shell Printed Hydrogel Scaffolds to Treat Soft Tissue Infections

“…Delivery of antibiotics from hydrogels (such as alginate, gelatin, chitosan, modified hyaluronic acid, etc.) have been extensively studied and their applicability for treating infections in open fractures and burn wounds was evaluated [19,[53][54][55]. However, in most of these studies, antibiotics were loaded in either beads, membranes, or thick hydrogels.…”

“…However, in most of these studies, antibiotics were loaded in either beads, membranes, or thick hydrogels. Various antibiotics are loaded by direct dissolving in hydrogels [19,53,56], absorbed [21,54,55,57,58] or as particles (preloaded in suitable carrier particles) [59] composed of hydrogels. Similar to our study, the release of the loaded antibiotics in these studies was also governed by their diffusivity, variable porosity of the hydrogel and their interaction with the hydrogel components.…”