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INTRODUCTION: The recurrence rate of chronic osteomyelitis in adults is close to 30% [1]. Bacteria are known to migrate deeper into bone tissue through canaliculi and evade common systemic- and local-antibiotic therapies [2]. By fabricating antibiotic loaded poly(ϵ-caprolactone) (PCL) microspheres conjugated with the bone-chelator poly(aspartic acid) (PAA) we aim to prolong the microsphere residency near the site of infection, increasing bactericidal potential. METHODS: Hydrophobic Gentamicin-dioctyl sulfosuccinate (Gen-AOT) loaded PCL microspheres were made by oil/water emulsion methods. In vitro antimicrobial properties were tested by zone of inhibition (ZOI) in a serial plate transfer test with S. aureus. In vivo antimicrobial efficacy of 1 mg of microspheres was tested in a femoral defect in rats (n =5), infected with 2·106 colony forming units (CFU) of bioluminescent Xen-29 a week prior to treatment. In a 2nd study, the PCL microspheres underwent conjugation with PAA by carbodiimide chemistry. Interaction with bone mineral was assessed in the same model as above. IR780 iodide loaded PCL or PCL-PAA microspheres (1 mg) were injected in the bone defect and traced using an in vivo imaging system (IVIS Lumina III, Perkin Elmer). RESULTS & DISCUSSION: ZOI of Gen-AOT loaded PCL was measurable for 5 days, while a ZOI for bactericidal collagen-sheets was visible for 3 days. The Gen-AOT loaded PCL microspheres caused an 81% reduction in CFU compared to untreated control. In vivo, a brighter signal was measured for PCL-PAA compared to PCL microspheres, validating the hypothesis that PAA-grafted PCL resides longer in bone as control PCL. CONCLUSIONS: In the presented animal model, a monotreatment of 1 mg PCL microspheres caused an 81% CFU reduction. PCL-PAA microspheres enhance bone affinity by chelation of the PAA to bone mineral at the femoral defect. Further work is required to optimize the bone-targeted drug delivery system to bone.

Fracture-related infection (FRI) is a common and serious complication in trauma surgery. Accurately estimating the impact of this complication has been hampered by the lack of a clear definition. The absence of a working definition of FRI renders existing studies difficult to evaluate or compare. In order to address this issue, an expert group comprised of a number of scientific and medical organizations has been convened, with the support of the AO Foundation, in order to develop a consensus definition. The process that led to this proposed definition started with a systematic literature review, which revealed that the majority of randomized controlled trials in fracture care do not use a standardized definition of FRI. In response to this conclusion, an international survey on the need for and key components of a definition of FRI was distributed amongst all registered AOTrauma users. Approximately 90% of the more than 2000 surgeons who responded suggested that a definition of FRI is required. As a final step, a consensus meeting was held with an expert panel. The outcome of this process led to a consensus definition of FRI. Two levels of certainty around diagnostic features were defined. Criteria could be confirmatory (infection definitely present) or suggestive. Four confirmatory criteria were defined: Fistula, sinus or wound breakdown; Purulent drainage from the wound or presence of pus during surgery; Phenotypically indistinguishable pathogens identified by culture from at least two separate deep tissue/implant specimens; Presence of microorganisms in deep tissue taken during an operative intervention, as confirmed by histopathological examination. Furthermore, a list of suggestive criteria was defined. These require further investigations in order to look for confirmatory criteria. In the current paper, an overview is provided of the proposed definition and a rationale for each component and decision. The intention of establishing this definition of FRI was to offer clinicians the opportunity to standardize clinical reports and improve the quality of published literature. It is important to note that the proposed definition was not designed to guide treatment of FRI and should be validated by prospective data collection in the future.

Designing calcium phosphate-loaded polymeric porous scaffolds with controlled architecture using stereolithography (SLA) has great potential in the field of bone tissue engineering. However, the use of poly(ester)s with suboptimal degradation property has mainly been reported. In the present work, we introduced a poly(trimethylene carbonate) (PTMC) and nano-hydroxyapatite (HA) resin suitable for SLA manufacturing and created cytocompatible 3D porous structure. First, the resin formulation and HA content were optimized for photo-crosslink-based SLA fabrication process. Subsequently, we evaluated the influence of the resin composition on physico-chemical characteristics of fabricated films and scaffolds. Then, the influence of the biomaterial composition on human bone marrow mesenchymal stem cell viability, adhesion and proliferation was assessed. Films and macroporous scaffolds were successfully produced by photo-crosslinking with up to 40 wt% of HA (relative to PTMC). We demonstrated that addition of HA in PTMC matrices induced a direct effect on the surface properties, in terms of wettability and topography. Additionally, mechanical tests revealed a correlation between the amounts of HA loaded in PTMC and the stiffness of the SLA-fabricated scaffolds. Importantly, the different photo-crosslinked biomaterials exhibited in vitro cytocompatibility, similar to tissue culture polystyrene. Those data suggest the possibility to fabricate highly tunable HA-loaded PTMC 3D porous structures for bone tissue engineering application.

Repeated administration of gentamicin (Gen) is often necessary to have efficacious pharmacokinetics in both infection prophylaxis and treatment. In order to increase the half-time of Gen sulfate and minimize the dosage, the antibiotic can be grafted to polymers as a prodrug or encapsulated within polymers. Gen is positively charged and can interact with negatively charged macromolecules to form polyelectrolyte complexes (PECs). The complexation of Gen with hyaluronic acid (HA) was investigated here. Subsequently, several HA conjugates were prepared and screened for their thermo-responsive behavior and their ability to form PECs with Gen. PEC formation with HA poly(N-isopropylacrylamide) yields an injectable formulation, which precipitates out of solution to form microscopic or macroscopic gels, depending on its concentration, at temperatures higher than the lower critical solution temperature