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Orthopaedic Proceedings
Vol. 104-B, Issue SUPP_10 | Pages 61 - 61
1 Oct 2022
TREATMENT OF IMPLANT-ASSOCIATED OSTEOMYELITIS WITH INJECTABLE IN SITU-FORMING DEPOT DRUG DELIVERY SYSTEM
Fuglsang-Madsen A Henriksen NL Kvich LA Birch JKM Hartmann KT Bjarnsholt T Andresen TL Jensen LK Henriksen JR Hansen AE
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Aim

Several local antibiotic-eluting drug delivery systems have been developed to treat bacterial bone infections. However, available systems have significant shortcomings, including suboptimal drug-release profiles with a burst followed by subtherapeutic release, which may lead to treatment failure and selection for drug resistance.

Here, we present a novel injectable, biocompatible, in situ-forming depot, termed CarboCells, which can be fine-tuned for the desired antibiotic-release profile. The CarboCell technology has flexible injection properties that allow surgeons to accurately place antibiotic-eluting depots within and surrounding infectious sites in soft tissue and bones. The CarboCell technology is furthermore compatible with clinical image-guided injection technologies.

These studies aimed to determine the therapeutic potential of CarboCell formulations for treatment of implant-associated osteomyelitis by mono- and dual antimicrobial therapy.

Methods

The solubility and stability of several antibiotics were determined in various CarboCell formulations, and in vitro drug release was characterized. Lead candidates for antimicrobial therapy were selected using a modified semi-solid biofilm model with 4-day-matured Staphylococcus aureus biofilm (osteomyelitis-isolate, strain S54F9). Efficacy was investigated in a rat implant-associated osteomyelitis model established in the femoral bone by intraosseous implantation of a stainless-steel pin with 4-day-old in vitro-matured S. aureus biofilm. CarboCells were injected subcutaneously at the femur, and antimicrobial efficacy was evaluated 7 days post-implantation. Lead formulations were subsequently tested in a well-established translational implant-associated tibial S. aureus osteomyelitis pig model. Infection was established for 7 days before revision surgery consisting of debridement, washing, implantation of a new stainless-steel pin, and injection of antibiotic-releasing CarboCells into the debrided cavity and in the surrounding bone- and soft-tissue. Seven days post-revision, pigs were euthanized, and samples were collected for microbial and histopathological evaluation.

Orthopaedic Proceedings
Vol. 101-B, Issue SUPP_14 | Pages 93 - 93
1 Dec 2019
GUIDELINE FOR PRECLINICAL STUDIES OF BONE INFECTIONS
Jensen LK Henriksen NL Blirup SA Jensen HE
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Aim

To conduct a systematic review of non-rodent animal models (rabbit, pig, dog, goat and sheep) of bone infection. In the future, anti-infective technologies aiming to fight bone infections are depending on evaluation in reliable animal models. Therefore, it is highly relevant to evaluate the scientific quality of existing bone infection models.

Method

PubMed and Web of Science were searched systematically. To be included in the systematic review, publications had to deal with bacterial inoculation of non-rodent animals in order to model bone infections in humans. Data was extracted on study design e.g. bacterial inoculation dose and infection time, methodological quality and post-mortem evaluation with respect to registration and quantification of pathology and microbiology.

Orthopaedic Proceedings
Vol. 100-B, Issue SUPP_17 | Pages 64 - 64
1 Dec 2018
EXTREME HIGH LOCAL INTRAOPERATIVE GENTAMICIN CONCENTRATIONS ARE NEEDED TO PREVENT BIOFILM FORMATION IN VIVO
Jensen LK Bjarnsholt T Henriksen NL Kragh KN Jensen HE
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Aim

To investigate the local intra-operative concentration of gentamicin needed to prevent biofilm formation in a porcine model of implant-associated osteomyelitis.

Method

In total 24 pigs were allocated to six groups. Group A (n=6) was inoculated with saline. Groups B (n=6), C (n=3), D (n=3), E (n=3) and F (n=4) were inoculated with 10 μL saline containing 104 CFU of Staphylococcus aureus, however, different minimal inhibitory concentrations (MIC) of gentamicin were added to the inoculum of Groups C(160xMIC), D(1600xMIC), E(16000xMIC) and F(160000xMIC). The inoculums were injected into a pre-drilled implant cavity proximally in the right tibial bone. Following inoculation, a steel implant (2 × 15 mm) was placed in the cavity. The pigs were euthanized after five days. The implants were sonicated and swabs were taken from the implant cavity for microbiological evaluation. The peri-implant tissue was analyzed by histopathology including estimation of neutrophil infiltration.

Orthopaedic Proceedings
Vol. 99-B, Issue SUPP_22 | Pages 60 - 60
1 Dec 2017
HISTOPATHOLOGICAL DIAGNOSIS OF BIOFILM
Jensen LK Henriksen NL Jensen HE
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Aim

Despite the expanding research focusing on bacterial biofilm formation, specific histochemical biofilm stains have not been developed for light microscopy. Therefore, pathologists are often not aware of the presence of biofilm formation when examining slides for diagnosing bacterial infections, including orthopaedic infections. The aim of the present study was to develop a combined histochemical and immunohistochemical biofilm stain for simultaneous visualization of Staphylococcus aureus bacteria and extracellular matrix in different colours using light microscopy.

Methods

Infected bone tissue was collected from two different porcine models of osteomyelitis inoculated with the biofilm forming S. aureus strain S54F9. The infection time was 5 and 15 days, respectively. First, 25 common histochemical protocols were used in order to find stains that could identify extracellular biofilm matrix. Hereafter, the histochemical protocols for Alcian Blue pH3, Luna and Methyl-pyronin green were combined with an immunohistochemical protocol based on a specific antibody against S. aureus. Finally, the three new combined protocols were applied to infected bone tissue from a child suffering from chronic staphylococcal osteomyelitis for more than a year. For all combined protocols applied on all types of tissue (porcine and human) the number of double stained bacterial aggregates were counted. On the same sections the percentage of extracellular matrix of representative bacterial aggregates was calculated by image analysis.

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