PhD candidate: Development of a multicellular 3-dimensional in vitro model of bone infection
Fracture related infection (FRI) is one of the most serious complications associated with the surgical fixation of bones fractured due to trauma. In our recent experimental studies in mice, we have characterized the pathology of Staphylococcus aureus FRI and shown that it involves the presence of bacterial biofilms on the surface of the implanted device, which is surrounded by accumulations of mostly necrotic neutrophils and fibrin. Finally, these structures are covered by an outer layer of fibrous encapsulation. We believe this clearly defined "FRI abscess" structure is central to the failure of the host defenses or antibiotic therapy to clear the infection, and ultimately for the failure of the fracture to heal.
The PhD candidate will be trained at the AMC in various courses relevant for his/her research, in compliance with the rules and regulations of the AMC Graduate School, and will graduate at the Faculty of Medicine of the University of Amsterdam. The project is performed within the research line of Dr. S.A.J. Zaat on “Biomaterial-associated infections and novel antimicrobial strategies” (http://www.amc.nl/SAJZaat) The research will mainly be carried out in the laboratories of the AO Research Institute in Davos, Switzerland, under the supervision of Dr. T.F. Moriarty, with regular visits to Amsterdam for training or specific research activities.
With this project, we aim to develop a 3-dimensional, multi-cellular in vitro cell culture model that replicates this "FRI abscess". This project will benefit from the availability of technical expertise within the project team in the use of 3-D cell culture models, which has been applied to tissue engineering and cancer immunology, but has not yet been extensively applied to infection biology. The key benefits of such a model will be the use of primary human cells, for which S. aureus has several specific targets not present in laboratory animals. This would also offer a more faithful recapitulation of the in vivo situation than may be achieved by conventional 2-dimensional co-culture systems. Once established, the 3-D model will be used to investigate the key bacterial and immune defense mechanisms responsible for abscess formation and resistance to therapy. Such advanced models will represent new tools for infection studies and for pre-clinical assessment of innovative treatments, and would be a significant advance for the field of implant related infection.
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