Local and long-term bacteriophage delivery by biomaterial-based concepts for the treatment of implant-associated infections

• Applicants: Dr. Anja Lode; Privatdozent Dr. Markus Rupp
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery ; Biomaterials
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 536226074

Multiple drug resistant (MDR) bacteria are an increasing worldwide problem. In orthopaedic and trauma surgery, implant-associated infections are devastating complications with high mortality rates. Therefore, there is an urgent need to develop innovative therapeutic ap-proaches for the treatment of severe infections. Bacteriophages (phages) are viruses that exclusively infect and finally kill bacteria; they often have a narrow host range making them highly specific. In recent years, first encouraging results have been reported in the application of phages for difficult-to-treat cases of implant-associated infections. Thus, they are considered a promising supplement and/or alternative when conventional antibiotic therapy fails due to MDR bacterial infection. However, in order to develop efficient treatment approaches, optimal dosages and application routes still have to be elucidated. Similar to antibiotic therapy, consensus exists about beneficial local application of phage at the site of infection during/after surgical treatment. The aim of this project is to develop and evaluate biomaterial-based delivery systems that can release phages locally over a long time to treat and prevent implant-associated infections. In order to enable a fast translation to the clinics, the project will focus on clinically established and approved biomaterials which are injectable: (1) bone cements, which are used to fix endoprostheses, for dead space management as well as defect reconstruction, and (2) hydro-gels as versatile drug delivery systems, which can be applied directly into infected joints, used as coating of indwelling implants or for treatment of open and chronic wounds. It will be investigated whether these implant materials can be efficiently loaded with phages and if they release the phages in a sustained manner and active form. Suitable loading protocols will be developed. With the intention to improve the capability of these biomaterials for long-term phage delivery and/or to modulate the release profile, two strategies will be pursued. Composite materials of the injectable implant materials and micro-particles of mesoporous bioactive glass, which possess excellent drug delivery properties, will be developed and characterized. Such injectable composite materials could also be used in the future for dual release of phages and antibiotics. In addition, approaches for a combined application of bone cements and hydrogels as hybrid materials will be explored. Finally, the cytocompatibility with respect to the response of tissue specific osteoblasts as well as of immune cells will be analyzed. It will be assessed of phage-loaded biomaterials are storable so that they can be used application by the surgeon as ready-to-use implant material and reproducibility, safety and quality are improved. At the end of the project, candidate materials for clinical application will be identified.

• DFG Programme: Research Grants