This PhD position is part of the PREPARE project (Programmable Release of Prophylactic Antibacterial & Response Enhancing agents), a collaborative initiative between the Infection Biology and Biomedical Materials Focus Areas at the AO Research Institute Davos and CK CARE (Prof. Pierre Yves Mantel). 

The Ph.D. student will carry out the experimental work at the AO Research Institute Davos under the supervision of Dr. Matteo D'Este in cooperation with Dr Fintan Moriarty and Prof. Pierre Yves Mantel. The formal academic affiliation will be with the University of Fribourg with supervision by Prof. Michael Walch, Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine at the University of Fribourg.

Fracture-related infection (FRI) remains a major clinical challenge despite current prophylactic strategies. Increasing evidence shows that early infection establishment is driven by rapid formation of Staphylococcus aureus microaggregates and transient impairment of neutrophil antibacterial function following trauma.

The PREPARE project aims to address this problem by:

• Defining the earliest events enabling bacterial survival in the surgical field (aggregate formation, fibrin encapsulation, antibiotic tolerance)
• Identifying small-molecule immunomodulators that enhance neutrophil antibacterial activity
• Contributing to the development of next-generation responsive biomaterials for localized infection prevention

Develop a hydrogel responsive to degrading enzymes for on demand release:

• Identify and select a linker sequence susceptible to enzymatic degradation by neutrophil-secreted enzymes with high specificity, synthetic accessibility, and suitability for subsequent conjugation to hyaluronan.
• Develop and optimize a di-telechelic crosslinker for hyaluronan hydrogel formation and characterize the resulting gels using NMR, FT-IR, and rheology.
• Demonstrate enzyme-triggered hydrogel degradation in vitro by monitoring changes in gel properties through rheological analysis.
• Evaluate the release kinetics of model compounds from the hydrogel using UV spectroscopy or HPLC to assess controlled release performance.

Incorporate small molecule immunomodulators into the hydrogel:

• Establish robust covalent ligation or encapsulation strategies to load selected immunomodulators into the hydrogel while preserving their biological activity.
• Develop and characterize hyaluronan-bound small molecule immunomodulator systems, including covalent tethering and enzymatic responsive designs, to prevent diffusion-driven release while enabling enzyme-triggered exposure of modulators.
• Engineer enzymatically-responsive core-shell microparticles with a core rich of immunomodulators and hyaluronan-based shell to achieve controlled, enzyme-triggered release from micron-scale delivery vehicles.

Evaluate functional performance of the loaded hydrogel:
This task will be carried out in close collaboration with the infection biology group at ARI. 

• Assess neutrophil-triggered hydrogel degradation, release kinetics, and material properties, and determine the biological efficacy of the released modulators using in vitro neutrophil assays relevant to early postoperative infection.

Carrying out this project, the successful candidate will:

• Apply advanced biomaterials synthesis and characterization techniques 
• Analyse and interpret complex experimental datasets
• Report the results to colleagues and present at local and international conferences
• Contribute to interdisciplinary collaboration with infection biology specialist in ARI within the PREPARE project

• Master's degree in pharmaceutical sciences, chemistry, biomaterials science/engineering or related discipline
• Exceptional drive and commitment to carry out a highly demanding and rewarding research project
• Excellent communication skills in English
• Ability to design, plan, and execute experimental studies independently
• Strong interest in biomaterials science, innate immunity, and translational research
• Motivation to work in a highly interdisciplinary and collaborative environment
• Interest in translational research and orthopaedic device related infection and microbiology 

Additional desirable skills:

• Practical experience in polymers derivatization, and the preparation/characterization of soft biomaterials 
• Practical experience in preparation of micro- or nano- particles based delivery systems
• Experience with tissue cell culture and immunological assays 
• Experience working with primary immune cells, especially neutrophils
• Familiarity with 3D cell/tissue culture