SUMMARY

Biomaterial associated infections remain an unsolvable issue for medical devices, despite advances in device sophistication and longevity, and account for over 1 million hospital cases per year. Current therapies to eliminate biofilm formation in medical devices have shown low levels of success due to the inherent resistance of the biofilm towards antimicrobial agents, as well as the diverse methods in which bacteria can be introduced to the site of infection. Lysostaphin is an enzyme derived from Staphylococcus simulans that is responsible for cleaving the pentaglycine cross-links of the staphylococcal cell wall, leading to cell lysis, making it a potentially useful agent to eradicate infection in both sites of bacterial growth, as well as established biofilms. Hydrogels have proven to be an effective agent for the site-specific introduction and release of therapeutics due to their modularity and highly favorable mechanical properties. The overall project seeks to take advantage of these properties to provide local and sustained release of lysostaphin and rifampin within PEG hydrogels with integrin specific ligands to simultaneously reduce infection and promote fracture repair in vivo using sophisticated bone defect infection models that provide complex and clinically relevant scenarios of S. aureus infection. This is accomplished through 1) the development of a two-stage established infection model of a murine femoral fracture defect utilizing different fixation hardware to assess antimicrobial hydrogel efficacy and 2) the translation of antimicrobial hydrogels into an ovine ulnar and metapodial bone defect model for therapeutic efficacy in acute and established infection scenarios. This work provides a novel platform for antimicrobial delivery that not only mitigates chronic infections in a wide variety of clinically relevant scenarios, but also promotes bone healing and resolution of the host inflammatory response.