Advisor:

Andrés García, Ph.D. (Georgia Institute of Technology)

Committee:

Edward Botchwey, Ph.D. (Georgia Institute of Technology)

Rodney Donlan, Ph. D. (Centers for Disease Control and Prevention)

John Peroni, DVM, MS, DACVS (University of Georgia)

Nick Willett, Ph.D. (Georgia Institute of Technology)

Lysostaphin-delivering Hydrogels for Local Drug Delivery in Bone Infection Models

Biomaterial associated infections remain a significant problem for medical devices 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. 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. Additionally, 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. Thus, the objective of this project is to engineer a synthetic poly(ethylene glycol)-based hydrogel platform for the encapsulation and delivery of lysostaphin to the site of complex infection. This will be achieved through two specific aims: 1) Development of a two-stage established infection model to assess bacterial mitigation and fracture healing of lysostaphin-encapsulated hydrogels synergistically with systemic antibiotics for a murine femoral fracture infection and 2) Investigation of bactericidal and pro-regenerative properties of lysostaphin-encapsulated hydrogels in an ovine ulnar osteotomy infection model. We expect that the local, sustained release of lysostaphin provided through the hydrogel carrier will lead to significant reduction in bacterial counts, as well as restorative function to the bone tissue at the site of fracture. This will be analyzed as a therapeutic that can be coupled with other forms of antimicrobial delivery, specifically with systemic antibiotics, which we anticipate will act synergistically with the lysostaphin-encapsulated hydrogels to provide heightened therapeutic delivery and bacterial mitigation.