ABATRACT: Osteomyelitis due to orthopaedic device-related infections (ODRIs), is a major complication in orthopaedic medicine, resulting in approximately 200,000 cases in the US per year (~3% of the estimated 6 million elective orthopaedic surgeries), and is predicted to rise as the US population ages. Current treatment requires 4 to 6 weeks of IV antibiotic administration and multiple surgeries to remove the infected implants and surrounding tissue and restore the device, resulting in a large economic burden and significant patient morbidity. ODRIs are extremely recalcitrant to antibiotic treatment as these are biofilm infections, in which the bacterial pathogens are attached to surfaces surrounded by a self-produced matrix. A hallmark of biofilms is their resistance to antibiotics and the host immune system. Furthermore, antibiotics administered orally or parenterally (intravenously or through intramuscular injection) have poor bone penetration. Another treatment complication is the rise in ODRIs due to antibiotic- and multidrug-resistant (MDR) bacteria. Local delivery of antibiotics by their incorporation into polymethylmethacrylate (PMMA) beads has improved treatment. We developed and tested a local antibiotic delivery system of biodegradable poly(lactic-co-glycolic acid) (PLGA) microspheres that retain the advantages of PMMA antibiotic delivery, but do not require removal. An emerging strategy to treat MDR infections is to directly target and lyse the bacterial pathogen using IV administration of bacteriophage (viruses that kill bacteria) or `phage'. Phage self-replicate at the site of infection, do not share resistance mechanisms with antibiotics, and may even restore bacterial susceptibility to antibiotics. As IV phage administration has drawbacks including the loss of phage during delivery and long-term exposure to the immune system, we propose here an innovative nanotechnology strategy using our biodegradable delivery system to locally administer lytic phage to treat ODRIs. We have recently demonstrated that phage K, which effectively lyses many strains of Staphylococcus aureus, the most common cause of ODRIs, can be incorporated into PLGA microspheres. Further, eluted phage are able to kill S. aureus within in vitro biofilms on orthopaedic materials. Our long-term goal is to develop effective local delivery of lytic phage to treat MDR ODRIs. We plan the following short-term goals: 1) optimize the phage incorporation into PLGA microspheres, 2) generate lytic phage cocktails to treat S. aureus ODRI that eliminate bacterial phage resistance, 3) test of the optimized phage-containing microspheres in in-vitro cell culture and an in-vivo rat model of ODRI. It is anticipated that the investigations proposed in this application will pave the way for clinical trials using local delivery of lytic phage to treat ODRI infections thereby improving patient outcomes.