MSS06: ANTIBACTERIAL EFFICACY OF MESENCHYMAL STEM CELL-DERIVED EXTRACELLULAR VESICLES IN A MOUSE MODEL OF S. AUREUS IMPLANT-ASSOCIATED INFECTION
Justin LaRocque1; Wendy Kurata2; J Polanco2; Ashley Chinn1; Daniel G Chen1; Lisa Pierce2; 1Department of Surgery, Tripler Army Medical Center; 2Department of Clinical Investigations, Tripler Army Medical Center
Introduction: Mesh infections after hernia repair occur in approximately 5% of cases causing significant morbidity and risk for reoperation. Contamination of implanted mesh leads to biofilm formation, which is present in up to 80% of infections. Biofilms increase organism virulence and development of multi-drug resistance, which is a global problem. Extracellular vesicles(EVs) may offer a novel, non-antibiotic approach to control chronic drug-resistant infections. EVs released from poly(I:C)-activated mesenchymal stem cells(MSCs) were shown to enhance antimicrobial activity through recruitment of host macrophages, potentiation of innate immunity, and induction of anti-biofilm compounds.
Objective: To investigate the antibacterial efficacy of poly(I:C)-primed and unprimed MSC-EVs in an established in vivo chronic S. aureus implant infection model as a potential modality to decrease global healthcare antibiotic utilization.
Methods: EVs were isolated from poly(I:C)-treated and untreated commercially obtained human MSCs. Mice (n=29) underwent subcutaneous(SQ) implantation of polypropylene mesh inoculated with a bioluminescent strain of S. aureus and were treated with EVs or saline injected SQ or via tail vein(IV) on postoperative days 2, 5, and 8 [n=4 poly(I:C) EVs SQ, n=4 saline SQ, n=8 poly(I:C) EVs IV, n=8 control EVs IV, n=5 saline IV]. All mice were administered oral antibiotics for 7 days and underwent bioluminescence imaging(BLI) every 2-3 days. Bacterial colonies were quantitated by conventional plating during tissue collection and were compared to BLI signal intensity at euthanasia(planned at 14 days).
Results: Bacterial numbers recovered from meshes correlated with imaging data(Spearman r=0.79, p<0.001). BLI signal intensity over time did not differ between groups injected SQ over the mesh site or among groups that underwent tail vein injection (p=0.69 and p=0.82 respectively, 2-way repeated measures ANOVA). EVs did not reduce bacterial burden recovered from explanted mesh on day 14 regardless of administration route [mean log10 CFU/mesh=5.6 poly(I:C) EVs SQ, 4.0 saline SQ, 6.3 poly(IC) EVs IV, 5.6 control EVs IV, 6.0 saline IV). A dose response study in IV-injected mice determined that ≥8×10 10 particles per injection was lethal to approximately 50% of mice after the third injection.
Conclusion: We were unable to demonstrate a benefit of poly(I:C)-primed or unprimed MSC-EVs in vivo in an established model of chronic S. aureus infection. IV injection of EVs led to greater than expected subject mortality, suggesting systemic toxicity via an unknown mechanism, which warrants further study. Additional work is indicated to establish a reproducible chronic mesh infection/biofilm model to quantify the safety and efficacy of extracellular vesicles.