Author ORCID Identifier

https://orcid.org/0000-0002-3638-6393

Semester

Summer

Date of Graduation

2025

Document Type

Dissertation (Campus Access)

Degree Type

PhD

College

School of Medicine

Department

Orthopaedics

Committee Chair

Matthew J. Dietz

Committee Member

John M. Hollander

Committee Member

Emidio Pistilli

Committee Member

Allison M. Lastinger

Committee Member

Kenneth L. Urish

Abstract

Periprosthetic joint infection (PJI) represents one of the most debilitating complications following total joint arthroplasty, driving high rates of morbidity, mortality, and revision surgery. Existing paradigms focus primarily on infection eradication through surgery and prolonged systemic antibiotics, but these approaches often fail to address the profound local tissue damage, metabolic disruption, and immunological imbalance that contribute to treatment failure. A growing body of literature implicates mitochondrial dysfunction as a key player in infection pathogenesis, yet its role in PJI has remained unexplored. With rising surgical volumes and limited efficacy of current treatment protocols, particularly against biofilm-forming bacteria, there remains a critical need for novel therapeutic strategies that protect local tissues and preserve mitochondrial function. This dissertation investigates the mitochondrial consequences of PJI and evaluates adjunct therapeutic strategies that aim to preserve host bioenergetics and enhance infection control. Using a validated methicillin-sensitive Staphylococcus aureus (MSSA) rat model of PJI, we first demonstrated that infected musculoskeletal tissues exhibit significant suppression of mitochondrial respiration and Adenosine Triphosphate (ATP) production despite preserved electron transport chain (ETC) complex activity. This respiratory suppression, characterized by reduced oxygen consumption rate (OCR) and elevated extracellular acidification rate (ECAR), reflected a shift toward glycolysis, suggestive of bioenergetic stress in infected tissues. Notably, this phenotype was confirmed across two independent experiments using Seahorse XF ATP coupling assays, validating the reproducibility of this metabolic signature. Building on these findings, we then explored whether targeted antibiotic delivery via intra-articular (IA) vancomycin could improve local infection control while preserving mitochondrial function. Escalating IA doses (5–100 mg/kg) were compared to standard intraperitoneal (IP) systemic vancomycin. IA-Van100 achieved the greatest bacterial clearance and bone tissue vancomycin concentrations, while IA-Van50 demonstrated superior mitochondrial respiration and ATP synthesis compared to other groups, with no evidence of systemic toxicity. These results suggest that IA delivery not only enhances local drug concentrations but also mitigates bioenergetic compromise in periprosthetic tissues. Finally, we evaluated metformin, a clinically available antidiabetic agent with emerging anti-inflammatory and mitochondrial-protective properties, as a host-directed therapy. Infected animals treated with IP metformin showed restored mitochondrial respiration, reduced ECAR, and trends toward reduced Interleukin-1 beta (IL-1β ) and Reactive Oxygen Species (ROS) levels, compared to both untreated and vancomycin-treated groups. While bacterial clearance was not significantly different, the observed metabolic recovery and anti-inflammatory profile highlight metformin’s potential as an adjunct strategy to bolster host resilience during infection. Taken together, these studies define a novel metabolic dimension of PJI, underscoring the importance of mitochondrial function in infection response and therapeutic success. This work supports a shift in treatment paradigms, from pathogen-directed therapies alone to strategies that preserve and restore host tissue metabolism. Intra-articular vancomycin and metformin represent promising candidates in this regard. Further translational research should explore combination approaches, timing of administration, and intermediate IA dosing (e.g., 75 mg/kg), as well as validate mitochondrial endpoints in clinical samples. Ultimately, integrating host-targeted bioenergetic preservation into PJI management may improve outcomes and reduce the burden of this complex and costly complication.

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