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The Bone & Joint Journal
Vol. 103-B, Issue 7 Supple B | Pages 135 - 144
1 Jul 2021
Inhibition of PAD4 mediated neutrophil extracellular traps prevents fibrotic osseointegration failure in a tibial implant murine model
Kuyl E Shu F Sosa BR Lopez JD Qin D Pannellini T Ivashkiv LB Greenblatt MB Bostrom MPG Yang X
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Aims

Aseptic loosening is a leading cause of uncemented arthroplasty failure, often accompanied by fibrotic tissue at the bone-implant interface. A biological target, neutrophil extracellular traps (NETs), was investigated as a crucial connection between the innate immune system’s response to injury, fibrotic tissue development, and proper bone healing. Prevalence of NETs in peri-implant fibrotic tissue from aseptic loosening patients was assessed. A murine model of osseointegration failure was used to test the hypothesis that inhibition (through Pad4-/- mice that display defects in peptidyl arginine deiminase 4 (PAD4), an essential protein required for NETs) or resolution (via DNase 1 treatment, an enzyme that degrades the cytotoxic DNA matrix) of NETs can prevent osseointegration failure and formation of peri-implant fibrotic tissue.

Methods

Patient peri-implant fibrotic tissue was analyzed for NETs biomarkers. To enhance osseointegration in loose implant conditions, an innate immune system pathway (NETs) was either inhibited (Pad4-/- mice) or resolved with a pharmacological agent (DNase 1) in a murine model of osseointegration failure.

The Bone & Joint Journal
Vol. 102-B, Issue 7 Supple B | Pages 3 - 10
1 Jul 2020
2020 John Charnley Award: The antimicrobial potential of bacteriophage-derived lysin in a murine debridement, antibiotics, and implant retention model of prosthetic joint infection
Sosa BR Niu Y Turajane K Staats K Suhardi V Carli A Fischetti V Bostrom M Yang X
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Aims

Current treatments of prosthetic joint infection (PJI) are minimally effective against Staphylococcus aureus biofilm. A murine PJI model of debridement, antibiotics, and implant retention (DAIR) was used to test the hypothesis that PlySs2, a bacteriophage-derived lysin, can target S. aureus biofilm and address the unique challenges presented in this periprosthetic environment.

Methods

The ability of PlySs2 and vancomycin to kill biofilm and colony-forming units (CFUs) on orthopaedic implants were compared using in vitro models. An in vivo murine PJI model of DAIR was used to assess the efficacy of a combination of PlySs2 and vancomycin on periprosthetic bacterial load.

Orthopaedic Proceedings
Vol. 101-B, Issue SUPP_12 | Pages 59 - 59
1 Oct 2019
BACTERIOPHAGE-DERIVED LYSIN COMBINATION WITH VANCOMYCIN DEMONSTRATES SUPERIOR ANTIMICROBIAL POTENTIAL IN MURINE DAIR MODEL OF PERIPROSTHETIC JOINT INFECTION (PJI)
Sosa B Niu Y Turajane K Staats K Suhardi V Carli A Fischetti V Bostrom MPG Yang X
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Introduction

PJI is a devastating complication following total joint arthroplasty. In this study, we explore the efficacy of a bacteriophage-derived lysin, PlySs2, against in-vitro biofilm on titanium implant surfaces and in an acute in-vivo murine debridement antibiotic implant retention (DAIR) model of PJI.

Methods

In-vitro: Xen 36 S. aureus biofilm was grown on Ti-6Al-4V mouse tibial implants for 1 day or 5 days and subsequently exposed to growth media, 1000× minimal inhibitory concentration (MIC) Vancomycin, or 5× MIC PlySs2. Implants were sonicated and analyzed for Colony Forming Units (CFU).

In-vivo: A Ti-6Al-4V implant was inserted into the proximal tibia of C57BL/6J mice (n=21). All mice received 104 CFU inoculation of Xen 36 S. aureus to the knee joint capsule and the infection was permitted 5 days to progress. On day 5 the mice were separated into three groups (n=7/group): (1) no further surgical intervention (control group), (2) irrigation and debridement (I&D) with saline, (3) I&D with 2mg/mL PlySs2. No implant-exchange was performed to mimic a debridement, antibiotic, and implant retention (DAIR) therapeutic strategy. All mice were sacrificed at day 10.

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