Periprosthetic joint infections are devastating complications for patients and for our health system. With growing demand for arthroplasty, the incidence of these infections is projected to increase exponentially. This paper is a review of existing animal models to study periprosthetic infection aimed at providing scientists with a succinct presentation of strengths and weaknesses of available in vivo systems. These systems represent the tools available to investigate novel antimicrobial therapies and reduce the clinical and economic impact of implant infections.

The purpose of this study was to determine what orthopaedic surgery department leadership characteristics are most closely correlated with securing NIH funding and increasing scholarly productivity. Scopus database was used to identify number of publications/h-index for 4,328 faculty, department chairs (DC), and research directors (RD), listed on departmental websites from 138 academic orthopaedic departments in the United States. NIH funding data was obtained for the 2013 fiscal year. While all programs had a DC, only 46% had a RD. Of $54,925,833 in NIH funding allocated to orthopaedic surgery faculty in 2013, 3% of faculty and 31% of departments were funded. 16% of funded institutions had a funded DC whereas 65% had a funded RD. Department productivity and funding were highly correlated to leadership productivity and funding(p< 0.05). Mean funding was $1,700,000 for departments with a NIH-funded RD, $104,000 for departments with an unfunded RD, and $72,000 for departments with no RD. These findings suggest that orthopaedic department academic success is directly associated with scholarly productivity and funding of both DC and RD. The findings further highlight the correlation between a funded RD and a well-funded department. This does not hold for an unfunded RD.

Introduction

Although a variety of agencies have attempted to evaluate the academic achievements of orthopaedic surgery academic centers, most use opaque criteria that are difficult to interpret and do not provide clear targets for improvement. This study leverages a weighted algorithm using objective measurements that has been linked to academic achievement to attempt to provide a comprehensive assessment of scholarly accomplishment for orthopaedic surgery academic centers.

Methods

We examined full-time faculty at 138 US orthopaedic surgery academic centers; part-time or volunteer faculty were excluded. Five metrics of academic achievement were assessed: National Institutes of Health funding (2013), number of publications, Hirschberg-index (ie, a metric of impact of publications), leadership positions held in orthopaedic surgery societies, and editorial board positions of top orthopaedic and subspecialty journals. Academic programs were given a score for every category, and the algorithm was used to calculate an overall score of academic achievement for each program.

Results

The five most academically productive programs were Washington University in St. Louis, Hospital for Special Surgery, Mayo Clinic, University of Pennsylvania, and Thomas Jefferson University.

Conclusion

This algorithm may provide faculty with an assessment tool that can establish benchmarks to help focus efforts toward increasing the academic productivity of their respective programs.

Study design

A controlled, interventional animal study.

Objective

Spinal implant infection (SII) is a devastating complication. The objective of this study was to evaluate the efficacy of a novel implant coating that has both a passive antibiotic elution and an active-release mechanism triggered in the presence of bacteria, using an in vivo mouse model of SII.

Summary of background data

Current methods to minimize the frequency of SII include local antibiotic therapy (vancomycin powder), betadine irrigation, silver nanoparticles, and passive release from antibiotic-loaded poly(methyl methacrylate) cement beads, all of which have notable weaknesses. A novel implant coating has been developed to address some of these limitations but has not been tested in the environment of a SII.

Methods

A biodegradable coating using branched poly(ethylene glycol)-poly(propylene sulfide) (PEG-PPS) polymer was designed to deliver antibiotics. The in vivo performance of this coating was tested in the delivery of either vancomycin or tigecycline in a previously established mouse model of SII. Noninvasive bioluminescence imaging was used to quantify the bacterial burden, and implant sonication was used to determine bacterial colony-forming units (CFUs) from the implant and surrounding bone and soft tissue.

Results

The PEG-PPS-vancomycin coating significantly lowered the infection burden from postoperative day 3 onwards (P < 0.05), whereas PEG-PPS-tigecycline only decreased the infection on postoperative day 5 to 10 (P < 0.05). CFUs were lower on PEG-PPS-vancomycin pins than PEG-PPS-tigecycline and PEG-PPS pins alone on both the implants (2.4 × 10, 8.5 × 10, and 1.0 × 10 CFUs, respectively) and surrounding bone and soft tissue (1.3 × 10, 4.8 × 10, and 5.4 × 10 CFUs, respectively) (P < 0.05).

Conclusion

The biodegradable PEG-PPS coating demonstrates promise in decreasing bacterial burden and preventing SII. The vancomycin coating outperformed the tigecycline coating in this model compared to prior work in arthroplasty models, highlighting the uniqueness of the paraspinal infection microenvironment.

Level of evidence

N/A.

Post-operative spine infections are a challenge, as hardware must often be retained to prevent destabilization of the spine, and bacteria form biofilm on implants, rendering them inaccessible to antibiotic therapy, and immune cells. A model of posterior-approach spinal surgery was created in which a stainless steel k-wire was transfixed into the L4 spinous process of 12-week-old C57BL/six mice. Mice were then randomized to receive either one of three concentrations (1 × 10² , 1 × 10³ , and 1 × 10⁴ colony forming units (CFU)) of a bioluminescent strain of Staphylococcus aureus or normal saline at surgery. The mice were then longitudinally imaged for bacterial bioluminescence to quantify infection. The 1 × 10² CFU group had a decrease in signal down to control levels by POD 25, while the 1 × 10³ and 1 × 10⁴ CFU groups maintained a 10-fold higher signal through POD 35. Bacteria were then harvested from the pin and surrounding tissue for confirmatory CFU counts. All mice in the 1 × 10⁴ CFU group experienced wound breakdown, while no mice in the other groups had this complication. Once an optimal bacterial concentration was determined, mice expressing enhanced green fluorescent protein in their myeloid cells (Lys-EGFP) were utilized to contemporaneously quantify bacterial burden, and immune response. Neutrophil fluorescence peaked for both groups on POD 3, and then declined. The infected group continued to have a response above the control group through POD 35. This study, establishes a noninvasive in vivo mouse model of spine implant infection that can quantify bacterial burden and host inflammation longitudinally in real time without requiring animal sacrifice. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:193-199, 2017.

Background

Postoperative infection is a devastating complication following arthroplasty. The goals of this study were to introduce a "smart" implant coating that combines passive elution of antibiotic with an active-release mechanism that "targets" bacteria, and to use an established in vivo mouse model of post-arthroplasty infection to longitudinally evaluate the efficacy of this polymer implant coating in decreasing bacterial burden.

Methods

A novel, biodegradable coating using branched poly(ethylene glycol)-poly(propylene sulfide) (PEG-PPS) polymer was designed to deliver antibiotics both passively and actively. In vitro-release kinetics were studied using high-performance liquid chromatography (HPLC) quantification in conditions representing both the physiologic environment and the more oxidative, hyperinflammatory environment of periprosthetic infection. The in vivo efficacy of the PEG-PPS coating delivering vancomycin and tigecycline was tested using an established mouse model of post-arthroplasty infection. Noninvasive bioluminescence imaging was used to quantify the bacterial burden; radiography, to assess osseointegration and bone resorption; and implant sonication, for colony counts.

Results

In vitro-release kinetics confirmed passive elution above the minimum inhibitory concentration (MIC). A rapid release of antibiotic was noted when challenged with an oxidative environment (p < 0.05), confirming a "smart" active-release mechanism. The PEG-PPS coating with tigecycline significantly lowered the infection burden on all days, whereas PEG-PPS-vancomycin decreased infection on postoperative day (POD) 1, 3, 5, and 7 (p < 0.05). A mean of 0, 9, and 2.6 × 10(2) colony-forming units (CFUs) grew on culture from the implants treated with tigecycline, vancomycin, and PEG-PPS alone, respectively, and a mean of 1.2 × 10(2), 4.3 × 10(3), and 5.9 × 10(4) CFUs, respectively, on culture of the surrounding tissue (p < 0.05).

Conclusions

The PEG-PPS coating provides a promising approach to preventing periprosthetic infection. This polymer is novel in that it combines both passive and active antibiotic-release mechanisms. The tigecycline-based coating outperformed the vancomycin-based coating in this study.

Clinical relevance

PEG-PPS polymer provides a controlled, "smart" local delivery of antibiotics that could be used to prevent postoperative implant-related infections.

Background

Postoperative infection is a devastating complication following arthroplasty. The goals of this study were to introduce a "smart" implant coating that combines passive elution of antibiotic with an active-release mechanism that "targets" bacteria, and to use an established in vivo mouse model of post-arthroplasty infection to longitudinally evaluate the efficacy of this polymer implant coating in decreasing bacterial burden.

Methods

A novel, biodegradable coating using branched poly(ethylene glycol)-poly(propylene sulfide) (PEG-PPS) polymer was designed to deliver antibiotics both passively and actively. In vitro-release kinetics were studied using high-performance liquid chromatography (HPLC) quantification in conditions representing both the physiologic environment and the more oxidative, hyperinflammatory environment of periprosthetic infection. The in vivo efficacy of the PEG-PPS coating delivering vancomycin and tigecycline was tested using an established mouse model of post-arthroplasty infection. Noninvasive bioluminescence imaging was used to quantify the bacterial burden; radiography, to assess osseointegration and bone resorption; and implant sonication, for colony counts.

Results

In vitro-release kinetics confirmed passive elution above the minimum inhibitory concentration (MIC). A rapid release of antibiotic was noted when challenged with an oxidative environment (p < 0.05), confirming a "smart" active-release mechanism. The PEG-PPS coating with tigecycline significantly lowered the infection burden on all days, whereas PEG-PPS-vancomycin decreased infection on postoperative day (POD) 1, 3, 5, and 7 (p < 0.05). A mean of 0, 9, and 2.6 × 10(2) colony-forming units (CFUs) grew on culture from the implants treated with tigecycline, vancomycin, and PEG-PPS alone, respectively, and a mean of 1.2 × 10(2), 4.3 × 10(3), and 5.9 × 10(4) CFUs, respectively, on culture of the surrounding tissue (p < 0.05).

Conclusions

The PEG-PPS coating provides a promising approach to preventing periprosthetic infection. This polymer is novel in that it combines both passive and active antibiotic-release mechanisms. The tigecycline-based coating outperformed the vancomycin-based coating in this study.

Clinical relevance

PEG-PPS polymer provides a controlled, "smart" local delivery of antibiotics that could be used to prevent postoperative implant-related infections.

Post-operative spine infections are a challenge, as hardware must often be retained to prevent destabilization of the spine, and bacteria form biofilm on implants, rendering them inaccessible to antibiotic therapy, and immune cells. A model of posterior-approach spinal surgery was created in which a stainless steel k-wire was transfixed into the L4 spinous process of 12-week-old C57BL/six mice. Mice were then randomized to receive either one of three concentrations (1 × 10² , 1 × 10³ , and 1 × 10⁴ colony forming units (CFU)) of a bioluminescent strain of Staphylococcus aureus or normal saline at surgery. The mice were then longitudinally imaged for bacterial bioluminescence to quantify infection. The 1 × 10² CFU group had a decrease in signal down to control levels by POD 25, while the 1 × 10³ and 1 × 10⁴ CFU groups maintained a 10-fold higher signal through POD 35. Bacteria were then harvested from the pin and surrounding tissue for confirmatory CFU counts. All mice in the 1 × 10⁴ CFU group experienced wound breakdown, while no mice in the other groups had this complication. Once an optimal bacterial concentration was determined, mice expressing enhanced green fluorescent protein in their myeloid cells (Lys-EGFP) were utilized to contemporaneously quantify bacterial burden, and immune response. Neutrophil fluorescence peaked for both groups on POD 3, and then declined. The infected group continued to have a response above the control group through POD 35. This study, establishes a noninvasive in vivo mouse model of spine implant infection that can quantify bacterial burden and host inflammation longitudinally in real time without requiring animal sacrifice. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:193-199, 2017.

Background

Despite recent advances, infection remains the most common etiology of arthroplasty failure. Recent work suggests that 25-hydroxyvitamin D (25D) deficiency correlates with the frequency of periprosthetic joint infection (PJI). We endeavored to examine whether 25D3 deficiency leads to increased bacterial burden in vivo in an established mouse model of PJI and, if so, whether this effect can be reversed by preoperative 25D3 supplementation.

Methods

Mice (lys-EGFP) possessing fluorescent neutrophils were fed a vitamin D3-sufficient (n = 20) or deficient (n = 40) diet for 6 weeks. A group of 25D3-deficient mice (n = 20) were "rescued" with 1 intraperitoneal dose of 25D3 at 3 days before surgery. A stainless steel implant was inserted into the knee joint and the joint space was inoculated with bioluminescent Staphylococcus aureus (1 × 10 colony forming units [CFUs]). In vivo imaging was used to monitor bacterial burden and neutrophil infiltration. Blood was drawn to confirm 25D3 levels 3 days before surgery and on postoperative days (PODs) 0 and 14. Mice were killed at POD 21, and CFUs were quantified after culture. Myeloperoxidase (MPO) and β-N-acetylglucosaminidase (NAG) were assayed to look at neutrophil infiltration and activated tissue macrophage recruitment, respectively.

Results

Serum values confirmed 25D3 deficiency and repletion of the 25D3-rescued group. Bacterial bioluminescence and neutrophil fluorescence were significantly greater (p < 0.05) in the 25D3-deficient group. CFU counts from the joint tissue and implant were also significantly greater in this group (p < 0.05). Rescue treatment significantly decreased bacterial burden and neutrophil infiltration (p < 0.05). Compared with the 25D3-sufficient and 25D3-rescued groups, MPO activity was higher (p < 0.02) and NAG activity was lower (p < 0.03) in the 25D3-deficient group.

Conclusions

This study demonstrated in vivo in a mouse model of PJI that (1) 25D3 deficiency results in increased bacterial burden and neutrophil infiltration, and (2) this effect can be reversed with preoperative repletion of 25D3.

Clinical relevance

Considering that >65% of patients undergoing arthroplasty have insufficient or low levels of total 25D and that 25D levels can be replenished with ease using a U.S. Food and Drug Administration (FDA)-approved, oral 25D3 product, 25D deficiency may be an important modifiable risk factor in humans undergoing joint replacement.

Background

Management of spine implant infections (SII) are challenging. Explantation of infected spinal hardware can destabilize the spine, but retention can lead to cord compromise and biofilm formation, complicating management. While vancomycin monotherapy is commonly used, in vitro studies have shown reduced efficacy against biofilm compared to combination therapy with rifampin. Using an established in vivo mouse model of SII, we aim to evaluate whether combination therapy has increased efficacy compared to both vancomycin alone and infected controls.

Methods

An L-shaped, Kirschner-wire was transfixed into the L4 spinous process of 12-week-old C57BL/6 mice, and inoculated with bioluminescent Staphylococcus aureus. Mice were randomized into a vancomycin group, a combination group with vancomycin plus rifampin, or a control group receiving saline. Treatment began on post-operative day (POD) 7 and continued through POD 14. In vivo imaging was performed to monitor bioluminescence for 35 days. Colony-forming units (CFUs) were cultured on POD 35.

Results

Bioluminescence peaked around POD 7 for all groups. The combination group had a 10-fold decrease in signal by POD 10. The vancomycin and control groups reached similar levels on POD 17 and 21, respectively. On POD 25 the combination group dropped below baseline, but rebounded to the same level as the other groups, demonstrating a biofilm-associated infection by POD 35. Quantification of CFUs on POD 35 confirmed an ongoing infection in all three groups.

Conclusions

Although both therapies were initially effective, they were not able to eliminate implant biofilm bacteria, resulting in a rebound infection after antibiotic cessation. This model shows, for the first time, why histologic-based, static assessments of antimicrobials can be misleading, and the importance of longitudinal tracking of infection. Future studies can use this model to test combinations of antibiotic therapies to see if they are more effective in eliminating biofilm prior to human trials.