Development of a large animal rabbit model for chronic periprosthetic joint infection.

AIMS: Periprosthetic joint infections (PJIs) and osteomyelitis are clinical challenges that are difficult to eradicate. Well-characterized large animal models necessary for testing and validating new treatment strategies for these conditions are lacking. The purpose of this study was to develop a rabbit model of chronic PJI in the distal femur. METHODS: Fresh suspensions of Staphylococcus aureus (ATCC 25923) were prepared in phosphate-buffered saline (PBS) (1 × 109 colony-forming units (CFUs)/ml). Periprosthetic osteomyelitis in female New Zealand white rabbits was induced by intraosseous injection of planktonic bacterial suspension into a predrilled bone tunnel prior to implant screw placement, examined at five and 28 days (n = 5/group) after surgery, and compared to a control aseptic screw group. Radiographs were obtained weekly, and blood was collected to measure ESR, CRP, and white blood cell (WBC) counts. Bone samples and implanted screws were harvested on day 28, and processed for histological analysis and viability assay of bacteria, respectively. RESULTS: Intraosseous periprosthetic introduction of planktonic bacteria induced an acute rise in ESR and CRP that subsided by day 14, and resulted in radiologically evident periprosthetic osteolysis by day 28 accompanied by elevated WBC counts and histological evidence of bacteria in the bone tunnels after screw removal. The aseptic screw group induced no increase in ESR, and no lysis developed around the implants. Bacterial viability was confirmed by implant sonication fluid culture. CONCLUSION: Intraosseous periprosthetic introduction of planktonic bacteria reliably induces survivable chronic PJI in rabbits. Cite this article: Bone Joint Res 2021;10(3):156-165.

Antimicrobial activity of mesenchymal stem cells against Staphylococcus aureus.

INTRODUCTION: There have been limited advances in the treatment of bone and joint infections, which currently involves a combination of surgery and antibiotic administration. There is a timely need in orthopedics to develop more effective and less invasive forms of antimicrobial prophylaxis and treatment. The antibacterial effect of adult tissue-derived mesenchymal stem cells (MSCs) has recently been investigated against Escherichia coli and Staphylococcus aureus. The main mechanism of action is postulated to be via MSC production of the cationic antimicrobial peptide, LL-37. METHODS: This study examines the antimicrobial activity of adipose-derived human MSCs (ASCs) on S. aureus, specifically examining the role of LL-37 and regulation of its expression. Bacteria colony-forming unit (CFU) assay was used to assess antimicrobial activity. RESULTS: Our results showed that the ASC-conditioned medium significantly inhibited the growth of S. aureus under standard culture conditions with or without the continued presence of ASCs. Also, the treatment of ASCs with 1,25-dihydroxy vitamin D3 elevated LL-37 expression and enhanced their antimicrobial activity. In support, treatment with the vitamin D receptor inhibitor, GW0742, blocked the antimicrobial activity of ASCs. CONCLUSION: Our findings clearly demonstrate the antimicrobial activity of adult ASCs against S. aureus and implicate a key regulatory role for vitamin D. Further testing in in vivo models is being pursued to assess the potential application of ASCs as a biocompatible, adjunct treatment for musculoskeletal infections.

The Coracoacromial Ligament: Anatomy, Function, and Clinical Significance.

The coracoacromial ligament (CAL) was first described as a pain generator by Dr Charles Neer in the early 1970s. Since that time, considerable controversy regarding CAL management during acromioplasty has persisted. This review aims to better understand the role of the CAL in shoulder physiology and pathology. Sixty-six articles from 1958 to 2016 were identified using an electronic search of PubMed, Cochrane Library, AccessMedicine, and MD Consult for case series as well as cohort and prospective studies. The authors used "coracoacromial ligament" and "coracoacromial veil" as medical subject headings (MeSH). In addition, reference lists from all identified articles were reviewed for studies that the search terms may have omitted. The CAL plays an important role in shoulder biomechanics, joint stability, and proprioception. Morphological variance of the CAL is evident throughout the literature. Age-dependent changes due to chronic stress and cellular degradation cause thickening and stiffening of the CAL that may contribute to a spectrum of shoulder pathology from capsular tightness to rotator cuff tear arthropathy and impingement syndrome. The CAL is an integral component of the coracoacromial arch. CAL release during acromioplasty remains controversial. Future clinical outcomes research should endeavor to advance the understanding of the CAL to refine clinical and intraoperative decision making regarding its management.

Sonication of Arthroplasty Implants Improves Accuracy of Periprosthetic Joint Infection Cultures.

BACKGROUND: There is evidence that sonication of explanted prosthetic hip and knee arthroplasty components with culture of the sonication fluid may enhance diagnostic sensitivity. Previous studies on the use of implant sonicate cultures have evaluated diagnostic thresholds but did not elaborate on the clinical importance of positive implant sonicate cultures in the setting of presumed aseptic revisions and did not utilize consensus statements on periprosthetic joint infection (PJI) diagnosis when defining their gold standard for infection. QUESTIONS/PURPOSES: (1) How do implant sonicate cultures compare with preoperative synovial fluid cultures and intraoperative tissue cultures in the diagnosis of PJI in both THA and TKA when compared against Musculoskeletal Infection Society (MSIS) criteria for PJI? (2) Utilizing implant sonicate cultures, what is the relative prevalence of bacterial species identified in PJIs? (3) What is the incidence of positive implant sonicate cultures in the setting of presumed aseptic revision hip and knee arthroplasty procedures, and what treatments did they receive? METHODS: Between 2012 and 2016 we performed implant sonicate fluid cultures on surgically removed implants from 565 revision THAs and TKAs. Exclusion criteria including insufficient data to determine Musculoskeletal Infection Society (MSIS) classification, fungal-only cultures, and absence of reported colony-forming units decreased the number of procedures to 503. Procedures represented each instance of revision surgery (sometimes multiple in the same patient). Of those, a definitive diagnosis of infection was made using the MSIS criteria in 178 of 503 (35%), whereas the others (325 of 503 [65%]) were diagnosed as without infection. A total of 53 of 325 (16%) were considered without infection based on MSIS criteria but had a positive implant sonicate culture. Twenty-five of 53 (47%) of these patients were followed for at least 2 years. The diagnosis of PJI was determined using the MSIS criteria. RESULTS: Sensitivity of implant sonicate culture was greater than synovial fluid culture and tissue culture (97% [89%-99%] versus 57% [44%-69%], p < 0.001; 97% [89%-99%] versus 70% [58%-80%], p < 0.001, respectively). The specificity of implant sonicate culture was not different from synovial fluid culture or tissue culture with the numbers available (90% [72%-97%] versus 100% [86%-100%], p = 0.833; 90% [72%-97%] versus 97% [81%-100%], p = 0.317, respectively). Coagulase-negative Staphylococcus was the most prevalent organism for both procedure types. In PJIs, the five most frequent bacteria identified by synovial fluid, tissue, and/or implant sonicate cultures were coagulase-negative Staphylococcus (26% [89 of 267]), methicillin-susceptible Staphylococcus aureus (19% [65 of 267]), methicillin-resistant S. aureus (12% [43 of 267]), α-hemolytic Streptococci (5% [19 of 267]), and Enterococcus faecalis (5% [19 of 267]). Fifty-three of 325 (16%) presumed aseptic revisions had a positive sonication culture. Thirty-four percent (18 of 53) of culture-positive aseptic revision patients received antibiotic treatment for infection and 8% (4 of 53) underwent a secondary revision. CONCLUSIONS: The routine use of implant sonicate cultures in arthroplasty revisions improves the diagnostic sensitivity for detecting the presence of bacteria in both clinical and occult infections. Future studies will need to refine colony-forming unit thresholds for determining clinical infection and indications for treatment. LEVEL OF EVIDENCE: Level III, diagnostic study.

Notch Signaling Mediates Skeletal Muscle Atrophy in Cancer Cachexia Caused by Osteosarcoma.

Skeletal muscle atrophy in cancer cachexia is mediated by the interaction between muscle stem cells and various tumor factors. Although Notch signaling has been known as a key regulator of both cancer development and muscle stem cell activity, the potential involvement of Notch signaling in cancer cachexia and concomitant muscle atrophy has yet to be elucidated. The murine K7M2 osteosarcoma cell line was used to generate an orthotopic model of sarcoma-associated cachexia, and the role of Notch signaling was evaluated. Skeletal muscle atrophy was observed in the sarcoma-bearing mice, and Notch signaling was highly active in both tumor tissues and the atrophic skeletal muscles. Systemic inhibition of Notch signaling reduced muscle atrophy. In vitro coculture of osteosarcoma cells with muscle-derived stem cells (MDSCs) isolated from normal mice resulted in decreased myogenic potential of MDSCs, while the application of Notch inhibitor was able to rescue this repressed myogenic potential. We further observed that Notch-activating factors reside in the exosomes of osteosarcoma cells, which activate Notch signaling in MDSCs and subsequently repress myogenesis. Our results revealed that signaling between tumor and muscle via the Notch pathway may play an important role in mediating the skeletal muscle atrophy seen in cancer cachexia.

The economic significance of orthopaedic infections.

Musculoskeletal infections are a leading cause of patient morbidity and rising healthcare expenditures. The incidence of musculoskeletal infections, including soft-tissue infections, periprosthetic joint infection, and osteomyelitis, is increasing. Cases involving both drug-resistant bacterial strains and periprosthetic joint infection in total hip and total knee arthroplasty are particularly costly and represent a growing economic burden for the American healthcare system. With the institution of the Affordable Care Act, there has been an increasing drive in the United States toward rewarding healthcare organizations for their quality of care, bundling episodes of care, and capitating approaches to managing populations. In current reimbursement models, complications following the index event, including infection, are not typically reimbursed, placing the burden of caring for infections on the physician, hospital, or accountable care organization. Without the ability to risk-stratify patient outcomes based on patient comorbidities that are associated with a higher incidence of musculoskeletal infection, healthcare organizations are disincentivized to care for moderate- to high-risk patients. Reducing the cost of treating musculoskeletal infection also depends on incentivizing innovations in infection prevention.

Increased incidence of patella baja after total knee arthroplasty revision for infection.

The incidence of patella baja in total knee arthroplasty (TKA) revisions for aseptic and septic causes is not well defined. We retrospectively reviewed 101 mobile-bearing TKA revisions performed between 2003 and 2009. Aseptic (n=67) and septic (n=34) revisions were compared for patella baja. A nonarticulating spacer was used as the initial treatment for infected cases. The Insall-Salvati ratio was radiographically measured before surgery (preexplant for septic revisions) and at latest follow-up (postreplant for septic revisions). Mean (SD) Insall-Salvati ratio did not differ between groups before surgery, 1.00 (0.25) for aseptic and 0.96 (0.22) for septic, but differed significantly after surgery, 0.99 (0.23) for aseptic and 0.77 (0.24) for septic. After correcting for preoperative patellar height, there was a statistically significant postoperative difference between aseptic cases, 1.09 (0.19), and septic cases, 0.82 (0.21). There was also a significant difference in mean (SD) postoperative range of motion (ROM) between aseptic cases, 108.0° (20.7°), and septic cases, 92.2° (34.6°), and decreased ROM between cases with patella baja, 95.1° (31.6°) and cases without patella baja, 106.8° (23.6°). TKA revisions done for septic causes using a nonarticulating spacer resulted in a higher incidence of patella baja and decreased ROM.

ALDH Activity Correlates with Metastatic Potential in Primary Sarcomas of Bone.

Osteosarcoma (OS), chondrosarcoma (CSA), and Ewings sarcoma (ES) are the most common primary malignancies of bone, and are rare diseases. As with all sarcomas, the prognosis of these diseases ultimately depends on the presence of metastatic disease. Survival is therefore closely linked with the biology and metastatic potential of a particular bone tumor's cells. Here we describe a significant correlation of aldehyde dehydrogenase (ALDH) activity and the presence/absence of distant metastases in ten consecutive cases of human bone sarcomas. Additionally, cultured human CSA cells, which are historically chemo- and radio-resistant, may be sensitive to the ALDH inhibitor, disulfiram. While it is premature to draw broad conclusions from such a small series, the importance of ALDH activity and inhibition in the metastatic potential of primary bone sarcomas should be investigated further.