Targeting CD34+ cells of the inflamed synovial endothelium by guided nanoparticles for the treatment of rheumatoid arthritis.

Despite the advances in the treatment of rheumatoid arthritis (RA) achieved in the last few years, several patients are diagnosed late, do not respond to or have to stop therapy because of inefficacy and/or toxicity, leaving still a huge unmet need. Tissue-specific strategies have the potential to address some of these issues. The aim of the study is the development of a safe nanotechnology approach for tissue-specific delivery of drugs and diagnostic probes. CD34 + endothelial precursors were addressed in inflamed synovium using targeted biodegradable nanoparticles (tBNPs). These nanostructures were made of poly-lactic acid, poly-caprolactone, and PEG and then coated with a synovial homing peptide. Immunofluorescence analysis clearly demonstrated their capacity to selectively address CD34 + endothelial cells in synovial tissue obtained from human, mouse, and rat. Biodistribution studies in two different animal models of rheumatoid arthritis (antigen-induced arthritis/AIA and collagen-induced arthritis/CIA) confirmed the selective accumulation in inflamed joints but also evidenced the capacity of tBNP to detect early phases of the disease and the preferential liver elimination. The therapeutic effect of methotrexate (MTX)-loaded tBNPs were studied in comparison with conventional MTX doses. MTX-loaded tBNPs prevented and treated CIA and AIA at a lower dose and reduced administration frequency than MTX. Moreover, MTX-loaded tBNP showed a novel mechanism of action, in which the particles target and kill CD34 + endothelial progenitors, preventing neo-angiogenesis and, consequently, synovial inflammation. tBNPs represent a stable and safe platform to develop highly-sensitive imaging and therapeutic approaches in RA targeting specifically synovial neo-angiogenesis to reduce local inflammation.

Screw Track Osteolysis in the Cementless Total Knee Replacement Design.

BACKGROUND: There is a paucity of reports on osteolysis associated with tibial screw fixation in cementless total knee arthroplasty (TKA), and the pathophysiology is not clear. This study aimed to describe the pathology related to screw track osteolysis around the tibia in cementless TKA. METHODS: The study cohort comprised 100 revised cementless TKAs with tibial screw fixation. Screw track osteolysis and various screw angles were analyzed radiologically. Tissue samples from the joint capsule and the osteolytic cavity were investigated for metal/polyethylene wear. The type of tissue response was determined using immunohistochemistry. Retrieved tibial polyethylene inserts were analyzed for screw hole impression and mode of wear. Tissue metal content was measured by inductively coupled plasma optical emission spectrometry. Electrochemical reactions between the tibial tray and the cancellous screws were investigated. RESULTS: Radiological analysis showed screw track osteolysis predominantly at the medial aspect of the tibial component, and the severity of osteolysis positively correlated with smaller medial proximal tibial screw angles. Osteolysis was associated with high titanium concentrations but not with polyethylene particles. An open circuit potential between the screw and the tibial base plate was measured. Necrosis, osteolytic cyst formation and macrophages, T and B cells, and dendritic cells were present. CONCLUSION: The present study highlights the risk for screw track osteolysis in cementless TKA with screw fixation. Our data collectively suggest that titanium wear may contribute to screw track osteolysis in the cementless TKA design. The contribution of screw angles is difficult to prove.

The effects of cobalt and chromium ions on transforming growth factor-beta patterns and mineralization in human osteoblast-like MG63 and SaOs-2 cells.

Bone homeostasis, the balance of bone formation and resorption is affected by numerous influences, such as, hormones, inflammation, mechanical load, and external stimuli. The transforming growth factor-beta (TGF-ß), which exists in three isoforms in humans, is a major factor in the maintenance of this balance by regulating osteoblast and osteoclast maturation, development, and function. In artificial joint replacements, release of particles or ions from arthroplasties may exert local effects on the periprosthetic tissue and modulate the expression of bone specific genes and functions. Therefore, the influence of cobalt (II) and chromium (III) ions on the expression levels of the three TGF-ß isoforms in human osteosarcoma cell lines MG63 and SaOs-2 was analyzed and the impact on mineralization was studied. The osteosarcoma cell lines expressed all three TGF-ß isoforms, with TGF-ß1 being the most abundant isoform. A dose dependent reduction of all TGF-ß isoforms by Co2+ ions was observed, the strongest effect was found on TGF-ß2. The effect was lesser pronounced in SaOs-2 cells. However, the Cr3+ ions had no significant effect on the expression of all TGF-ß isoforms. In contrast, Co2+ ions in a concentration range of 50-250 µM did not impair the mineralization, but Cr3+ exerted a strong inhibitory effect on the mineralization in a dose dependent fashion. These data suggest that the influence of cobalt ions on bone homeostasis may in part result from the inhibitory effect on the transcription of the bone regulating cytokines TGF-ß1-3 whereas the chromium ions affect the process of mineralization. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2105-2115, 2018.

Ballooning osteolysis in 71 failed total ankle arthroplasties.

Background and purpose - Aseptic loosening is a major cause of failure in total ankle arthroplasty (TAA). In contrast to other total joint replacements, large periarticular cysts (ballooning osteolysis) have frequently been observed in this context. We investigated periprosthetic tissue responses in failed TAA, and performed an element analysis of retrieved tissues in failed TAA. Patients and methods - The study cohort consisted of 71 patients undergoing revision surgery for failed TAA, all with hydroxyapatite-coated implants. In addition, 5 patients undergoing primary TAA served as a control group. Radiologically, patients were classified into those with ballooning osteolysis and those without, according to defined criteria. Histomorphometric, immunohistochemical, and elemental analysis of tissues was performed. Von Kossa staining and digital microscopy was performed on all tissue samples. Results - Patients without ballooning osteolysis showed a generally higher expression of lymphocytes, and CD3+, CD11c+, CD20+, and CD68+ cells in a perivascular distribution, compared to diffuse expression. The odds of having ballooning osteolysis was 300 times higher in patients with calcium content >0.5 mg/g in periprosthetic tissue than in patients with calcium content ≤0.5 mg/g (p < 0.001). Interpretation - There have been very few studies investigating the pathomechanisms of failed TAA and the cause-effect nature of ballooning osteolysis in this context. Our data suggest that the hydroxyapatite coating of the implant may be a contributory factor.

Expression of CD11c in periprosthetic tissues from failed total hip arthroplasties.

In this work, we characterize integrin CD11c (αXß2) expression in periprosthetic tissues of 45 hip revisions. Tissues were retrieved from 23 ceramic-on-ultra-high molecular weight polyethylene (UHMWPE), 20 metal-on-UHMWPE, and 2 metal-on-metal total hip arthroplasties (THAs). Capsular tissue retrieved during primary THA from 19 patients served as controls. We identified a system to identify important immunohistochemical markers that are expressed in aseptic loosening. We focused on CD11c, CD68 and CD14. We observed that the CD11c molecule possesses four different cellular patterns in the periprosthetic tissues. Three of them are associated with the occurrence of UHMWPE abrasive material. Double staining with CD14 and CD68 was used for a more detailed analysis of the CD11c expressing cells. We observed that all forms of CD11c positive cells are CD68 positive however, only two forms of CD11c expressing cells are positive for CD14. Providing cellular diversity of CD11c expression in periprosthetic tissue, our results provide a contribution toward the further understanding of different cellular mechanisms to foreign body material.

Metallic wear debris may regulate CXCR4 expression in vitro and in vivo.

CXCR4, the chemokine receptor for CXCL12, also known as SDF-1 (stromal cell derived factor-1), has been shown to play a pivotal role in bone metastasis, inflammatory, and autoimmune conditions but has not been investigated in periprosthetic osteolysis. We co-cultured osteoblast-like cells with increasing concentrations of metallic (Co-35Ni-20Cr-10Mo and Co-28Cr-6Mo) and Co-ions simulating wear debris. Real-time polymerase chain reaction (RT-PCR) and Western blotting were used to quantify gene and protein expression of CXCR4. The expression of tumor necrosis factor-alpha (TNF-α) and the effects of AMD3100 (bicyclam) on both CXCR4 and TNF-α expression among these cells was investigated. RT-PCR showed an increase in CXCR4 mRNA (7.5-fold for MG63 and 4.0-fold for SaOs-2 cells) among cells co-cultured with metal alloy particles. Western blotting showed a time-dependent increase in protein expression of CXCR4. The attempted blockade of CXCR4 by its known competitive receptor agonist AMD3100 led to a significant inhibition TNF-α mRNA expression. Immunohistochemistry showed CXCR4 positivity among patients with failed metal-on-metal hip replacements and radiographic evidence of osteolysis. Our data collectively suggest that the CXCR4 chemokine is upregulated in a dose- and time-dependent manner in the presence of metallic wear debris.

Low-frequency sonication may alter surface topography of endoprosthetic components and damage articular cartilage without eradicating biofilms completely.

Two-stage exchange arthroplasty is the current standard of care for arthroplasty-related infections. Reinfection rates up to 30% are reported, and there is significant morbidity for the patient. In cases of failure, arthrodesis or amputation may result. Ultrasonic treatment has the potential to eradicate biofilms and avoid two-stage exchange arthroplasty. Data in the specific context of arthroplasty infections is scant, and there is debate regarding optimal frequency and intensity of treatment. Surface topography alterations of the endoprosthetic components and damage to adjacent bone and cartilage have not been investigated. We found incomplete biofilm eradication and significant increase in surface roughness (maximum peak-to-valley height) of cobalt-chrome unicondylar knee components as well as reduction in articular cartilage thickness area from 10 retrieved femoral heads after low-frequency sonication treatment according to manufacturer-specified recommendations. Our data collectively suggest that sonication treatment for biofilm eradication in arthroplasty infections may not be effective and surface topography alterations may potentially reduce implant longevity.

Ceramic femoral component fracture in total knee arthroplasty: an analysis using fractography, fourier-transform infrared microscopy, contact radiography and histology.

Ceramic components in total knee arthroplasty (TKA) are evolving. We analyze the first case of BIOLOX delta ceramic femoral component fracture. A longitudinal midline fracture in the patellar groove was present, with an intact cement mantle and no bony defects. Fractographic analysis with laser scanning microscopy and white light interferometry showed no evidence of arrest lines, hackles, wake hackles, material flaws, fatigue or crack propagation. Analysis of periprosthetic tissues with Fourier-transform infrared (FT-IR) microscopy, contact radiography, histology, and subsequent digestion and high-speed centrifugation did not show ceramic debris. A macrophage-dominated response was present around polyethylene debris. We conclude that ceramic femoral component failure in this case was related to a traumatic event. Further research is needed to determine the suitability of ceramic components in TKA.

Large-diameter metal-on-metal total hip arthroplasties: a page in orthopedic history?

Large-diameter metal-on-metal (MoM) bearings evolved from the success of hip resurfacing. These implants were used in revision surgery in cases with well-fixed acetabular cups but loose or failed femoral stems, to avoid cup revision. Early data showed low rates of dislocation and potentially low wear profiles due to better fluid film lubrication. The risk of impingement was also thought to be low due to the increased head-neck ratio. Subsequently large-diameter MoM heads gained popularity in primary hip replacement. Recent data has emerged on the unacceptably high revision rates among patients with large-diameter MoM total hip arthroplasties (THAs), high blood levels of metal ions, and adverse tissue reactions. The head-neck (cone-taper) modular interface probably represents the weak link in large metal heads that have been used on conventional tapers. Increased torque of the large head, micromotion, and instability at the cone-taper interface, synergistic interactions between corrosion and wear, edge loading, low clearance, and psoas impingement are the likely causes for early failure of these prostheses.