Wear debris from implant interfaces is the major factor leading to periprosthetic osteolysis. Fibroblast-like synoviocytes (FLSs) populate the intimal lining of the synovium and are in direct contact with wear debris. This study aimed to elucidate the effect of Ti particles as wear debris on human FLSs and the mechanism by which they might participate in the bone remodeling process during periprosthetic osteolysis. FLSs were isolated from synovial tissue from patients, and the condition medium (CM) was collected after treating FLSs with sterilized Ti particles. The effect of CM was analyzed for the induction of osteoclastogenesis or any effect on osteogenesis and signaling pathways. The results demonstrated that Ti particles could induce activation of the NFκB signaling pathway and induction of COX-2 and inflammatory cytokines in FLSs. The amount of RANL in the conditioned medium collected from Ti particle-stimulated FLSs (Ti CM) showed the ability to stimulate osteoclast formation. The Ti CM also suppressed the osteogenic initial and terminal differentiation markers for osteoprogenitors, such as alkaline phosphate activity, matrix mineralization, collagen synthesis, and expression levels of Osterix, Runx2, collagen 1α, and bone sialoprotein. Inhibition of the WNT and BMP signaling pathways was observed in osteoprogenitors after the treatment with the Ti CM. In the presence of the Ti CM, exogenous stimulation by WNT and BMP signaling pathways failed to stimulate osteogenic activity in osteoprogenitors. Induced expression of sclerostin (SOST: an antagonist of WNT and BMP signaling) in Ti particletreated FLSs and secretion of SOST in the Ti CM were detected. Neutralization of SOST in the Ti CM partially restored the suppressed WNT and BMP signaling activity as well as the osteogenic activity in osteoprogenitors. Our results reveal that wear debris-stimulated FLSs might affect bone loss by not only stimulating osteoclastogenesis but also suppressing the bone-forming ability of osteoprogenitors. In the clinical setting, targeting FLSs for the secretion of antagonists like SOST might be a novel therapeutic approach for preventing bone loss during inflammatory osteolysis.

Failure of osseointegration and periprosthetic joint infection (PJI) are the two main reasons of implant failure after total joint replacement (TJR). Nanofiber (NF) implant surface coating represents an alternative local drug eluting device that improves osseointegration and decreases the risk of PJI. The purpose of this study was to investigate the therapeutic efficacies of erythromycin (EM)-loaded coaxial PLGA/PCL-PVA NF coating in a rat S. aureus-infected tibia model.

NF coatings with 100mg and 1000mg EM were prepared. NF without EM was included as positive control. 56 Sprague Dawley rats were divided into 4 groups. A titanium pin (1.0-mm x 8 mm) was placed into the tibia through the intercondylar notch. S. aureus (SA) was introduced by both direct injection of 10 μl broth (1 × 10⁴ CFU) into the medullary cavity and single dip of Ti pins into a similar solution prior to insertion. Rats were sacrificed at 8 and 16 weeks after surgery. The outcome measurements include μCT based quantitative osteolysis evaluation and hard tissue histology.

Results: EM-NF coating (EM100 and EM1000) reduced osteolysis at 8 and 16 weeks, compared to EM0 and negative control. The effective infection control by EM-NFs was further confirmed by hard tissue section analysis. The Bone implant contact (BIC) and bone area fraction Occupancy (BAFO) within 200 µm of the surface of the pins were used to evaluate the osseointegration and new bone formation around the implants. At 16 weeks, the bone implant contact (BIC) of EM 100 (35.08%) was higher than that of negative control (3.43%) and EM0 (0%). The bone area fraction occupancy within 200 µm (BAFO) of EM100 (0.63 mm2) was higher than that of negative control (0.390 mm2) and EM0 (0.0 mm²). The BAFO of EM100 was also higher than that of EM1000 (0.3mm²).

There was much less osteolysis observed with EM100 and EM1000 NF coatings at 16 weeks, as compared to EM0 positive control, p=0.08 and p=0.1, respectively. Osseointegration and periprosthetic bone formation was enhanced by EM-NFs, especially EM100. Data from this pilot study is promising for improving implant surface fabrication strategies.

As peri-prosthetic aseptic loosening is one of the main causes of implant failure, inhibiting wear particles induced macrophages inflammation is considered as a promising therapy for AL to expand the lifespan of implant. Here, we aim at exploring the role of p110δ, a member of class IA PI3K family, and Krüppel-like factor 4 (KLF4) in titanium particles (TiPs) induced macrophages-inflammation and osteolysis.

Firstly, IC87114, the inhibitor of p110δ and siRNA targeting p110δ were applied and experiments including ELISA and immunofluorescence assay were conducted to explore the role of p110δ. Sequentially, KLF4 was predicted as the transcription factor of p110δ and the relation was confirmed by dual luciferase reporter assay. Next, assays including RT-PCR, western blotting and flow cytometry were performed to ensure the specific role of KLF4. Finally, TiPs-induced mice cranial osteolysis model was established, and micro-CT scanning and immunohistochemistry assay were performed to reveal the role of p110δ and KLF4 in vivo.

Here, we found that p110δ was upregulated in TiPs-stimulated macrophages. The inhibition of p110δ or knockdown of p110δ could significantly dampen the TiPs-induced secretion of TNFα and IL-6. Further mechanistic studies confirmed that p110δ was responsible for TNFα and IL-6 trafficking out of Golgi complex without affecting their expression in TiPs-treated macrophages. Additionally, we explored the upstream regulators and confirmed that Krüppel-like factor 4 (KLF4) was the transcription repressor of p110δ. Apart from that, KLF4, targeted by miR-92a, could also attenuate TiPs-induced inflammation by mediating NF-κB pathway and M1/M2 polarization. By the establishment of TiPs-induced mice cranial osteolysis model, we found that KLF4 knockdown exacerbated TiPs-induced osteolysis which was strikingly ameliorated by knockdown of p110δ.

In summary, our study suggests the key role of miR-92a/KLF4/p110δ signal in TiPs-induced macrophages inflammation and osteolysis.

Introduction. Alumina ceramic-on-highly cross-linked polyethylene bearings (Al-on-X-linked PE) are attractive because of the potential for reduced wear, osteolysis and loosening of the component. The purpose of this study was to evaluate the clinical and radiographic outcomes of cementless total hip arthroplasties (THAs) using an Al-on-X-linked PE bearing and to determine the rates of osteolysis using radiographs and computer tomographic (CT) scans in young patients with osteonecrosis of femoral head. Methods. Consecutive primary cementless THAs using Al-on-X-linked PE bearing were performed in 71 patients (73 hips) who were younger than 50 years of age with osteonecrosis of the femoral head. There were 48 men (51 hips) and 23 women (23 hips). The average age at the time of the index arthroplasty was 46 years (range, 20 to 50 years). Osteolysis was evaluated using radiographs and CT scanning. The average follow-up was 11 years (range, 10 to 13 years). Results. The mean preoperative Harris hip score was 51 points (range, 27 to 55 points), which was improved to 96 points (range, 85 to 100 points) at the final follow-up. Preoperative functional activity was improved significantly (p=0.001) at the latest follow-up. All acetabular and femoral components were fixed by bone ingrown. The mean polyethylene linear penetration was 0.05 ?0.02 mm per year (range, 0.02 mm to 0.08 mm per year). Radiographic and CT scan evaluation demonstrated that no acetabular or femoral osteolysis was detected in any hip at the latest follow-up. Conclusion. The current generation of anatomic tapered cementless femoral component with Al-on-X-linked PE bearing is functioning well with no osteolysis at a 10-year minimum and average of 11-year follow-up in this series of young patients with osteonecrosis of the femoral head

Summary Statement

Using the latest Next Generation Sequencing technologies, we have investigated miRNA expression profiles in human trabecular bone from total hip replacement (THR) revision surgery where wear particle associated osteolysis was evident.

Summary

Wear particles from joint replacements may result in loosening and periprosthetic osteolysis. Interference with systemic macrophage trafficking to the implant, modulation of macrophage phenotype from M1 to M2, and inhibition of NFκB may mitigate these adverse effects.

Summary

Osteoporosis reduces particle-induced osteolysis in rat model.

INTRODUCTION

Staphylococci species account for ∼80 % of osteomyelitis cases. While the most severe infections are caused by Staphylococcus aureus (S. aureus), the clinical significance of coagulase negative Staphylococcus epidermidis (S. epidermidis) infections remain controversial. In general, S. epidermidis was known to be a protective commensal bacterium. However, recent studies have shown that intra-operative low-grade S. epidermidis contamination prevents bone healing. Thus, the purpose of this study is to compare the pathogenic features of S. aureus and S. epidermidis in an established murine model of implant-associated osteomyelitis.

Our aim was to analyse the influence of the size, shape and number of particles on the pathogenesis of osteolysis. We obtained peri-implant tissues from 18 patients having revision surgery for aseptically loosened Freeman total knee replacements (10), Charnley total hip replacements (3) and Imperial College/London Hospital double-cup surface hip replacements (5). The size and shape of the polyethylene particles were characterised using SEM and their concentration was calculated. The results were analysed with reference to the presence of radiological osteolysis.

The concentration of polyethylene particles in 6 areas with osteolysis was significantly higher than that in 12 areas without osteolysis. There were no significant differences between the size and shape of the particles in these two groups.

We conclude that the most critical factor in the pathogenesis of osteolysis is the concentration of polyethylene particles accumulated in the tissue.

Foreign-body reaction to polyglycolide (PGA) implants has been described in man. Many animal experiments have verified the mechanical properties of fixation devices made from PGA, but a significant foreign-body reaction has not been described. We studied the effect of PGA rods in 12 sheep with standardized osteochondral fractures of the medial femoral condyle fixed with uncoloured, self-reinforced PGA rods (Biofix). Radiographs were taken at intervals ranging from two weeks to two years, and the sheep were killed at intervals ranging from six to 24 months. All knees were examined histologically.

Eleven of the 12 fractures healed radiologically and histologically. Moderate to severe osteolysis was seen at four to six weeks with maximum changes at 12 weeks in ten animals. Six knees showed fistula-like connections between the implant site and the joint space. Three developed synovitis, one with inflammatory changes involving the whole cartilage and one with destruction of the medial condyle.

Although in our study osteochondral fractures fixed with PGA rods healed reliably, there were frequent, significant foreign-body reactions. Caution is needed when considering the use of PGA fixation devices in vulnerable regions such as the knee.

Summary

RNAi targeting TNF-alpha inhibits particle-induced inflammation and osteolysis.

Summary

Particulate wear debris with different chemical composition induced similar periprosthetic tissue reactions in patients with loosened uncemented and cemented titanium hip implants, which suggests that osteolysis can develop independent of particle composition.

Summary Statement

Vitamin E-UHMWPE particles have a reduced osteolysis potential in vivo when compared to virgin, highly cross-linked UHMWPE in a murine calvarial bone model.

Summary

RNAi targeting p110β reduces TNF-alpha production and osteolysis in response to wear particles.

According to the latest report from the German Arthroplasty Registry, aseptic loosening is the primary cause of implant failure following primary hip arthroplasty. Osteolysis of the proximal femur due to the stress-shielding of the bone by the implant causes loss of fixation of the proximal femoral stem, while the distal stem remains fixed. Removing a fixed stem is a challenging process. Current removal methods rely on manual tools such as chisels, burrs, osteotomes, drills and mills, which pose the risk of bone fracture and cortical perforation. Others such as ultrasound and laser, generate temperatures that could cause thermal injury to the surrounding tissues and bone. It is crucial to develop techniques that preserve the host bone, as its quality after implant removal affects the outcome of a revision surgery. A gentler removal method based on the transcutaneous heating of the implant by induction is proposed. By reaching the glass transition temperature (T. G. ) of the periprosthetic cement, the cement is expected to soften, enabling the implant to be gently pulled out. The in-vivo environment comprises body fluids and elevated temperatures, which deteriorate the inherent mechanical properties of bone cement, including its T. G. We aimed to investigate the effect of fluid absorption on the T. G. (ASTM E2716-09) and Vicat softening temperature (VST) (ISO 306) of Palacos R cement (Heraeus Medical GmbH) when dry and after storage in Ringer's solution for up to 8 weeks. Samples stored in Ringer's solution exhibited lower T. G. and VST than those stored in air. After 8 weeks, the T. G. decreased from 95.2°C to 81.5°C in the Ringer's group, while the VST decreased from 104.4°C to 91.9°C. These findings will be useful in the ultimate goal of this project which is to design an induction-based system for implant removal. Acknowledgements: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – SFB/TRR-298-SIIRI – Project-ID 426335750

Background. Dissociation of the polyethylene liner is a known failure mechanism of the Harris Galante I and II uncemented acetabular components. The outcomes of revision surgery for this indication and the influence of time to diagnosis are not well described. Methods. We report a series of 29 cases revised due to this failure mechanism. Results. The median time from primary to revision surgery was 13 years. At a median of 4 years follow up, the mean OHS was 34 (range 6–48) but results were poorer (mean 29, range 6–45) when the diagnosis and revision was delayed compared to when it was not (mean 39, range 20–48). A large proportion of our patients (n=14) presented with sudden onset of symptoms with or without trauma. Osteolysis was common in this series but the cup was well fixed in 20/29 cases. There was macroscopic damage to the shell in all cases. Conclusion. In our experience, prompt revision of liner dissociation optimises outcomes in this group of patients and radiology reporting alone is not sufficient to identify these cases. Level of evidence. 4

We have reviewed 70 patients with bilateral simultaneous total hip arthroplasties to determine the rate of failure and to compare polyethylene wear and osteolysis between an implant with a cobalt-chrome head and Hylamer liner with that of a zirconia head and Hylamer liner. The mean thickness of the polyethylene liner was 11.0 mm (8.8 to 12.2) in the hip with a zirconia head and 10.7 mm (8.8 to 12.2) in that with a cobalt-chrome head. At follow-up at 6.4 years no acetabular or femoral component had been revised for aseptic loosening and no acetabular or femoral component was loose according to radiological criteria in both the cemented and cementless groups. The mean rate of linear wear and annual wear rate were highest in the 22 mm zirconia femoral head (1.25 mm (SD 1.05) and 0.21 mm (SD 0.18), respectively) and lowest in the 22 mm cobalt-chrome femoral head (0.70 mm (SD 0.39) and 0.12 mm (SD 0.07), respectively). The mean volumetric wear was highest in the 28 mm zirconia femoral head (730.79 mm. 3. ) and lowest in the 22 mm cobalt-chrome femoral head (264.67 mm. 3. ), but if the results were compared by size of the femoral head and type of material there was no statistical difference (p > 0.05). Sequential measurements of annual wear showed that the zirconia femoral head had a relatively higher rate of penetration than the cobalt-chrome head over the first three years; thereafter the rate of wear was reduced and compared favourably with that of cobalt-chrome heads. There was a statistically significant relationship between the wear of the polyethylene liner and the age of the patient, male gender and the degree of abduction angle of the cup, but not diagnosis, weight, hip score, range of movement, or amount of anteversion. Osteolysis was identified on both sides of the acetabulum in six patients (9%). Of 12 hips with acetabular osteolysis, six had a 28 mm cobalt-chrome femoral head and the remaining six a 28 mm zirconia head. Osteolysis was observed in zones 1A and 7A of the femur in two hips (3%) with a 28 mm zirconia head (cemented hip) and in four (6%) with a 28 mm cobalt-chrome femoral head (cementless hip). Our findings suggest that although the performance of a zirconia femoral head with a Hylamer liner was not statistically different from that of a cobalt-chrome femoral head and Hylamer liner, there was a trend for the zirconia head to be worse than the cobalt-chrome femoral head

Total ankle replacement (TAR) has a mean survivorship of 77% at 10 years which is poor compared to other types of joint arthroplasty. Osteolysis and aseptic loosening are commonly cited TAR failure modes, the mechanisms of which are unknown. Retrieval analyses of TAR devices may reveal mechanisms of failure similar or dissimilar to other joint replacements. This study investigated whether TAR explants exhibit similar damage modes to those recognised in other total joint replacements. 22 Ankle Evolution System TARs (Transystème, Nimes, France) were implanted and retrieved by the same surgeon. Mean implantation time was 7.8 yrs (5.3 to 12.1 range). Pain and/or loosening were the indications for revision. Macro photography, an Alicona Infinite microscope and the Hood/Wasielewski scale were used to classify damage modes on the polyethylene insert. Scanning electron microscopy with energy dispersive X-ray spectroscopy was used to determine the composition of third body debris and to image the fixation surface of the tibial components. Mean damage score was 185.4 (± 40.0 SD). Damage modes common to total knee replacements were identified on both the superior and inferior insert surfaces, these included: burnishing, scratching, pitting and abrasion. Titanium particles, hydroxyapatite fragments and bone debris were embedded in the insert surfaces. Fixation surface delamination was identified by the ongrowth of tissue between the cobalt chromium substrate and titanium alloy coating. Damage modes indicative of high levels of wear and deformation were evident. Pitting caused by third body debris was abundant and suggested fixation surface wear and failure

Increased failure rates due to metallic wear particle-associated adverse local tissue reactions (ALTR) is a significant clinical problem in resurfacing and total hip arthroplasty. Histological analysis and particle characterization are important elements for understanding the biological mechanisms of the reaction and different histological subtypes may have unique needs for longitudinal clinical follow-up and complication rates after revision arthroplasty. Consecutive patients (N=285 cases) presenting with ALTR from three major hip implant classes, metal-on-metal resurfacing and total hip arthroplasty (THA) and non-metal-on-metal THA with dual modular neck were identified from our prospective Osteolysis Tissue Database and Repository and 53 cases were selected for wear particle nano-analysis. Conventional histology: Tissue samples taken from multiple regions around the hip with extensive sampling performed at macroscopic examination were examined by light microscopy. Particle analysis: Tissue samples selected after frozen section evaluation for cellularity and particle content were examined by scanning electron microscopy (SEM), backscatter scanning electron microscopy (BSEM), BSEM-energy-dispersive X-ray spectroscopy (EDS) element mapping examination, transmission electron microscopy (TEM), TEM-EDS element mapping, and X-ray diffraction spectrometry (XRD) examination. ALTR encompasses three main histological patterns: 1) macrophage predominant, 2) mixed lymphocytic and macrophagic, and 3) predominant sarcoid-like granulomas. Duration of implantation and composition of periprosthetic cellular infiltrates was significantly different among the three implant types examined. Distinct differences in the size, shape, and element composition of the metallic particulate material were detected in each implant class, with correlation of the severity of the adverse reaction with element complexity of the particles. ALTR encompasses a diverse range of histological patterns, which are reflective of both the implant configuration independent of manufacturer and clinical features such as duration of implantation. Distinct differences in the metallic particulate material can contribute to explain the histological features of the ALTR and variability of performance of the implants. ALTR exhibits different histological patterns and is dependent on the characteristics of the wear particulate material of each implant class and host immunological reaction

Introduction. The purpose of this study was to evaluate the functional and radiographical mid-term follow-up results of a second generation metal-on-metal cementless total hip arthroplasty for the treatment of osteonecrosis of the femoral head in patients younger than 50 years. Methods. Twenty eight patients (35 hips) who underwent total hip arthroplasty with second generation metal-on-metal bearings for osteonecrosis of the femoral head at a minimum 5-year follow-up were included in this study. There were 5 women (6 hips) and 23 men (29 hips) who had a mean age of 40 years (range, 23 to 49 years) and a mean follow-up of 7 years. We used a Fitmore (Zimmer) cup and a 28mm Metasul femoral head in all cases. A CLS (Protek AG/Zimmer) femoral stem was used in 30 hips and a Cone prosthesis¯ (Protek AG) was used in 5 hips. Functional results were measured by Harris hip (HHS) and WOMAC scores. Radiographic evaluations were used to assess loosening and osteolysis according to Gruen and Delee and Charnley criteria. Results. The mean Harris hip score improved from 58 points (range, 35 to 67 points) pre-operatively to 92 points (range, 84 to 99 points) post-operatively, and the mean WOMAC score improved from 73 points (range, 63 to 89 points) to 30 points (range, 24 to 41 points). On radiological evaluation, all femoral and acetabular components were well-fixed without loosening or subsidence. Osteolysis was observed in 5 hips (14%) (acetabular osteolysis in 2 cases-Zone 2; 1, Zone 3; 1, femoral osteolysis in 3 cases- Zone 1; 2, Zone 7; 1). There were no complications including immediate post-operative deep infection, delayed infection, or recurrent dislocation. There was no case of revision for aseptic loosening. Conclusion. Second generation metal-on-metal cementless total hip arthroplasty for the treatment of osteonecrosis of the femoral head in patients younger than 50 years showed favorable functional and radiographic results