The Impact of 45S5-Bioactive Glass on Synovial Cells in Knee Osteoarthritis-An In Vitro Study.

Synovial inflammation in osteoarthritis (OA) is characterized by the release of cartilage-degrading enzymes and inflammatory cytokines. 45S5-bioactive glass (45S5-BG) can modulate inflammation processes; however, its influence on OA-associated inflammation has hardly been investigated. In this study, the effects of 45S5-BG on the release of cartilage-degrading metalloproteinases and cytokines from synovial membrane cells (SM) isolated from patients with knee OA was assessed in vitro. SM were cultivated as SM monocultures in the presence or absence of 45S5-BG. On day 1 (d1) and d7 (d7), the concentrations of Matrix Metalloproteinases (MMPs) and cytokines were assessed. In 45S5-BG-treated SM cultures, MMP9 concentration was significantly reduced at d1 and d7, whilst MMP13 was significantly increased at d7. Concentrations of interleukin (IL)-1B and C-C motif chemokine ligand 2 (CCL2) in 45S5-BG-treated SM cultures were significantly increased at both time points, as were interferon gamma (IFNG) and IL-6 at d7. Our data show an effect of 45S5-BG on SM activity, which was not clearly protective, anti-inflammatory, or pro-inflammatory. The influence of 45S5-BG on MMP release was more suggestive of a cartilage protective effect, but 45S5-BG also increased the release of pro-inflammatory cytokines. Further studies are needed to analyze the effect of BGs on OA inflammation, including the anti-inflammatory modification of BG compositions.

The anterior transmuscular intrapelvic approach for the treatment of acetabular fractures-a new anterior surgical strategy.

The anterior ilioinguinal and the posterior Kocher-Langenbeck approach have long been the standard surgical approaches to the acetabulum. The last decade has witnessed the development of so-called intrapelvic approaches for anterior pathologies because they provide better exposure of the quadrilateral plate. Currently, the modified Stoppa approach and the pararectus approach are frequently used by surgeons for the treatment of acetabular fractures. We investigated an even more direct access to the entire anterior column and the quadrilateral plate via the abdominal wall muscles, between the incisions for the ilioinguinal and the pararectus approach.After intensive study of anatomic specimens, a cadaver dissection was performed prior to clinical application. The approach was then used in 20 patients who were assessed retrospectively.Postoperative CT scans showed that, according to the Matta scoring system, the quality of fracture reduction was "anatomical" (≤ 1 mm) in 12 (60%), "imperfect" (2-3 mm) in four (20%), and "poor" (> 3 mm) in four (20%) patients. Numerous minor complications were observed; the majority of these had resolved at the time of discharge.In conclusion, the anterior transmuscular intrapelvic approach (ATI) is a safe and effective alternative to the ilioinguinal and pararectal approaches, and may be regarded as an evolutionary advancement of traditional procedures.

Infiltration Profile of Regulatory T Cells in Osteoarthritis-Related Pain and Disability.

Emerging evidence indicates that regulatory T cells (Treg) intervene in the inflammatory processes that drive osteoarthritis (OA). However, whether polarized Tregs affect clinical features of the disease in the short- or long-term, and if so, what their role in OA-related pain and functional disability really is, remains elusive. Thus, the aim of the current study was to characterize the infiltration profile of Tregs in systemic (peripheral blood) and joint-derived (synovial fluid and synovial membrane) samples from patients with knee OA in relation to OA-induced symptoms. To this end, Treg infiltration (CD4+CD25+/high CD127low/-) was analyzed in matched samples of peripheral blood (PB), synovial fluid (SF) and synovial membrane (SM) from a total of 47 patients undergoing elective knee arthroplasty using flow cytometry. At the same time, knee pain and function were assessed and correlated with Treg proportions in different compartments (PB, SF, SM). Interestingly, matched-pair analysis revealed significantly higher Treg proportions in joint-derived samples than in PB, which was mainly attributed to the high Treg frequency in SF. Moreover, we found significant associations between infiltrating Tregs and OA-related symptoms which indicate that lower Treg proportions-especially in the SM-are related to increased pain and functional disability in knee OA. In conclusion, this study highlights the importance of local cellular inflammatory processes in OA pathology. Intra-articular Treg infiltration might play an important role not only in OA pathogenesis but also in the development of OA-related symptoms.

CD8+ T Cells in OA Knee Joints Are Differentiated into Subsets Depending on OA Stage and Compartment.

Osteoarthritis (OA) is no longer considered a purely degenerative disease. OA is defined as a disease of the entire joint, in which inflammation occurs in various joint tissues. The overall aim of this study was to analyze the presence and polarization of CD8+ T cell subsets in OA knee joints, in relation to the OA stage and compartment (synovial fluid (SF), synovial membrane (SM,) peripheral blood (PB)). A quantitative flow analysis of CD8+ T cell subsets to compare the SF, SM, PB, was performed in patients with different stages of OA (early, unicondylar and bicondylar OA). Samples of the SF, SM and PB were harvested from a total of 55 patients at the time of surgery. Early OA was confirmed by independent surgeons intraoperatively. Uni- and bicondylar OA was confirmed and graded by two plane radiographs. Samples were analyzed by flow cytometry for surface markers, and cytokines by intracellular staining (ICS). CD8+ T cells were shown to be differentiated into pro-inflammatory IFN-γ producing Tc1 and IL-17A producing Tc17, as well as anti-inflammatory IL-4 producing Tc2. All CD8+ T cell subsets (Tc1, Tc17, and Tc2) were detected in both the SM and SF. The percentage of CD8+ T cell subsets of the total CD8+ T cell population was dependent on the OA stage and compartment. Compared with the peripheral blood (PB), the proportion of CD8+IFN-γ+ Tc1 and CD8+IL-17A+ Tc17 was significantly increased in OA SF. This was confirmed in our data for both early OA and end-stage OA. In the SM samples of end-stage OA patients, the proportion of CD8+IL-17A+ Tc17 was significantly increased compared to the PB. Comparing SF and SM samples of end-stage OA patients, the proportion of CD8+IFN-γ+ Tc1 was significantly increased in SF, whereas there were no differences concerning CD8+IL-4+ Tc2 and CD8+IL-17A+ Tc17. End-stage OA samples showed a significant increase of CD8+IL-4+ Tc2 in the SM for both unicondylar and bicondylar OA compared to early OA. CD8+ T cells infiltrating the SM and SF in OA knees are differentiated into IFN-γ-, IL-17A-, and IL-4-producing CD8+ T cell subsets (Tc1, Tc17, Tc2). This differentiation depends on the OA stage and OA compartment. Further investigation of CD8+ T cell subsets and their interaction with other inflammatory cells such as CD4+ T cells and macrophages may help to identify novel therapeutic anti-inflammatory strategies for containing OA progression.

Quality of life, infection control, and complication rates using a novel custom-made articulating hip spacer during two-stage revision for periprosthetic joint infection.

INTRODUCTION: Two-stage revision remains the gold standard treatment for most chronically infected and complex total hip arthroplasty infections. To improve patient outcome and reduce complication rates, we have developed a novel custom-made articulating hip spacer technique and present our short-term results. MATERIALS AND METHODS: Between November 2017 and November 2019, 27 patients (mean age 70 years) underwent two-stage revision for periprosthetic joint infection of the hip using the articulating spacer design described here. We retrospectively analyzed spacer-related complications as well as rates for complication, infection control, and implant survivorship after final reimplantation. Furthermore, we prospectively collected patient-reported health-related quality of life (HRQoL) scores prior to spacer implantation, with the spacer and after reimplantation of the new prosthesis. RESULTS: An additional round of spacer exchange was performed in two patients (8.3%), persistent wound discharge was the reason in both cases. We had one (4.2%) spacer-related mechanical complication, a dislocation that was treated with closed reduction. After reimplantation, infection control was achieved in 96% with an implant survivorship of 92% after a mean follow-up time of 19 (range 7-32, SD 7.2) months. While the scores for VR-12 MCS, VAS hip pain and patient-reported overall satisfaction significantly improved after first stage surgery, the scores for WOMAC, UCLA and VR-12 PCS significantly improved after second stage surgery. CONCLUSIONS: Our two-stage approach for periprosthetic joint infection shows high infection eradication and implant survivorship rates at short-term follow-up. Spacer-related complication rates were low, and we achieved high patient satisfaction rates and low pain levels already during the spacer period. To further simplify comparison between different spacer designs, we propose a new hip spacer classification system.

Monocytes, Macrophages, and Their Potential Niches in Synovial Joints - Therapeutic Targets in Post-Traumatic Osteoarthritis?

Synovial joints are complex structures that enable normal locomotion. Following injury, they undergo a series of changes, including a prevalent inflammatory response. This increases the risk for development of osteoarthritis (OA), the most common joint disorder. In healthy joints, macrophages are the predominant immune cells. They regulate bone turnover, constantly scavenge debris from the joint cavity and, together with synovial fibroblasts, form a protective barrier. Macrophages thus work in concert with the non-hematopoietic stroma. In turn, the stroma provides a scaffold as well as molecular signals for macrophage survival and functional imprinting: "a macrophage niche". These intricate cellular interactions are susceptible to perturbations like those induced by joint injury. With this review, we explore how the concepts of local tissue niches apply to synovial joints. We introduce the joint micro-anatomy and cellular players, and discuss their potential interactions in healthy joints, with an emphasis on molecular cues underlying their crosstalk and relevance to joint functionality. We then consider how these interactions are perturbed by joint injury and how they may contribute to OA pathogenesis. We conclude by discussing how understanding these changes might help identify novel therapeutic avenues with the potential of restoring joint function and reducing post-traumatic OA risk.

Proinflammatory T cell polarization is already present in patients with early knee osteoarthritis.

BACKGROUND: Investigating the pathophysiological mechanisms of early osteoarthritis (OA) is of utmost interest since this stage holds the strongest promise for therapeutic interventions. The aims of this study were to analyze if synovial inflammation is already present in early OA and to characterize the involved cell populations, by investigating synovial fluid (SF) and synovial membrane (SM) of early OA patients for the presence and polarization status of CD4 T cells. METHODS: A quantitative analysis of CD4+ T cell infiltration in SF and SM compared to peripheral blood (PB) was performed in patients with early stages of OA. We further investigated intracellular staining (ICS), surface marker, and chemokine receptor expression profiles of CD4+ T cells in SF, SM, and PB, as well as cytokine expression in native SF and PB. Matched samples of SF, SM, and PB were harvested from 40 patients with early OA at the time of surgery. Early OA was confirmed by independent surgeons intraoperatively. Samples were analyzed by flow cytometry for surface markers and cytokines, which are preferentially expressed by distinct T cell subsets (Th1, Th2, Th17, regulatory T cells). Furthermore, we analyzed native SF and PB supernatants using MACSPlex for multiple cytokine expression profiles. RESULTS: SF and SM showed a distinct infiltration of CD4+ T lymphocytes, with significantly increased expression of chemokine receptors CXCR3/CCR5, cytokine IFN-γ (preferentially expressed by Th1 cells), and CD161 (preferentially expressed by IL-17 producing Th17 cells) compared to PB. Furthermore, the percentage of CD4+ T cells polarized to Treg was significantly increased in SM compared to SF and PB. No significant differences were observed for CCR3 and CCR4 (preferentially expressed by Th2 cells), although IL-4 values were significantly higher in SM and SF compared to PB. Cytokine analysis showed comparable results between PB and SF, with only IL-6 being significantly increased in SF. CONCLUSIONS: Early OA joints show already significant inflammation through CD4+ T cell infiltration, with predominant Th1 cell polarization. Inflammation seems to be driven by direct proinflammatory cell interaction. Cytokine signaling seems to be negligible at the site of inflammation in early OA, with only IL-6 being significantly increased in SF compared to PB.

Assessment of oxidative stress response genes in Avicennia marina exposed to oil contamination - Polyphenol oxidase (PPOA) as a biomarker.

Mangrove plants, which inhabit and form sensitive ecosystems in the intertidal zones of tropical and subtropical coastlines, though vulnerable to petroleum pollution, still maintain their growth under oil contamination. To elucidate the molecular response of mangrove plants to crude oil-sediment mixture, seeds of Avicennia marina were planted and grown on 0, 2.5, 5.0, 7.5 and10 % (w/w) oil-contaminated soil. Plant biomass was highly affected from 3.05 ± 0.28 (Control) to 0.50 ± .07 (10 %) and from 3.47 ± 0.12 to 1.88 ± 0.08 in 2 and 4 months old plants respectively. The expression analysis of 11genes belonging to detoxification pathways in the roots and leaves of 2 and 4 month-old plants was evaluated by qRT-PCR. Our results showed changes in expression levels of Fe-SOD, Mn-SOD, CAT, PRX, PPOs, GSTs, and NAP2 whose products are involved in reactive oxygen species (ROS) and xenobiotic detoxification. PPOA showed the highest expression induction of 43 ± 1.15, followed by CAT (12.61 ± 3.25) and PPOB (6.38 ± 1.34) in leaves of 2 months old seedlings grown on 7.5, 10 and 7.5 % oil contaminated soil respectively. PPOA (39.23 ± 2.1), PRX (32.13 ± 1.2) as well as PPOB (26.11 ± 1.3) showed the highest expression induction in leaves of 4 months old plants grown in 2.5 % oil contaminated soil. Our data indicated that PPOA can be a good biomarker candidate gene for long term exposure to oil contamination in A. marina.

Peripheral Blood Lymphocyte Subpopulations in Patients Following Small Diameter Metal-On-Metal Total Hip Replacement at Long-Term Follow-Up.

(1) Background: The objective of the present study was to investigate peripheral blood lymphocyte subpopulations in patients with small diameter metal-on-metal total hip arthroplasty (MoM THA) and elevated blood metal ion concentrations at long-term follow-up. The hypothesis was that increased blood metal ion levels or the presence of adverse local tissue reactions (ALTR) would be associated with changes in the peripheral expression of lymphocyte subpopulations, which could potentially serve as early diagnostic markers for metal wear related complications. (2) Methods: Peripheral blood samples were analyzed for leucocyte subgroups (CD3+, CD4+, CD8+, CD14+, CD16+/CD56+, CD25+/CD127-, CD19+, IFN-γ+, IL-4+ and IL-17A+ cells) in 34 patients with elevated blood metal ion levels (combined cobalt and chromium levels >2 µg/L) following small head MoM THA at a mean follow-up of 15.6 years. Fifteen patients with small head MoM THA and blood metal ion levels within the normal range and 15 patients with conventional ceramic-on-polyethylene THA served as control groups. In addition, blood metal ion levels and leucocyte subpopulations were compared between patients with and without adverse local tissue reactions (ALTR), which was investigated by MRI in 27 patients of the study cohort. (3) Results: There was a significant decrease in the levels of IFN-γ+ Type-1 T helper cells (Th1) in patients with MoM THA compared to the ceramic-on-polyethylene control group (p < 0.001). No statistically significant differences in the cell counts of other lymphocyte subpopulations were found between the three groups. Cobalt ion levels were significantly higher in patients with ALTR (p < 0.001) compared to the non-ALTR group, but no differences in the levels of lymphocyte subsets were found between the two groups. (4) Conclusions: No adverse systemic effects with respect to peripheral blood leucocyte subpopulations could be detected in the present study in patients following THA with a small diameter MoM articulation at long-term follow-up. We found a significant decrease of IFN-γ+ Th1 cells in patients with MoM THA compared to the control group, but no differences in the peripheral expression of leucocyte subpopulations were seen between patients with and without ALTR. Future studies with larger patient cohorts and additional histopathological investigations could help to better understand the role of Th1 cells and other cell lines of the adaptive immune system in the development of metal wear related complications after total joint replacement.

T Helper Cell Infiltration in Osteoarthritis-Related Knee Pain and Disability.

Despite the growing body of literature demonstrating a crucial role of T helper cell (Th) responses in the pathogenesis of osteoarthritis (OA), only few clinical studies have assessed interactions between Th cells and OA-related symptoms. Yet, the inclusion of clinical data in the interpretation of cellular analyses of Th cell infiltration is essential to reveal the mechanisms underlying the complex pathophysiology of OA pain and disability. Thus, the aim of the study was to analyze the infiltration pattern of Th cells in systemic (peripheral blood) and joint-derived (synovial membrane and fluid) samples from patients with knee OA in relation to OA-induced pain and disability. Therefore, radiographic OA severity, knee pain and function of 47 OA patients undergoing knee arthroplasty were evaluated prior to surgery. In parallel, samples of peripheral blood (PB), synovial membrane (SM) and synovial fluid (SF) were harvested and analyzed for different Th subsets using flow cytometry. According to surface marker expression Th cells (CD3+ CD4+ CD8-) were assigned to the Th subsets Th1 (CXCR3+, CCR5+), Th2 (CCR3+, CCR4+) and Th17 (CD161+, CCR6+). Interestingly, infiltration of the SM with all Th subtypes (Th1, Th2, Th17) significantly correlated with OA-induced disability. Most importantly, synovial CCR5+ and CCR3+ Th cell infiltration was associated with OA-related knee pain and disability. Furthermore, higher percentage rates of CXCR3+ Th cells in all tissue samples (PB, SM, SF) showed significant associations with OA severity. In contrast, increasing percentage rates of CD161+ Th cells in SM samples corresponded to a better functional outcome. In conclusion, the current study provides an extensive profile of the Th cell infiltration pattern in PB, SF and SM from patients with clinically relevant knee OA. Th cell infiltration of the SM might play a crucial role not only in the pathogenesis of OA but also in the development of OA-related knee pain and disability.

Prospective Long-term Follow-up of Autologous Chondrocyte Implantation With Periosteum Versus Matrix-Associated Autologous Chondrocyte Implantation: A Randomized Clinical Trial.

BACKGROUND: Matrix-associated autologous chondrocyte implantation (MACI) is a further development of the original autologous chondrocyte implantation periosteal flap technique (ACI-P) for the treatment of articular cartilage defects. PURPOSE: We aimed to establish whether MACI or ACI-P provides superior long-term outcomes in terms of patient satisfaction, clinical assessment, and magnetic resonance imaging (MRI) evaluation. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: A total of 21 patients with cartilage defects at the femoral condyle were randomized to MACI (n = 11) or ACI-P (n = 10) between the years 2004 and 2006. Patients were assessed for subjective International Knee Documentation Committee (IKDC) score, Lysholm and Gillquist score, Tegner Activity Score, and 36-Item Short Form Health Survey (SF-36) preoperatively (T0), at 1 and 2 years postoperatively (T1, T2), and at the final follow-up 8 to 11 years after surgery (T3). Onset of osteoarthritis was determined using the Kellgren-Lawrence score and Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score, and delayed gadolinium-enhanced MRI of cartilage was used to evaluate the cartilage. Adverse events were recorded to assess safety. RESULTS: There were 16 patients (MACI, n = 9; ACI-P, n = 7) who were reassessed on average 9.6 years after surgery (76% follow-up rate). The Lysholm and Gillquist score improved in both groups after surgery and remained elevated but reached statistical significance only in ACI-P at T1 and T2. IKDC scores increased significantly at all postoperative evaluation time points in ACI-P. In MACI, IKDC scores showed a significant increase at T1 and T3 when compared with T0. In the majority of the patients (10/16; MACI, 5/9; ACI-P, 5/7) a complete defect filling was present at the final follow-up as shown by the MOCART score, and 1 patient in the ACI-P group displayed hypertrophy of the repair tissue, which represents 6% of the whole study group and 14.3% of the ACI-P group. Besides higher SF-36 vitality scores in ACI-P at T3, no significant differences were seen in clinical scores and MRI scores between the 2 methods at any time point. Revision rate was 33.3% in MACI and 28.6% in ACI-P at the last follow-up. CONCLUSION: Our long-term results suggest that first- and third-generation ACI methods are equally effective treatments for isolated full-thickness cartilage defects of the knee. With the number of participants available, no significant difference was noted between MACI and ACI-P at any time point. Interpretation of our data has to be performed with caution due to the small sample size, which was further limited by a loss to follow-up of 24%.

The Migration Pattern of a Cementless Hydroxyapatite-Coated Titanium Stem under Immediate Full Weight-Bearing-A Randomized Controlled Trial Using Model-Based RSA.

(1) Background: High primary stability is important for the long-term survival of cementless femoral stems in total hip arthroplasty (THA). The objective of this study was to investigate the migration pattern of a hydroxyapatite-coated cementless hip stem developed for minimally invasive surgery using model-based radiostereometric analysis (RSA). (2) Methods: In this randomized controlled trial, 44 patients with an indication for cementless primary THA were randomly allocated to receive either the SL-PLUS MIA stem, developed for minimally invasive surgery, or the SL-PLUS stem (Smith & Nephew Orthopaedics, Baar, Switzerland) which served as a control group. Unlimited weight-bearing was permitted postoperatively in both groups. Model-based RSA was performed after six weeks and after 3, 6, 12 and 24 months postoperatively. (3) Results: Mean total stem subsidence at two-year follow-up was 0.40 mm (SD 0.66 mm) in the SL-PLUS group and 1.08 mm (SD 0.93 mm) in the SL-PLUS MIA group (p = 0.030). Stem subsidence occurred during the first six weeks after surgery, indicating initial settling of the stem under full weight-bearing. Both stem designs showed good osseointegration and high secondary stability with no further migration after initial settling. (4) Conclusions: Settling of a cementless straight femoral stem occurs during the first six weeks after surgery under full weight-bearing. Although initial stem migration was higher in the SL-PLUS MIA group, it had no influence on secondary stability. All implants showed good osseointegration and high secondary stability with no signs of implant loosening during this two-year follow-up period.

Impact of Mononuclear Cell Infiltration on Chondrodestructive MMP/ADAMTS Production in Osteoarthritic Knee Joints-An Ex Vivo Study.

Progressive loss of joint function in osteoarthritis (OA) is driven by degenerative and inflammatory processes and their complex interaction. Decoding the link between degeneration and inflammation is one of the most exciting approaches in understanding OA pathophysiology and holds the promise to open new therapeutic avenues. The overarching goal of this project was to analyze the impact of mononuclear cells (MNC) on enzymatic chondrodestructive processes (MMP/ADAMTS) in OA. Synovial membrane (SM), articular cartilage (AC) and peripheral blood (PB) were obtained from a total of 21 patients with advanced knee OA who underwent arthroplastic surgery. In supernatants of native synovial cell cultures, T cell-depleted synovial cell cultures and macrophage-depleted synovial cell cultures, the concentrations of various metalloproteinases were examined by Enzyme Linked Immunosorbent Assay (ELISA). Furthermore, ELISA was used to analyze concentrations of metalloproteinases in supernatants of chondrocyte monocultures and chondrocyte co-cultures with CD4+CD127dim/- enriched peripheral blood mononuclear cells (PBMC), Treg depleted CD4+CD25-CD127dim/- enriched PBMC and CD4+CD25+CD127dim/- Treg. Compared to native synovial cell culture, T cell depletion led to significantly lower levels of MMP1, MMP3 and MMP-9 and macrophage depletion led to a significant decline of MMP1, MMP3, MMP9 and ADAMTS-5 concentration. Compared to T cell depletion, macrophage depletion resulted in a significantly stronger reduction of MMP1, MMP3, MMP9 and ADAMTS5. In chondrocyte co-culture with CD4+CD127dim/- enriched PBMC the concentration of MMP1 and ADAMTS5 was significantly increased compared to chondrocyte monoculture. No significant differences were found between chondrocyte monoculture and chondrocyte coculture with Treg as well as between co-culture with CD4+CD127dim/- enriched PBMC containing Treg and co-culture with Treg-depleted CD4+CD25-CD127dim/- enriched PBMC. In conclusion, our data suggests that both synovial macrophages and T cells have a catabolic potential by inducing the release of chondrodestructive metalloproteinases in OA synovium. This study also supports the hypothesis that MNC affect the release of metalloproteinases by chondrocytes and are hereby involved in the cartilageinduced chondrodestructive process. In this study no suppressive effect of Treg was shown.

What Is the Long-term (27- to 32-year) Survivorship of an Uncemented Tapered Titanium Femoral Component and Survival in Patients Younger Than 50 Years?

BACKGROUND: Uncemented femoral components in primary THA are in widespread use, especially in patients younger than 50 years, but few studies have evaluated their survival into the late third and early fourth decade. QUESTIONS/PURPOSES: We evaluated (1) survivorship using femoral revision for any reason as the endpoint, (2) survivorship using femoral revision for aseptic loosening as the endpoint, (3) survival in patients younger than 50 years, (4) cumulative incidence of stem revision for periprosthetic femoral fracture and (5) the overall risk of revision (change of any part of the implanted components) at a minimum of 27 years of follow-up with an uncemented tapered titanium stem still in clinical use today. METHODS: We reviewed the clinical and radiographic results of 326 THAs performed in 326 patients (for 28 patients with bilateral THA, only the first hip was included in the analysis to ensure independent observations) using an uncemented grit-blasted, tapered collarless titanium alloy (TiAl6Nb7) stem between January 1985 and December 1989. In that same timeframe, we performed 1038 primary THAs. During that time, we used cementless stems in patients without severe femoral canal deformity and adequate bone stock for uncemented femoral fixation as determined by using the indication criteria described by the developer. In all, 34% (354 of 1038) were cementless; all cementless stems implanted during that time were the stem being studied here. No others were used. The mean (range) age at the time of surgery was 56 years (13-81 years). Sixty-seven patients were younger than 50 years at the time of primary THA. A competing risk survivorship analysis was used to estimate long-term survival. The minimum follow-up was 27 years (mean 28 years; range 27-32 years); at that time, 169 patients had died, and four patients were lost to follow-up. RESULTS: Survivorship at 28 years with revision of the femoral component for any reason as the endpoint was 87% (95% CI 83 to 90). Survivorship for femoral revision for aseptic loosening as the endpoint was 94% at 28 years (95% CI 90 to 96). Survival in patients younger than 50 years at the time of primary THA was 89% (95% CI 78 to 95) and 95% (95% CI 86 to 98) at 28 years for the endpoints of all stem revisions and aseptic stem loosening, respectively. The overall cumulative incidence of stem revision for periprosthetic femoral fracture was 4% (95% CI 2 to 7) at 28 years. The overall THA survival rate at 28 years with revision for any reason as the endpoint was 57% (95% CI 51 to 62). CONCLUSIONS: Uncemented femoral fixation of a tapered collarless titanium alloy stem was reliable into the early fourth decade, especially in patients younger than 50 years. Late stem failures in the third and early fourth decade were mainly because of periprosthetic femoral fracture, while aseptic loosening occurred in undersized stems during the early second decade. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Blood Metal Ion Release After Primary Total Knee Arthroplasty: A Prospective Study.

OBJECTIVES: To investigate the course of in vivo blood metal ion levels in patients undergoing primary total knee arthroplasty (TKA) and to investigate potential risk factors associated with metal ion release in these patients. METHODS: Twenty-five patients with indication for TKA were included in this prospective study. Whole blood metal ion analysis was performed pre-operatively and at 1 week, 6 weeks, 3 months, 6 months, and 12 months postoperatively. Clinical scores were obtained using the American Knee Society Score (AKSS) and the Oxford Knee Score (OKS) at each follow-up and patients' activity levels were assessed by measuring the mean annual walking cycles at 12 months follow-up. Anteroposterior and lateral radiographs of the operated knee were evaluated postoperatively and at 12-month follow-up with regard to implant position and radiological signs of implant loosening. Correlation analysis using multivariate linear regression was performed to investigate the influence of different variables (age, gender, functional scores, number of walking cycles, and body mass index [BMI]) on blood cobalt ion concentrations. RESULTS: Mean metal ion levels of cobalt, chromium, molybdenum, and titanium were 0.28 µg/L (SD, 0.14), 0.43 µg/L (SD, 0.49), 0.62 µg/L (SD, 0.45), and 1.96 µg/L (SD, 0.98), respectively at 12-month follow-up. Mean cobalt ion levels significantly increased 1-year after surgery compared to preoperative measurements. There was no statistically significant increase of mean metal ion levels of chromium, titanium, and molybdenum at 1-year follow-up. Overall, metal ion levels were low and no patient demonstrated cobalt ion levels above 1 µg/L. Postoperative radiographs demonstrated well-aligned TKAs in all patients and no signs of osteolysis or implant loosening were detected at 1-year follow-up. Both the AKSS and OKS significantly improved during the course of the study up to the final follow-up. Multivariate regression analysis did not show a statistically significant correlation between the tested variables and blood cobalt ion concentrations. CONCLUSION: A statistically significant increase of mean cobalt ion concentration at 1-year follow-up was found in this cohort of patients with well-functioning TKA, although overall blood metal ion levels were relatively low. Despite low systemic metal ion concentrations seen in this cohort, the local effects of increased metal ion concentrations in the periprosthetic environment on the long-term outcome of TKA should be further investigated.

Long-Term Results of a Second-Generation, Small-Diameter, Metal-On-Metal Bearing in Primary Total Hip Arthroplasty at 14-year Follow-Up.

(1) Background: The objective of the present study was to review the clinical and radiological results of a small-head, MoM bearing in primary THA and to determine blood metal ion levels at long-term follow-up. (2) Methods: We retrospectively evaluated the clinical and radiological results of 284 small-diameter, MoM 28-mm Metasul THA at a mean follow-up of 14.5 years, and measured blood metal ion concentrations in 174 of these patients. (3) Results: After 14 years, survival free for revision due to any reason was 94%. Proximal femoral osteolysis was seen in 23% of hips, and MRI demonstrated ARMD in 27 of the 66 investigated hips (41%). Mean cobalt, chromium, and titanium ion concentrations were 0.82 µg/L (range 0.22-4.45), 1.51 µg/L (0.04-22.69), and 2.68 µg/L (0.26-19.56) in patients with unilateral THA, and 2.59 µg/L (0.43-24.75), 2.50 µg/L (0.26-16.75), and 3.76 µg/L (0.67-19.77), respectively in patients with bilateral THA. Twenty-nine percent of patients showed cobalt or chromium ion levels > 2 µg/L. (4) Conclusions: Despite good clinical long-term results, increased blood metal ion levels (cobalt or chromium > 2 µg/L) were found in approximately one-third of asymptomatic patients, and proximal femoral osteolysis and ARMD were frequently seen in this cohort. Blood metal ion analysis appears helpful in the long-term follow-up of these patients in order to identify individuals at risk. In accordance with contemporary consensus statements, symptomatic patients with elevated metal ion levels and/or progressive osteolysis should be considered for additional CT or MARS MRI to determine the extent of soft tissue affection prior to revision surgery. Further studies are necessary to investigate the clinical relevance of ARMD in asymptomatic patients with small-head, MoM THA.

Minimally invasive lateral unicompartmental knee replacement: Early results from an independent center using the Oxford fixed lateral prosthesis.

PURPOSE: The aim of the present study was to assess clinical outcome as well as short-term survivorship of fixed-bearing lateral unicompartmental knee replacement (UKR) from a non-designer centre using the Oxford Fixed Lateral prosthesis. METHODS: This single-centre retrospective cohort study reports the short-term results of 51 consecutive patients (52 knees) after fixed-bearing lateral UKR with a minimum follow-up of one year. Survivorship analysis was performed with different endpoints and clinical outcome was measured using the Oxford Knee Score (OKS), objective American Knee Society Score (AKSS-O), range-of-motion (ROM), visual analog scale for pain (VAS), Tegner activity score and UCLA score. RESULTS: There was no revision surgery, defined as exchange of at least one of the components resulting in a survival rate of 100% at two years. Three patients required further surgical treatment resulting in a survival rate of 94.2% (95% confidence interval (CI): 83.2-98.1%) with the endpoint 'any reoperation'. Outcome scores, VAS and ROM showed a statistically significant improvement at final follow-up (P < .001). The OKS improved from 26.4 ±â€¯6.9 (12-41) preoperatively to 39.7 ±â€¯8.4 (15-48), the AKSS-O from 54.3 ±â€¯15.3 (18-90) to 82.2 ±â€¯15.6 (40-100), the American Knee Society Functional Score from 56.4 ±â€¯21.3 (10-100) to 83.1 ±â€¯20.2 (five to 100) and the ROM from 123.5 ±â€¯13.5 (90-140) to 134 ±â€¯10.3 (95-150). CONCLUSION: Early results of fixed-bearing lateral UKR using the Oxford-Fixed-Lateral prosthesis were encouraging with a significant improvement in pain and knee function as well as an excellent survivorship of 100% at a mean follow-up of two years. Further follow-up is necessary to evaluate the long-term effectiveness of this device and the surgical technique. LEVEL OF EVIDENCE: Level IV, retrospective cohort study.

Chondral Differentiation of Induced Pluripotent Stem Cells Without Progression Into the Endochondral Pathway.

A major problem with chondrocytes derived in vitro from stem cells is undesired hypertrophic degeneration, to which articular chondrocytes (ACs) are resistant. As progenitors of all adult tissues, induced pluripotent stem cells (iPSCs) are in theory able to form stable articular cartilage. In vitro differentiation of iPSCs into chondrocytes with an AC-phenotype and resistance to hypertrophy has not been demonstrated so far. Here, we present a novel protocol that succeeded in deriving chondrocytes from human iPSCs without using pro-hypertrophic bone-morphogenetic-proteins. IPSC-chondrocytes had a high cartilage formation capacity and deposited two-fold more proteoglycans per cell than adult ACs. Importantly, cartilage engineered from iPSC-chondrocytes had similar marginal expression of hypertrophic markers (COL10A1, PTH1R, IBSP, ALPL mRNAs) like cartilage from ACs. Collagen X was barely detectable in iPSC-cartilage and 30-fold lower than in hypertrophic cartilage derived from mesenchymal stromal cells (MSCs). Moreover, alkaline phosphatase (ALP) activity remained at basal AC-like levels throughout iPSC chondrogenesis, in contrast to a well-known significant upregulation in hypertrophic MSCs. In line, iPSC-cartilage subjected to mineralizing conditions in vitro showed barely any mineralization, while MSC-derived hypertrophic cartilage mineralized strongly. Low expression of Indian hedgehog (IHH) like in ACs but rising BMP7 expression like in MSCs suggested that phenotype stability was linked to the hedgehog rather than the bone morphogenetic protein (BMP) pathway. Taken together, unlimited amounts of AC-like chondrocytes with a high proteoglycan production reminiscent of juvenile chondrocytes and resistance to hypertrophy and mineralization can now be produced from human iPSCs in vitro. This opens new strategies for cartilage regeneration, disease modeling and pharmacological studies.

Divergent Mononuclear Cell Participation and Cytokine Release Profiles Define Hip and Knee Osteoarthritis.

Osteoarthritis (OA) is a progressive joint disease driven by a blend of inflammatory and biomechanical processes. Studies using human samples to understand inflammatory mechanisms in OA frequently recruit OA patients with different affected joints, even though recent evidence indicates that OA is a heterogeneous disease which only culminates in a common end point. Differences in age of onset and the dynamics of disease progression suggest that different joints may represent different disease entities, thereby diluting the discovery potential in a combined analysis. We hypothesized that different OA joints may also differ in immunopathology within the synovium. To investigate this hypothesis, we profiled the immune cell contribution (flow cytometry) and cytokine release profiles (ELISA) in purified synovial membrane mononuclear cells from 50 patients undergoing either hip (n = 34) or knee (n = 16) replacement surgery. Unsupervised computational approaches were used for disease deconstruction. We found that hip and knee osteoarthritis are not identical in respect to the inflammatory processes that take place in the synovial membrane. Instead, we report that principally CD14+ macrophages are expanded fourfold in the synovial membrane of patients with knee OA compared to hip OA, with a trend to higher expression in CD8+ T cells, while CD4+ T cells, B cells, and NK cells were found at comparable quantities. Upon isolation and culture of cells from synovial membrane, isolates from hip OA released higher concentrations of Eotaxin (CCL11), G-CSF, GM-CSF, INF-γ, IP-10 (CXCL10), TNF-α, MIP-1α (CCL3), MIP-1ß (CCL4), IL-4, IL-10, IL-17, and lower concentrations of stem cell factor (SCF), thereby highlighting the difference in the nature of hip and knee osteoarthritis. Taken together, this study establishes hip and knee OA as immunologically distinct types of OA, and creates a resource of the cytokine expression landscape and mononuclear cell infiltration pattern of patients with hip and knee osteoarthritis.

Synovial Cytokines Significantly Correlate with Osteoarthritis-Related Knee Pain and Disability: Inflammatory Mediators of Potential Clinical Relevance.

The aim of this study was to identify inflammatory mediators of potential clinical relevance in synovial fluid (SF) samples of patients with knee osteoarthritis (OA). Therefore, radiographic OA severity, knee pain and function of 34 OA patients undergoing unicompartmental (UC) and bicompartmental (BC) knee arthroplasty were assessed prior to surgery and SF samples were analyzed for a broad variety of inflammatory mediators, including interleukins (ILs), interferons (IFNs), C-X-C motif ligand chemokines (CXCLs), and growth factors (nerve growth factor; NGF, vascular endothelial growth factor; VEGF, and stem cell growth factor ß; SCGF-ß) using multiplex assay. Significant differences were observed between the SF levels of different inflammatory markers. When compared to UC OA, significantly higher concentrations of IL-7, IL-8, IL-10, IL-12, IL-13, IFN-γ, VEGF and CXCL1 were detected in BC OA. Correlation analyses revealed significant associations between OA severity and IL-6, IL-8, IFN-γ, SCGF-ß, VEGF, CXCL1. Interestingly, increases in both anti- (IL-10, IL-13) and pro-inflammatory (IL-7, IL-12, IFN-γ) cytokines, as well as growth factors (SCGF-ß, VEGF), correlated significantly with the level of knee pain. Poorer knee function was associated with higher IL-6, IL-10, IL-12, IL-13, IL-18, ßNGF, SCGF-ß, VEGF and CXCL9 levels. In conclusion, this study provides an extensive profile of synovial inflammatory mediators in knee OA and identifies cytokines of potential clinical relevance. In fact, five of the mediators examined (IL-10, IL-12, IL-13, SCGF-ß, VEGF) significantly correlate with both knee pain and function.