Elevated glucose promotes MMP13 and ADAMTS5 production by osteoarthritic chondrocytes under oxygenated but not hypoxic conditions.

Type 2 diabetes is linked with increased incidence and severity of osteoarthritis. The purpose of this study was to determine the effect of extracellular glucose within the normal blood glucose and hyperglycemic range on catabolic enzyme production by chondrocytes isolated from osteoarthritic (OA) and macroscopically normal (MN) human cartilage under oxygenated (18.9% oxygen) and hypoxic (1% oxygen) conditions. OA and MN chondrocytes were maintained in 4, 6, 8, or 10 mM glucose for 24 h. Glucose consumption, GLUT1 glucose transporter levels, MMP13 and ADAMTS5 production, and levels of RUNX2, a transcriptional regulator of MMP13, ADAMTS5, and GLUT1, were assessed by enzyme-linked assays, RT-qPCR and/or western blot. Under oxygenated conditions, glucose consumption and GLUT1 protein levels were higher in OA but not MN chondrocytes in 10 mM glucose compared to 4 mM. Both RNA and protein levels of MMP13 and ADAMTS5 were also higher in OA but not MN chondrocytes in 10 mM compared to 4 mM glucose under oxygenated conditions. Expression of RUNX2 was overall lower in MN than OA chondrocytes and there was no consistent effect of extracellular glucose concentration on RUNX2 levels in MN chondrocytes. However, protein (but not RNA) levels of RUNX2 were elevated in OA chondrocytes maintained in 10 mM versus 4 mM glucose under oxygenated conditions. In contrast, neither RUNX2 levels or MMP13 or ADAMTS5 expression were increased in OA chondrocytes maintained in 10 mM compared to 4 mM glucose in hypoxia. Elevated extracellular glucose leads to increased glucose consumption and increased RUNX2 protein levels, promoting production of MMP13 and ADAMTS5 by OA chondrocytes in oxygenated but not hypoxic conditions. These findings suggest that hyperglycaemia may exacerbate chondrocyte-mediated cartilage catabolism in the oxygenated superficial zone of cartilage in vivo in patients with undertreated type 2 diabetes, contributing to increased OA severity.

High in-vivo accuracy of a novel robotic-arm-assisted system for total knee arthroplasty.

PURPOSE: Robotic-assisted total knee arthroplasty (TKA) has been shown to improve the accuracy and precision of bony resections and implant position. However, the in vivo accuracy of the full surgical workflow has not been widely reported. The primary objective of this study is to determine the accuracy and precision of a robotic-arm-assisted system throughout the intraoperative workflow. METHODS: This was a retrospective cohort study of adult patients who underwent primary TKA with various workflows and alignment targets by three arthroplasty-trained surgeons with previous experience using the ROSA® Knee System (Zimmer Biomet) over a 3-month follow-up period. Accuracy and precision were determined by measuring the difference between various workflow time points, including the final preoperative plan (PP), robot-validated (RV) resection angle and postoperative radiographs (PR). The absolute mean difference between the measurements determined accuracy, and the standard deviation represented precision. The lateral distal femoral angle, medial proximal tibial angle, femoral flexion angle and tibial slope were measured on postoperative coronal long-leg radiographs and true short-leg lateral radiographs. RESULTS: A total of 77 patients were included in the final analyses. The accuracy for the coronal femoral angle was 1.62 ± 1.11°, 0.75 ± 0.79° and 1.96 ± 1.29° for the differences between PP and PR, PP and RV and RV and PR. The tibial coronal accuracy was 1.44 ± 1.03°, 0.81 ± 0.67° and 1.57 ± 1.14° for PP/PR, PP/RV and RV/PR, respectively. Femoral flexion accuracy was 1.39 ± 1.05°, 0.83 ± 0.59° and 1.81 ± 1.21° for PP/PR, PP/RV and RV/PR, respectively. Tibial slope accuracy was 0.99 ± 0.72°, 1.19 ± 0.87° and 1.63 ± 1.11°, respectively. The proportion of patients within 3° was 93.2%, 95.3%, 97.3% and 94.6% for the distal femur, proximal tibia, femoral flexion and tibial slope angles when the final intraoperative plan was compared to PRs. No patients had a postoperative complication at the final follow-up. CONCLUSIONS: The ROSA Knee System has acceptable accuracy and precision of coronal and sagittal plane resections with few outliers at various steps throughout the platform's entire workflow in vivo. LEVEL OF EVIDENCE: Level III.

Reverse total shoulder arthroplasty for acute proximal humeral fracture has comparable 10-year outcomes to elective indications: results from the New Zealand Joint Registry.

HYPOTHESIS AND BACKGROUND: Recently, the indication of reverse total shoulder arthroplasty (RTSA) has expanded beyond rotator cuff arthropathy to include treatment of complex acute proximal humeral fracture (PHF). Limited previous studies have compared the long-term clinical and functional outcomes of patients undergoing RTSA for PHF vs. elective indications for degenerative conditions. The purpose of this study was to compare implant survivorship, reasons for revision and functional outcomes in patients undergoing RTSA for acute PHF with those undergoing elective RTSA in a population-based cohort study. METHODS: Prospectively collected data from the New Zealand Joint Registry from 1999 to 2021 and identified 6862 patients who underwent RTSA. Patients were categorized by preoperative indication, including PHF (10.8%), rotator cuff arthropathy (RCA) (44.5%), osteoarthritis (OA) (34.1%), rheumatoid arthritis (RA) (5.5%), and old traumatic sequelae (5.1%). Revision-free implant survival and functional outcomes (Oxford Shoulder Scores [OSSs] at the 6-month, 5-year, and 10-year follow-ups) were adjusted by age, sex, American Society of Anesthesiologists class, and surgeon experience and compared. RESULTS: Revision-free implant survival at 10 years for RTSA for PHF was 97.3%, compared with 96.1%, 93.7%, 92.8%, and 91.3% for OA, RCA, RA and traumatic sequelae, respectively. When compared with RTSA for PHF, the adjusted risk of revision was significantly higher for traumatic sequelae (hazard ratio = 2.3, P = .023) but not for other elective indications. The most common reason for revision in the PHF group was dislocation or instability (42.9%), which was similar to the OA (47.6%) and traumatic sequelae (33.3%) groups. At 6 months post-surgery, OSSs were significantly lower for the PHF group compared with the RCA, OA, and RA groups (31.1 vs. 35.6, 37.7, and 36.5, respectively, P < .001), and similar to traumatic sequelae (31.7, P = .431). At 5 years, OSSs were only significantly lower for PHF compared with OA (37.4 vs. 41.0, P < .001) and there was no difference between the PHF and other groups. At 10 years, there were no significant differences between groups. CONCLUSIONS: RTSA for PHF demonstrated reliable long-term survivorship and functional outcomes compared with elective indications. Despite lower functional outcomes in the early postoperative period for the PHF group, implant survivorship was similar in patients undergoing RTSA for the primary indication of acute PHF compared with RCA, OA, and RA and superior compared to the primary indication of traumatic sequelae.

Phenotype and energy metabolism differ between osteoarthritic chondrocytes from male compared to female patients: Implications for sexual dimorphism in osteoarthritis development?

OBJECTIVES: The prevalence and severity of knee osteoarthritis (OA) are greater in females than males. The purpose of this study was to determine whether there is an underlying difference in the biology of OA chondrocytes between males and females. METHODS: Chondrocytes were obtained following knee arthroplasty from male and female patients with primary OA. Phenotype marker expression, glucose and fat consumption, and rates of glycolysis and oxidative phosphorylation were compared between females and males. RNAi was used to determine the consequences of differential expression of Sry-box transcription factor 9 (SOX9) and PGC1α between males and females. RESULTS: OA chondrocytes from male donors showed elevated ribonucleic acid (RNA) and protein levels of SOX9, elevated COL2A1 protein synthesis, higher glucose consumption, and higher usage of glycolysis compared to females. OA chondrocytes from females had higher PGC1α protein levels, higher fat consumption, and higher oxidative energy metabolism than males. Knockdown of SOX9 reduced expression of COL2A1 to a greater extent in male OA chondrocytes than females whereas knockdown of PGC1α reduced COL2A1 expression in females but not males. Expression of ACAN and the glycolytic enzyme PGK1 was also reduced in males but not females following SOX9 knockdown. CONCLUSIONS: OA chondrocyte phenotype and energy metabolism differ between males and females. Our results indicate transcriptional control of COL2A1 differs between the two. Differences in chondrocyte biology between males and females imply the underlying mechanisms involved in OA may also differ, highlighting the need to consider sex and gender when investigating pathogenesis and potential treatments for OA.

Concentration-dependent effects of leptin on osteoarthritis-associated changes in phenotype of human chondrocytes.

Metabolic syndrome is a risk factor for osteoarthritis. Elevated leptin levels have been implicated as a potential cause of this association. Previous studies have shown that supra-physiological leptin concentrations can induce osteoarthritis-like changes in chondrocyte phenotype. Here, we tested the effects of leptin in the concentration range found in synovial fluid on chondrocyte phenotype. Chondrocytes isolated from macroscopically normal regions of cartilage within osteoarthritic joints from patients undergoing knee arthroplasty, all with body mass index >30 kg/m2 were treated with 2-40 ng/ml leptin for 24 h. Chondrocyte phenotype marker expression was measured by RT-qPCR and western blot. The role of HES1 in mediating the effects of leptin was determined by gene knockdown using RNAi and over-expression using adenoviral-mediated gene delivery. Treatment of chondrocytes with 20 or 40 ng/ml leptin resulted in decreased SOX9 levels and decreased levels of the SOX9-target genes COL2A1 and ACAN. Levels of HES1 were lower and ADAMTS5 higher in chondrocytes treated with 20 or 40 ng/ml leptin. HES1 knockdown resulted in increased ADAMTS5 expression whereas over-expression of HES1 prevented the leptin-induced increase in ADAMTS5. An increase in MMP13 expression was only evident in chondrocytes treated with 40 ng/ml leptin and was not mediated by HES1 activity. High concentrations of leptin can cause changes in chondrocyte phenotype consistent with those seen in osteoarthritis. Synovial fluid leptin concentrations of this level are typically observed in patients with metabolic syndrome and/or women, suggesting elevated leptin levels may form part of the multifactorial network that leads to osteoarthritis development in these patients.

Robotic-arm assisted unicompartmental knee arthroplasty system has a learning curve of 11 cases and increased operating time.

PURPOSE: UKA has higher revision risk, particularly for lower volume surgeons. While robotic-arm assisted systems allow for increased accuracy, introduction of new systems has been associated with learning curves. The aim of this study was to determine the learning curve of a UKA robotic-arm assisted system. The hypothesis was that this may affect operative times, patient outcomes, limb alignment, and component placement. METHODS: Between 2017 and 2021, five surgeons performed 152 consecutive robotic-arm assisted primary medial UKA, and measurements of interest were recorded. Patient outcomes were measured with Oxford Knee Score, EuroQol-5D, and Forgotten Joint Score at 6 weeks, 1 year, and 2 years. Surgeons were grouped into 'low' and 'high' usage groups based on total UKA (manual and robotic) performed per year. RESULTS: A learning curve of 11 cases was found with operative time (p < 0.01), femoral rotation (p = 0.02), and insert sizing (p = 0.03), which highlighted areas that require care during the learning phase. Despite decreased 6-week EQ-5D-5L VAS in the proficiency group (77 cf. 85, p < 0.01), no difference was found with implant survival (98.2%) between phases (p = 0.15), or between 'high' and 'low' usage surgeons (p = 0.23) at 36 months. This suggested that the learning curve did not lead to early adverse effects in this patient cohort. CONCLUSION: Introduction of a UKA robotic-arm assisted system showed learning curves for operative times and insert sizing but not for implant survival at early follow-up. The short learning curve regardless of UKA usage indicated that robotic-arm assisted UKA may be particularly useful for low-usage surgeons. LEVEL OF EVIDENCE: Level III, Retrospective cohort study.

Better post-operative outcomes at 1-year follow-up are associated with lower levels of pre-operative synovitis and higher levels of IL-6 and VEGFA in unicompartmental knee arthroplasty patients.

PURPOSE: Osteoarthritis (OA) is associated with inflammation, and residual inflammation may influence outcomes following knee arthroplasty. This may be more relevant for patients undergoing unicompartmental knee arthroplasty (UKA) due to larger remaining areas of native tissue. This study aimed to: (1) characterise inflammatory profiles for medial UKA patients and (2) investigate whether inflammation markers are associated with post-operative outcomes. METHODS: This prospective, observational study has national ethics approval. Bloods, synovial fluid, tibial plateaus and synovium were collected from medial UKA patients in between 1 January 2021 and 31 December 2021. Cytokine and chemokine concentrations in serum and synovial fluid (SF) were measured with multiplexed assays. Disease severity of cartilage and synovium was assessed using validated histological scores. Post-operative outcomes were measured with Oxford Knee Score (OKS), Forgotten Joint Score (FJS-12) and pain scores. RESULTS: The study included 35 patients. SF VEGFA was negatively correlated with pre-operative pain at rest (r - 0.5, p = 0.007), and FJS-12 at six-week (r 0.44, p = 0.02), six-month (r 0.61, p < 0.01) and one-year follow-up (r 0.63, p = 0.03). Serum and SF IL-6 were positively correlated with OKS at early follow-up (serum 6 weeks, r 0.39, p = 0.03; 6 months, r 0.48, p < 0.01; SF 6 weeks, r 0.35, p = 0.04). At six weeks, increased synovitis was negatively correlated with improvements in pain at rest (r - 0.41, p = 0.03) and with mobilisation (r - 0.37, p = 0.047). CONCLUSION: Lower levels of synovitis and higher levels of IL-6 and VEGFA were associated with better post-operative outcomes after UKA, which could be helpful for identifying UKA patients in clinical practice. LEVEL OF EVIDENCE: Level IV case series.

Ethnicity, sex, and socioeconomic disparities in the treatment of traumatic rotator cuff injuries in Aotearoa/New Zealand.

HYPOTHESIS AND BACKGROUND: Traumatic rotator cuff injuries can be a leading cause of prolonged shoulder pain and disability and contribute to significant morbidity and health care costs. Previous studies have shown evidence of sociodemographic disparities with these injuries. The purpose of this nationwide study was to better understand these disparities based on ethnicity, sex, and socioeconomic status, in order to inform future health care strategies. METHODS: Accident Compensation Corporation (ACC) is a no-fault comprehensive compensation scheme encompassing all of Aotearoa/New Zealand (population in 2018, 4.7 million). Using the ACC database, traumatic rotator cuff injuries were identified between January 2010 and December 2018. Injuries were categorized by sex, ethnicity, age, and socioeconomic deprivation index of the claimant. RESULTS: During the 9-year study period, there were 351,554 claims accepted for traumatic rotator cuff injury, which totaled more than NZ$960 million. The greatest proportion of costs was spent on vocational support (49.8%), then surgery (26.3%), rehabilitation (13.1%), radiology (8.1%), general practitioner (1.6%), and "Other" (1.1%). Asian, Maori (indigenous New Zealanders), and Pacific peoples were under-represented in the age-standardized proportion of total claims and had lower rates of surgery than Europeans. Maori had higher proportion of costs spent on vocational support and lower proportions spent on radiology, rehabilitation, and surgery than Europeans. Males had higher number and costs of claims and were more likely to have surgery than females. There were considerably fewer claims from areas of high socioeconomic deprivation. DISCUSSION AND CONCLUSION: This large nationwide study demonstrates the important and growing economic burden of rotator cuff injuries. Indirect costs, such as vocational supports, are a major contributor to the cost, suggesting improving treatment and rehabilitation protocols would have the greatest economic impact. This study has also identified sociodemographic disparities that need to be addressed in order to achieve equity in health outcomes.

Differential Effects of Hypoxia versus Hyperoxia or Physoxia on Phenotype and Energy Metabolism in Human Chondrocytes from Osteoarthritic Compared to Macroscopically Normal Cartilage.

Chondrocyte phenotype and energy metabolism are altered in osteoarthritis (OA). However, most studies characterising the change in human chondrocyte behaviour in OA have been conducted in supraphysiological oxygen concentrations. The purpose of this study was to compare phenotype and energy metabolism in chondrocytes from macroscopically normal (MN) and OA cartilage maintained in 18.9% (standard tissue culture), 6% (equivalent to superficial zone of cartilage in vivo) or 1% oxygen (equivalent to deep zone of cartilage in vivo). MMP13 production was higher in chondrocytes from OA compared to MN cartilage in hyperoxia and physoxia but not hypoxia. Hypoxia promoted SOX9, COL2A1 and ACAN protein expression in chondrocytes from MN but not OA cartilage. OA chondrocytes used higher levels of glycolysis regardless of oxygen availability. These results show that differences in phenotype and energy metabolism between chondrocytes from OA and MN cartilage differ depending on oxygen availability. OA chondrocytes show elevated synthesis of cartilage-catabolising enzymes and chondrocytes from MN cartilage show reduced cartilage anabolism in oxygenated conditions. This is relevant as a recent study has shown that oxygen levels are elevated in OA cartilage in vivo. Our findings may indicate that this elevated cartilage oxygenation may promote cartilage loss in OA.

Five-year results after total knee arthroplasty in lymphoedema and lipoedema: encouraging functional and clinical outcomes and low rates of infection.

BACKGROUND: The aim of this study was to define outcomes after total knee arthroplasty (TKA) in lymphoedema and lipoedema patients managed by a multidisciplinary team and daily compression bandaging. METHODS: A retrospective study was performed in a single centre. Between 2007 and 2018, 36 TKA procedures were performed on 28 consecutive patients with a diagnosis of lymphoedema and lipoedema. Oxford Knee Scores (OKS), EuroQol-5D (EQ-5D) scores, satisfaction scores, radiographs, and complications were obtained at the final follow-up. Patients were admitted to the hospital up to two weeks prior to surgery and remained on the ward for daily compression bandaging by the specialist lymphoedema team. RESULTS: Over the study period, 36 TKAs were performed on 28 patients (5 males, 23 females) with a mean age of 71 years (range 54-90). Of these, 30 TKAs were in patients with lymphoedema, five with lipoedema, and one with a dual diagnosis. Overall, 28 TKAs (21 patients) were available at the final follow-up with a mean follow-up time of 61 months (range 9-138). The mean BMI was 38.5 kg/m2. The mean pre-operative and post-operative Oxford Knee Score increased from 18 (range 2-38) to 29 (range 10-54); p < 0.001. EQ-5D score increased from 0.48 (range 0.15-0.80) to 0.74 (0.34-1.00) (p < 0.001). Mean post-operative satisfaction was 7.6/10 (range 2-10), with 89.3% TKAs satisfied. Complications were one (4%, 1/28) deep vein thrombosis, one superficial wound infection, one prosthetic joint infection, one stiff knee requiring manipulation, and one intra-operative femoral fracture. CONCLUSIONS: Lymphoedema and lipoedema should not be seen as barriers to TKA if adopting a multidisciplinary approach.

A high-fat diet has negative effects on tendon resident cells in an in vivo rat model.

BACKGROUND: Tendinopathy is a major complication of diet-induced obesity. However, the effects of a high-fat diet (HFD) on tendon have not been well characterised. We aimed to determine: [1] the impact of a HFD on tendon properties and gene expression; and [2] whether dietary transition to a control diet (CD) could restore normal tendon health. METHODS: Sprague-Dawley rats were randomised into three groups from weaning and fed either a: CD, HFD or HFD for 12 weeks and then CD thereafter (HF-CD). Biomechanical, histological and structural evaluation of the Achilles tendon was performed at 17 and 27 weeks of age. Tail tenocytes were isolated with growth rate and collagen production determined. Tenocytes and activated THP-1 cells were exposed to conditioned media (CM) of visceral adipose tissue explants, and gene expression was analysed. RESULTS: There were no differences in the biomechanical, histological or structural tendon properties between groups. However, tenocyte growth and collagen production were increased in the HFD group at 27 weeks. There was lower SOX-9 expression in the HFD and HF-CD groups at 17 weeks and higher expression of collagen-Iα1 and matrix metalloproteinase-13 in the HFD group at 27 weeks. THP-1 cells exposed to adipose tissue CM from animals fed a HFD or HF-CD had lower expression of Il-10 and higher expression of Il-1ß. CONCLUSIONS: In this rodent model, a HFD negatively altered tendon cell characteristics. Dietary intervention restored some gene expression changes; however, adipose tissue secretions from the HF-CD group promoted an increased inflammatory state in macrophages. These changes may predispose tendon to injury and adverse events later in life.

Toxicity of tranexamic acid (TXA) to intra-articular tissue in orthopaedic surgery: a scoping review.

PURPOSE: Intra-articular administration of tranexamic acid (TXA) in orthopaedic arthroplasty and arthroscopic procedures has become increasingly common over the past decade. However, several recent reports have shown that TXA has the potential to be cytotoxic to cartilage, tendon and synovium. Our aim was to review the literature for evidence of toxic effects from TXA exposure to intra-articular tissue. METHODS: A scoping review methodology was used to search for studies assessing the toxic effects of TXA exposure to intra-articular tissues. MEDLINE, EMBASE, SCOPUS and The Cochrane Library were searched. Relevant information was extracted and synthesis of the retrieved data followed a basic content analytical approach. RESULTS: A total of 15 laboratory studies were retrieved. No clinical studies reporting a toxic effect of TXA on intra-articular tissue were identified in our search. Studies were analysed according to species of origin, tissue of origin and study setting (in vitro, ex vivo, or in vivo). There was increasing cytotoxicity to chondrocytes, tenocytes, synoviocytes and periosteum-derived cells with TXA concentrations beyond 20 mg/ml. Monolayer cell cultures appear more susceptible to TXA exposure, than three-dimensional and explant culture models. In vivo studies have not demonstrated a major toxic effect. CONCLUSIONS: Current evidence suggests a dose-dependent toxic effect on cartilage, tendon, and synovial tissue. Concentrations of 20 mg/ml or less are expected to be safe. There is a significant body of evidence to suggest the need for caution with intraarticular administration of TXA. There is a need for further human clinical trials in order to clarify the long-term safety of TXA topical application.

Remote Patient Monitoring with Wearable Sensors Following Knee Arthroplasty.

(Background) Inertial Measurement Units (IMUs) provide a low-cost, portable solution to obtain functional measures similar to those captured with three-dimensional gait analysis, including spatiotemporal gait characteristics. The primary aim of this study was to determine the feasibility of a remote patient monitoring (RPM) workflow using ankle-worn IMUs measuring impact load, limb impact load asymmetry and knee range of motion in combination with patient-reported outcome measures. (Methods) A pilot cohort of 14 patients undergoing primary knee arthroplasty for osteoarthritis was prospectively enrolled. RPM in the community was performed weekly from 2 up to 6 weeks post-operatively using wearable IMUs. The following data were collected using IMUs: mobility (Bone Stimulus and cumulative impact load), impact load asymmetry and maximum knee flexion angle. In addition, scores from the Oxford Knee Score (OKS), EuroQol Five-dimension (EQ-5D) with EuroQol visual analogue scale (EQ-VAS) and 6 Minute Walk Test were collected. (Results) On average, the Bone Stimulus and cumulative impact load improved 52% (p = 0.002) and 371% (p = 0.035), compared to Post-Op Week 2. The impact load asymmetry value trended (p = 0.372) towards equal impact loading between the operative and non-operative limb. The mean maximum flexion angle achieved was 99.25° at Post-Operative Week 6, but this was not significantly different from pre-operative measurements (p = 0.1563). There were significant improvements in the mean EQ-5D (0.20; p = 0.047) and OKS (10.86; p < 0.001) scores both by 6 weeks after surgery, compared to pre-operative scores. (Conclusions) This pilot study demonstrates the feasibility of a reliable and low-maintenance workflow system to remotely monitor post-operative progress in knee arthroplasty patients. Preliminary data indicate IMU outputs relating to mobility, impact load asymmetry and range of motion can be obtained using commercially available IMU sensors. Further studies are required to directly correlate the IMU sensor outputs with patient outcomes to establish clinical significance.

Vancouver B2 Peri-Prosthetic Fractures in Cemented Femoral Implants can be Treated With Open Reduction and Internal Fixation Alone Without Revision.

BACKGROUND: The aim of this study is to assess the outcomes of 52 consecutive Vancouver B2 peri-prosthetic fractures around cemented polished double-tapered stems treated by open reduction and internal fixation in 2 trauma centers in 2 countries. METHODS: Outcomes included modified Harris Hip Score (mHHS), Harris Pain Score, and return to pre-injury mobility. Fracture healing was assessed; implant subsidence measured and complications including re-operations reported. RESULTS: No patient was lost to follow-up. Median patient age at operation was 82 years (range 43-98); Harris pain scores showed minimal pain (median 42, range 10-44) at latest follow-up. Median total subsidence at 1 year was 1.1 mm (range 0-5.4), the majority of which occurred within the cement mantle. No subsequent femoral stem revision was required (median 2.9 years, 0-10); however, there were 3 re-operations: 1 re-operation for pre-existing recurrent dislocation involving head liner exchange and 2 for repeat fixation due to metal fatigue. Two additional fractures occurred below the new plating, requiring further plating whilst still retaining the original stems. CONCLUSION: Anatomical reduction and open reduction and internal fixation of Vancouver B2 peri-prosthetic fractures should be considered as an appropriate treatment solution for frail elderly patients with a peri-prosthetic fracture around cemented polished double-tapered stems.

In Vitro Cell Surface Marker Expression on Mesenchymal Stem Cell Cultures does not Reflect Their Ex Vivo Phenotype.

Cell surface marker expression is one of the criteria for defining human mesenchymal stem or stromal cells (MSC) in vitro. However, it is unclear if expression of markers including CD73 and CD90 reflects the in vivo origin of cultured cells. We evaluated expression of 15 putative MSC markers in primary cultured cells from periosteum and cartilage to determine whether expression of these markers reflects either the differentiation state of cultured cells or the self-renewal of in vivo populations. Cultured cells had universal and consistent expression of various putative stem cell markers including > 95% expression CD73, CD90 and PDPN in both periosteal and cartilage cultures. Altering the culture surface with extracellular matrix coatings had minimal effect on cell surface marker expression. Osteogenic differentiation led to loss of CD106 and CD146 expression, however CD73 and CD90 were retained in > 90% of cells. We sorted freshly isolated periosteal populations capable of CFU-F formation on the basis of CD90 expression in combination with CD34, CD73 and CD26. All primary cultures universally expressed CD73 and CD90 and lacked CD34, irrespective of the expression of these markers ex vivo indicating phenotypic convergence in vitro. We conclude that markers including CD73 and CD90 are acquired in vitro in most 'mesenchymal' cells capable of expansion. Overall, we demonstrate that in vitro expression of many cell surface markers in plastic-adherent cultures is unrelated to their expression prior to culture.

Characterization of adult human skeletal cells in different tissues reveals a CD90+CD34+ periosteal stem/progenitor population.

The periosteum plays a crucial role in bone healing and is an important source of skeletal stem and progenitor cells. Recent studies in mice indicate that diverse populations of skeletal progenitors contribute to growth, homeostasis and healing. Information about the in vivo identity and diversity of skeletal stem and progenitor cells in different compartments of the adult human skeleton is limited. In this study, we compared non-hematopoietic populations in matched tissues from the femoral head and neck of 21 human participants using spectral flow cytometry of freshly isolated cells. High-dimensional clustering analysis indicated significant differences in marker distribution between periosteum, articular cartilage, endosteum and bone marrow populations, and identified populations that were highly enriched or unique to specific tissues. Periosteum-enriched markers included CD90 and CD34. Articular cartilage, which has very poor regenerative potential, showed enrichment of multiple markers, including the PDPN+CD73+CD164+CD146- population previously reported to represent human skeletal stem cells. We further characterized periosteal populations by combining CD90 with other strongly expressed markers. CD90+CD34+ cells sorted directly from periosteum showed significant colony-forming unit fibroblasts (CFU-F) enrichment, rapid expansion, and consistent multi-lineage differentiation of clonal populations in vitro. In situ, CD90+CD34+ cells include a perivascular population in the outer layer of the periosteum and non-perivascular cells closer to the bone surface. CD90+ cells are also highly enriched for CFU-F in bone marrow and endosteum, but not articular cartilage. In conclusion, our study indicates considerable diversity in the non-hematopoietic cell populations in different tissue compartments within the adult human skeleton, and suggests that periosteal progenitor cells reside within the CD90+CD34+ population.

Clinical and Functional Outcomes of the Exeter V40 Short Stem in Primary and Revision Arthroplasty: Does the Indication Affect Outcomes in the Short Term?

Purpose: A variety of short Exeter stems designed specifically for use in performance of total hip arthroplasty (THA) in primary and revision settings have recently been introduced. Some have been used 'off label' for hip reconstruction. The aim of this study is to report clinical and radiological results from the Exeter V40 125 mm stem in performance of primary THA and revision THA. Materials and Methods: This study had a retrospective design. Insertion of 58 (24 primary, 34 revision) Exeter V40 125 mm stems was performed between 2015 and 2017. The minimum follow-up period was two years. Assessment of the Oxford hip score (OHS), EuroQol-5 Dimension (EQ-5D), and radiological follow-up was performed at one and two years. Results: In the primary group, the preoperative, mean OHS was 13.29. The mean OHS was 32.86 and 23.39 at one-year and two-year post-surgery, respectively. The mean EQ-5D-3L scores were at 0.14, 0.59, and 0.35, preoperatively, at one-year follow-up and two-year follow-up, respectively. In the revision group, the mean preoperative OHS was 19.41. The mean OHS was 30.55 and 26.05 at one-year and two-year post-surgery, respectively. The mean EQ-5D-3L scores were 0.33, 0.61, and 0.48 preoperatively, at one-year follow-up and two-year follow-up, respectively. No progressive or new radiolucent lines were observed around any stem at the time of the final follow-up in all patients in both groups. Conclusion: Encouraging results regarding use of Exeter V40 125 mm stems have been reported up to two years following surgery in primary and revision THA settings.

Similar Survivorship but Different Revision Reasons for Uncemented Mobile-Bearing and Cemented Fixed-Bearing Medial UKA: A Long-Term Population-Based Cohort Study of 2,015 Patients.

BACKGROUND: Long-term survivorship and accurate characterization of revision reasons in unicompartmental knee arthroplasty (UKA) are limited by a lack of long-term data and standardized definitions of revision. The aim of this study was to identify survivorship, risk factors, and reasons for revision in a large cohort of medial UKAs with long-term follow-up (up to 20 years). METHODS: Patient, implant, and revision details for 2,015 primary medial UKAs (mean follow-up, 8 years) were recorded following systematic clinical and radiographic review. Survivorship and risk of revision were analyzed using Cox proportional hazards. Reasons for revision were analyzed using competing-risk analysis. RESULTS: Implant survivorship at 15 years was 92% for cemented fixed-bearing (cemFB), 91% for uncemented mobile-bearing (uncemMB), and 80% for cemented mobile-bearing (cemMB) UKAs (p = 0.02). When compared with cemFB, the risk of revision was higher for cemMB implants (hazard ratio [HR] = 1.9, 95% confidence interval [CI] = 1.1 to 3.2; p = 0.03). At 15 years, cemented implants had a higher cumulative frequency of revision due to aseptic loosening (3% to 4%, versus 0.4% for uncemented; p < 0.01), cemMB implants had a higher cumulative frequency of revision due to osteoarthritis progression (9% versus 2% to 3% for cemFB/uncemMB; p < 0.05), and uncemMB implants had a higher cumulative frequency of revision due to bearing dislocation (4% versus 2% for cemMB; p = 0.02). Compared with the oldest patients (≥70 years), younger patients had a higher risk of revision (<60 years: HR = 1.9, 95% CI = 1.2 to 3.0; 60 to 69 years: HR = 1.6, 95% CI = 1.0 to 2.4; p < 0.05 for both). At 15 years, there was a higher cumulative frequency of revision for aseptic loosening in these younger groups (3.2% and 3.5% versus 2.7% for ≥70 years; p < 0.05). CONCLUSIONS: Implant design and patient age were risk factors for revision of medial UKA. The findings from this study suggest that surgeons should consider using cemFB or uncemMB designs because of their superior long-term implant survivorship compared with cemMB designs. Additionally, for younger patients (<70 years), uncemMB designs had a lower risk of aseptic loosening than cemFB designs at the expense of a risk of bearing dislocation. LEVEL OF EVIDENCE: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

REST, RCOR1 and RCOR2 expression is reduced in osteoarthritic chondrocytes and contributes to increasing MMP13 and ADAMTS5 expression through upregulating HES1.

Expression of key transcriptional regulators is altered in chondrocytes in osteoarthritis (OA). This contributes to an increase in production of cartilage-catabolizing enzymes such as MMP13 and ADAMTS5. RCOR1 and RCOR2, binding partners for the transcriptional repressor REST, have previously been found to be downregulated in OA chondrocytes although their function in chondrocytes is unclear. HES1 is a known REST/RCOR1 target gene and HES1 has been shown to promote MMP13 and ADAMTS5 expression in murine OA chondrocytes. The purpose of this study was to determine whether reduced REST/RCOR levels leads to increased HES1 expression in human OA chondrocytes and whether HES1 also promotes ADAMTS5 and MMP13 expression in these cells. Chondrocytes were isolated from osteoarthritic and adjacent macroscopically normal cartilage obtained from patients undergoing total knee arthroplasty. RNA and protein levels of REST, RCOR1 and RCOR2 were lower, but levels of HES1 higher, in chondrocytes isolated from osteoarthritic compared to macroscopically normal cartilage. Over-expression of either REST, RCOR1 or RCOR2 resulted in reduced HES1 levels in OA chondrocytes whereas knockdown of REST, RCOR1 or RCOR2 led to increased HES1 expression in chondrocytes from macroscopically normal cartilage. In OA chondrocytes, ADAMTS5 and MMP13 expression were reduced following HES1 knockdown, but further enhanced following HES1 over-expression. Levels of phosphorylated CaMKII were higher in chondrocytes from OA cartilage consistent with previous findings that HES1 only promotes gene transcription in the presence of active CaMKII. These findings identify the REST/RCOR/HES1 pathway as a contributing factor leading to increased ADAMTS5 and MMP13 expression in OA chondrocytes.

Rat model of recalcitrant prosthetic joint infection using biofilm inocula.

Prosthetic joint infection (PJI) is a rare but devastating complication of joint arthroplasty. Biofilm formation around the prosthesis confers tolerance to antibiotics so that treatment is challenging. Most animal models of PJI use planktonic bacteria to establish the infection which fails to reproduce the pathology of chronic infection. We aimed to establish a rat model of Staphylococcus aureus PJI in male Sprague-Dawley rats using biofilm inocula and demonstrate its tolerance to frontline antibiotics. Pilot studies indicated that infection could be introduced to the knee joint by a biofilm-coated pin but that handling the prosthetic without disturbing the biofilm was difficult. We, therefore, developed a pin with a slotted end and used a miniature-biofilm reactor to develop mature biofilm in this niche. These biofilm-laden pins consistently produced infection of the bone and joint space. Treatment with high dose cefazolin, 250 mg/kg, starting the day of surgery reduced or cleared pin-adherent bioburden within 7 days, however when escalation from 25 to 250 mg/kg cefazolin treatment was delayed for 48 h, rats were unable to clear the infection. To track infections, we used bioluminescent bacteria, however, the bioluminescent signal did not accurately track the degree of infection in the bone and joint space as the signal did not penetrate the bone. In conclusion, we demonstrate that using a custom prosthetic pin, we can generate biofilm in a specific niche using a novel bioreactor setup and initiate a rat PJI that rapidly develops tolerance to supra-clinical doses of cefazolin.