Genicular Artery embolisation in Patients with Osteoarthritis of the Knee (GENESIS) Using Permanent Microspheres: Long-Term Results.

PURPOSE: To report the 2-year follow-up of patients with mild-to-moderate knee osteoarthritis (OA) treated with genicular artery embolisation (GAE) as part of the GENESIS study. MATERIALS AND METHODS: Forty-six patients, median age = 60 (45-83) underwent GAE using permanent microspheres (100-300 µm). Technical success was defined as embolisation of the targeted genicular arteries. Knee Injury and Osteoarthritis Outcome Score (KOOS) and Visual Analogue Scale (VAS) (0-100 mm) were recorded at baseline, 6 weeks, 3 months, 1, 2 years. Contrast-enhanced MRI knee scans were acquired at baseline and 1 year, and evaluated with the Whole-Organ Magnetic Resonance Imaging Score (WORMS). Functional MRI brain imaging and psychometric assessments were undertaken to investigate correlation between neuropsychological phenotypes and clinical outcome. Adverse events were recorded prospectively. RESULTS: Technical success was achieved in forty patients (87%). Mean VAS improved from 58.63 (SD = 20.57, 95% CI 52.7-65.5) at baselines to 37.7 at 2-years (SD = 26.3, 95% CI 27.0-47.5). Whole and subgroup KOOS were significantly improved at each timepoint with associated reductions in analgesia usage. WORMS analysis demonstrated significant reduction in synovitis (p < 0.05) with no cases of osteonecrosis. Self-limiting skin discolouration occurred in four patients. A self-limiting groin haematoma and single case of deep-vein thrombosis due to immobilisation were also recorded. Nine patients subsequently underwent knee arthroplasty with no additional operational complexities identified. Neuropsychometric assessment elucidated a correlation between baseline catastrophising and greater reduction in pain post GAE. CONCLUSION: GAE is a safe intervention for mild-moderate knee osteoarthritis, with sustained efficacy at 2 years. These results are promising and justify ongoing controlled trials.

Genicular artEry embolizatioN in patiEnts with oSteoarthrItiS of the Knee (GENESIS) Using Permanent Microspheres: Interim Analysis.

PURPOSE: Planned interim analysis of GENESIS; a prospective pilot study investigating the role of genicular artery embolization (GAE) in patients with mild to moderate osteoarthritis of the knee using permanent microspheres. METHODS: Thirty-eight patients, median age = 60 (45-83), attended for GAE using 100-300 µm permanent microspheres. All patients had mild to moderate knee OA, resistant to conservative treatments over 6 months. Knee MRI was performed at baseline, and 12 months, enabling semi-quantitative analysis using Whole-Organ Magnetic Resonance Imaging Score (WORMS). Knee Injury and Osteoarthritis Outcome Score (KOOS) and visual analogue scale (VAS) (0-100 mm) were completed at baseline, 6 weeks, 3 months (n = 32), and 1-year (n = 16). Adverse events were recorded prospectively. RESULTS: Technical success of accessing and embolizing the target genicular arteries was 84%. Six patients were not embolized: four due to a presumed risk of non-target embolization, and two due to a lack of hyperaemic target. Mean VAS improved from 60 (SD = 20, 95% CI 53-66) at baseline to 36 (SD = 24, 95% CI 28-44) at 3 months (p < 0.001) and 45 (SD = 30, 95% CI 30-60) at 1-year (p < 0.05). All KOOS subscales showed a significant improvement at 6-weeks, 3-months, and 1-year follow-up, except function in daily living, which reached borderline significance (p = 0.06) at 1-year. Four patients experienced mild self-limiting skin discoloration over the embolized territory. One patient experienced a small self-limiting groin haematoma. WORMS scores at 1-year follow-up showed significant improvement in synovitis (p < 0.05). There were no cases of osteonecrosis. CONCLUSION: GAE using permanent microspheres in patients with mild to moderate knee OA is safe, with potential efficacy at early follow-up.

The impact of patient and surgical factors on the rate of infection after primary total knee arthroplasty: an analysis of 64,566 joints from the New Zealand Joint Registry.

AIMS: The aim of this study was to identify risk factors for prosthetic joint infection (PJI) following total knee arthroplasty (TKA). PATIENTS AND METHODS: The New Zealand Joint Registry database was analysed, using revision surgery for PJI at six and 12 months after surgery as primary outcome measures. Statistical associations between revision for infection, with common and definable surgical and patient factors were tested. RESULTS: A total of 64 566 primary TKAs have been recorded on the registry between 1999 and 2012 with minimum follow-up of 12 months. Multivariate analysis showed statistically significant associations with revision for PJI between male gender (odds ratio (OR) 1.85, 95% confidence interval (CI) 1.24 to 2.74), previous surgery (osteotomy (OR 2.45 95% CI 1.2 to 5.03), ligament reconstruction (OR 1.85, 95% CI 0.68 to 5.00)), the use of laminar flow (OR 1.6, 95% CI 1.04 to 2.47) and the use of antibiotic-laden cement (OR 1.93, 95% CI 1.19 to 3.13). There was a trend towards significance (p = 0.052) with the use of surgical helmet systems at six months (OR 1.53, 95% CI 1.00 to 2.34). CONCLUSION: These findings show that patient factors remain the most important in terms of predicting early PJI following TKA. Furthermore, we found no evidence that modern surgical helmet systems reduce the risk of PJI and laminar flow systems may actually increase risk in TKA. The use of this registry data assists the estimation of the risk of PJI for individual patients, which is important for both informed consent and the interpretation of infection rates at different institutions. TAKE HOME MESSAGE: Infection rates in TKA are related to both individual patient and surgical factors, and some modern methods of reducing infection may actually increase infection risk.

A comparison of polymer and polymer-hydroxyapatite composite tissue engineered scaffolds for use in bone regeneration. An in vitro and in vivo study.

Previous in vitro work demonstrated porous PLA and PLGA both had the mechanical strength and sustained the excellent skeletal stem cell (SSC) growth required of an osteogenic bonegraft substitute, for use in impaction bone grafting. The purpose of this investigation was to assess the effects of the addition of hydroxyapatite (HA) to the scaffolds before clinical translation. PLA, PLA+10% HA, PLGA, and PLGA+10% HA were milled and impacted into discs before undergoing a standardized shear test. Cellular compatibility analysis followed 14 days incubation with human skeletal stems cells (SSC). The best two performing polymers were taken forward for in vivo analysis. SSC seeded polymer discs were implanted subcutaneously in mice. All polymers had superior mechanical shear strength compared with allograft (p < 0.01). Excellent SSC survival was demonstrated on all polymers, but the PLA polymers showed enhanced osteoblastic activity (ALP assay p < 0.01) and collagen-1 formation. In vivo analysis was performed on PLA and PLA+10% HA. MicroCT analysis revealed increased bone formation on the PLA HA (p < 0.01), and excellent neo-vessel formation in both samples. Histology confirmed evidence of de novo bone formation. PLA HA showed both enhanced osteoinductive and osteogenic capacity. This polymer composite has been selected for scaled-up experimentation before clinical translation.

From bench to clinic and back: skeletal stem cells and impaction bone grafting for regeneration of bone defects.

Tissue engineering offers enormous potential for bone regeneration. Despite extensive in vitro and in vivo work, few strategies translate into clinical practice. This paper describes the combination of skeletal stem cells (SSCs) and impaction bone grafting (IBG) for the treatment of patients with bone defects associated with avascular necrosis of the femoral head. SSCs and milled allograft were impacted into necrotic bone in the femoral heads of four patients. Three patients remained asymptomatic at 22-44 month follow-up, but one patient has required total hip replacement (both hips). This has allowed retrieval of the femoral heads, which were analysed structurally and functionally by µCT, histology and mechanical testing. A central channel of impacted bone was found in the femoral heads, which displayed a mature trabecular micro-architecture. The impacted bone was denser than the surrounding trabecular bone, as strong in compression and with histological micro-architecture comparable to that of trabecular bone. Analysis of the retrieved femoral head samples has demonstrated that this tissue-engineering strategy regenerates bone that is both structurally and functionally analogous to normal trabecular bone. SSCs, together with IBG, have proved an effective treatment for avascular necrosis of the femoral head and offer significant potential for the broader spectrum of bone defects.

Tantalum trabecular metal - addition of human skeletal cells to enhance bone implant interface strength and clinical application.

The osteo-regenerative properties of allograft have recently been enhanced by addition of autogenous human bone marrow stromal cells (HBMSCs). Limitations in the use of allograft have prompted the investigation of tantalum trabecular metal (TTM) as a potential alternative. TTM is already in widespread orthopaedic use, although in applications where there is poor initial stability, or when TTM is used in conjunction with bone grafting, initial implant loading may need to be limited. The aim of this study was to evaluate the osteo-regenerative potential of TTM with HBMSCs, in direct comparison to human allograft and autograft. HBMSCs were cultured on blocks of TTM, allograft or autograft in basal and osteogenic media. Molecular profiling, confocal and scanning electron microscopy (SEM) and biochemical assays were used to characterize cell adherence, proliferation and phenotype. Mechanical testing was used to define the tensile characteristics of the constructs. HBMSCs displayed adherence and proliferation throughout TTM, evidenced by immunocytochemistry and SEM, with significant cellular ingrowth and matrix production through TTM. In contrast to cells cultured with allograft, cell proliferation assays showed significantly higher activity with TTM (p < 0.001), although molecular profiling confirmed no significant difference in expression of osteogenic genes. In contrast to acellular constructs, mechanical testing of cell-TTM constructs showed enhanced tensile characteristics, which compared favourably to cell-allograft constructs. These studies demonstrated the ability of TTM to support HBMSC growth and osteogenic differentiation comparable to allograft. Thus, TTM represents an alternative to allograft for osteo-regenerative strategies, extending its clinical applications as a substitute for allograft.

A tissue engineering strategy for the treatment of avascular necrosis of the femoral head.

BACKGROUND & PURPOSE: Skeletal stem cells (SSCs) and impaction bone grafting (IBG) can be combined to produce a mechanically stable living bone composite. This novel strategy has been translated to the treatment of avascular necrosis of the femoral head. Surgical technique, clinical follow-up and retrieval analysis data of this translational case series is presented. METHODS: SSCs and milled allograft were impacted into necrotic bone in five femoral heads of four patients. Cell viability was confirmed by parallel in vitro culture of the cell-graft constructs. Patient follow-up was by serial clinical and radiological examination. Tissue engineered bone was retrieved from two retrieved femoral heads and was analysed by histology, microcomputed tomography (µCT) and mechanical testing. RESULTS: Three patients remain asymptomatic at 22- to 44-month follow-up. One patient (both hips) required total hip replacement due to widespread residual necrosis. Retrieved tissue engineered bone demonstrated a mature trabecular micro-architecture histologically and on µCT. Bone density and axial compression strength were comparable to trabecular bone. CONCLUSIONS: Clinical follow-up shows this to be an effective new treatment for focal early stage avascular necrosis of the femoral head. Unique retrieval analysis of clinically translated tissue engineered bone has demonstrated regeneration of tissue that is both structurally and functionally analogous to normal trabecular bone.

Translational hurdles for tissue engineering: an in vitro analysis of commonly used local anaesthetics on skeletal stem cell survival.

When transferring tissue regenerative strategies involving skeletal stem cells to human application, consideration needs to be given to factors that may affect the function of the cells that are transferred. Local anaesthetics are frequently used during surgical procedures, either administered directly into the operative site or infiltrated subcutaneously around the wound. The aim of this study was to investigate the effects of commonly used local anaesthetics on the morphology, function and survival of human adult skeletal stem cells. Cells from three patients who were undergoing elective hip replacement were harvested and incubated for two hours with 1% lidocaine, 0.5% levobupivacaine or 0.5% bupivacaine hydrochloride solutions. Viability was quantified using WST-1 and DNA assays. Viability and morphology were further characterised using CellTracker Green/Ethidium Homodimer-1 immunocytochemistry and function was assessed by an alkaline phosphatase assay. An additional group was cultured for a further seven days to allow potential recovery of the cells after removal of the local anaesthetic. A statistically significant and dose dependent reduction in cell viability and number was observed in the cell cultures exposed to all three local anaesthetics at concentrations of 25% and 50%, and this was maintained even following culture for a further seven days. This study indicates that certain local anaesthetic agents in widespread clinical use are deleterious to skeletal progenitor cells when studied in vitro; this might have relevance in clinical applications.

Mapping the strain distribution on the proximal femur with titanium and flexible-stemmed implants using digital image correlation.

We implanted titanium and carbon fibre-reinforced plastic (CFRP) femoral prostheses of the same dimensions into five prosthetic femora. An abductor jig was attached and a 1 kN load applied. This was repeated with five control femora. Digital image correlation was used to give a detailed two-dimensional strain map of the medial cortex of the proximal femur. Both implants caused stress shielding around the calcar. Distally, the titanium implant showed stress shielding, whereas the CFRP prosthesis did not produce a strain pattern which was statistically different from the controls. There was a reduction in strain beyond the tip of both the implants. This investigation indicates that use of the CFRP stem should avoid stress shielding in total hip replacement.

Femoral anteversion: a necessary angle or an evolutionary vestige?

In an adult man the mean femoral anteversion angle measures approximately 15 degrees, for which the reasons have never been fully elucidated. An assortment of simian and quadruped mammalian femora was therefore examined and the anteversion angles measured. A simple static mathematical model was then produced to explain the forces acting on the neck of the femur in the quadruped and in man. Femoral anteversion was present in all the simian and quadruped femora and ranged between 4 degrees and 41 degrees. It thus appears that man has retained this feature despite evolving from quadrupedal locomotion. Quadrupeds generally mobilise with their hips flexed forwards from the vertical; in this position, it is clear that anteversion gives biomechanical advantage against predominantly vertical forces. In man with mobilisation on vertical femora, the biomechanical advantage of anteversion is against forces acting mainly in the horizontal plane. This has implications in regard to the orientation of hip replacements.