Summary Statement. The chemistry, amount, morphology, and size distribution of wear debris from silicon nitride coatings generated in the bearing surface can potentially reduce the negative biological response and increase the longevity compared to conventional materials in joint replacements. Introduction. Total hip implants have a high success rate at 15 years of implantation, but few survive over 25 years. At present, revisions are mostly due to aseptic loosening, believed to mainly be caused by the biological response to wear debris generated in the joint bearing. For the polymer liners the size of the wear debris determines the biological response, while for metal bearing surfaces a limitation is the metal ion release. When ceramics are used, the wear debris is in general small and mechanical factors may be the main cause for failure. A more recent, experimental alternative is to let the well-known metallic substrate serve as the soft, tough bulk, and additionally apply a hard and smooth ceramic coating. In this way a lower wear rate and reduced metal ion release could be obtained. Furthermore, the chosen composition, silicon nitride (SixNy), contains no detrimental ions, and silicon nitride debris has been shown to slowly dissolve in aqueous medium. Altogether, it can potentially increase the longevity of the implant. However, the debris from SixNy coatings has not yet been characterised. In this study, a wear model test was performed to generate wear debris from SixNy coatings. The debris was characterised using scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS) in combination with computational calculations. Methods. Silicon nitride coatings deposited on flat cobalt chromium alloy (ASTM F75) were worn in a reciprocating ball on disc setup in a 25% serum solution at 37°C against an alumina ball with a load of 1.5 N. Wear debris was separated using serum digestion with hydrochloric acid (ISO 17853:2011) and examined in SEM in combination with EDS. As reference polyethylene (PE) was used to verify that relevant particles sizes were achieved. The SEM images were processed using a modified MATLAB-script originating from Cervera Gontard et al. [1], identifying the particles and calculating their size. Results. Particles generated from SixNy coatings (n=62) a size distribution D50 [D10-D90] of 0.29 µm [0.16–0.69] and were round to oval in shape. The PE particles (n=70) had a size distribution of 0.29 µm [0.13–1.3], shaped similar to the SixNy particles or with a more elongated shape. Discussion and conclusions. PE wear debris has been reported to lie in the size range of nm up to several μm in vivo, with a large proportion within the critical size for macrophage activation (0.2 to 0.8 μm). The model test reports relevant sizes and shape of PE debris, confirming the validity of the method. Particles generated from the SixNy coatings showed a smaller size range than PE, however most particles were within the critical size range for biological activation. In conclusion, this model test could be used to generate what we believe are relevant sizes and shapes of PE and SixNy wear debris and to learn more at an early stage of prediction of wear debris. Further dissolution studies as well as studies on the in vitro and in vivo cell response to these types of particles will be performed. The authors thank the Swedish Foundation for Strategic Research (SSF) through MS2E and FP7 NMP project LifeLongJoints for financial support, as well as Linköping University for the coating facilities and expertise

Background. Resveratrol is a polyphenolic compound commonly found in the skins of red grapes. Sirtuin 1 (SIRT1) is a human gene that is activated by resveratrol and has been shown to promote longevity and boost mitochondrial metabolism. We examined the effect of resveratrol on normal and osteoarthritic (OA) human chondrocytes. Methods. Normal and OA chondrocytes were incubated with various concentrations of resveratrol (1 µM, 10 µM, 25 µM and 50 µM) and cultured for 24, 48 or 72 hours or for six weeks. Cell proliferation, gene expression, and senescence were evaluated. Results. SIRT1 was significantly upregulated in normal chondrocytes with resveratrol concentrations of 25 µM and 50 µM on both two- (2D) (both p = 0.001) and three-dimensional (3D) cultures (p = 0.008 and 0.001, respectively). It was significantly upregulated in OA chondrocytes treated with 10 µM, 25 µM and 50 µM resveratrol on 2D cultures (p = 0.036, 0.002 and 0.001, respectively) and at 50 µM concentration on 3D cultures (p = 0.001). At 72 hours, the expression of collagen (COL)-10, aggrecan (AGG), and runt-related transcription factor 2 (RUNX2) was significantly greater in both 25 µM (p = 0.011, 0.006 and 0.015, respectively) and 50 µM (p = 0.019, 0.004 and 0.002, respectively) resveratrol-treated normal chondrocyte cultures. In OA chondrocytes, expression of COL10 and RUNX2 was significantly greater in 25 µM (p = 0.004 and 0.024) and 50 µM (p = 0.004 and 0.019) cultures at 72 hours on 3D cultures. Conclusions. At concentrations of 25 µM and/or 50 µM, resveratrol treatment significantly upregulates SIRT1 gene expression in normal and osteoarthritic chondrocytes. Resveratrol induces chondrocytes into a hypertrophic state through upregulation of COL1, COL10, and RUNX2. Cite this article: Bone Joint Res 2014;3:51–9

Total joint replacement (TJR) was one of the most revolutionary breakthroughs in joint surgery. The majority studies had shown that most implants could last about 25 years, anyway, there is still variation in the longevity of implants. In US, for all the hip revisions from 2012 to 2017 in the United States, 12.0% of the patients were diagnosed as aseptic loosening. Variable studies have showed that any factor that could cause a systemic or partial bone loss, might be the risk of periprosthetic osteolysis and aseptic loosening. Breast cancer is the most frequent malignancy in women, more than 2.1 million women were newly diagnosed with breast cancer, 626,679 women with breast cancer died in 2018. It's been reported that the mean incidence of THA was 0.29% for medicare population with breast cancer in USA, of which the incidence was 3.46% in Norwegian. However, the effects of breast cancer chemotherapy and hormonotherapy, such as aromatase inhibitors (AI), significantly increased the risk of osteoporosis, and had been proved to become a great threat to hip implants survival. In this case, a 46-year-old female undertook chemotherapy and hormonotherapy of breast cancer 3 years after her primary THA, was diagnosed with aseptic loosening of the hip prosthesis. Her treatment was summarized and analyzed. Breast cancer chemotherapy and hormonotherapy might be a threat to the stability of THA prosthesis. More attention should be paid when a THA paitent occurred with breast cancer. More studies about the effect of breast cancer treatments on skeleton are required

A number of techniques have been developed to improve the immediate mechanical anchorage of implants for enhancing implant longevity. This issue becomes even more relevant in patients with osteoporosis who have fragile bone. We have previously shown that a dynamic hip screw (DHS) can be augmented with a calcium sulphate/hydroxyapatite (CaS/HA) based injectable biomaterial to increase the immediate mechanical anchorage of the DHS system to saw bones with a 400% increase in peak extraction force compared to un-augmented DHS. The results were also at par with bone cement (PMMA). The aim of this study was to investigate the effect of CaS/HA augmentation on the integration of a different fracture fixation device (gamma nail lag-screw) with osteoporotic saw bones. Osteoporotic saw bones (bone volume fraction = 15%) were instrumented with a gamma nail without augmentation (n=8) or augmented (n=8) with a CaS/HA biomaterial (Cerament BVF, Bonesupport AB, Sweden) using a newly developed augmentation method described earlier. The lag-screws from both groups were then pulled out at a displacement rate of 0.5 mm/s until failure. Peak extraction force was recorded for each specimen along with photographs of the screws post-extraction. A non-parametric t-test was used to compare the two groups. CaS/HA augmentation of the lag-screw led to a 650% increase in the peak extraction force compared with the controls (p<0.01). Photographs of the augmented samples shows failure of the saw-bones further away from the implant-bone interface indicating a protective effect of the CaS/HA material. We present a novel method to enhance the immediate mechanical anchorage of a lag-screw to osteoporotic bone and it is also envisaged that CaS/HA augmentation combined with systemic bisphosphonate treatment can lead to new bone formation and aid in the reduction of implant failures and re-operations

Variations in component positioning of total hip replacements can lead to edge loading of the liner, and potentially affect device longevity. These effects are evaluated using ISO 14242:4 edge loading test results in a dynamic system. Mediolateral translation of one of the components during testing is caused by a compressed spring, and therefore the kinematics will depend on the spring stiffness and damping coefficient, and the mass of the translating component and fixture. This study aims to describe the sensitivity of the liner plastic strain to these variables, to better understand how tests using different simulator designs might produce different amounts of liner rim deformation. A dynamic explicit deformable finite element model with 36mm Pinnacle metal-on-polyethylene bearing geometry (DePuy Synthes, Leeds, UK) was used with material properties for conventional UHMWPE. Setup was 65° clinical inclination, 4mm mismatch, 70N swing phase load, and 100N/mm spring. Fixture mass was varied from 0.5-5kg, spring damping coefficient was varied from 0-2Ns/mm. They were changed independently, and in combination. Maximum separation values were relatively insensitive to changes in the mass, damping coefficient, or both. The sensitivity of peak plastic strain, to this range of inputs, was similar to changing the swing phase load from 70N to approximately 150N – 200N. Increasing the fixture mass and/or damping coefficient increased the peak plastic strain, with values from 0.15-0.19. Liner plastic deformation was sensitive to the spring damping and fixture mass, which may explain some of the differences in fatigue and deformation results in UHMWPE liners tested on different machines or with modified fixtures. These values should be described when reporting the results of ISO14242:4 testing. Acknowledgements. Funded by EPSRC grant EP/N02480X/1; CAD supplied by DePuy Synthes

The implantation of endoprosthesis is a routine procedure in orthopaedics. Endoprosthesis are mainly manufactured from ceramics, polymers, metals or metal alloys. To ensure longevity of the implants they should be as biocompatible as possible and ideally have antibacterial properties, to avoid periprosthetic joint infections (PJI). Various antibacterial implant materials have been proposed, but have so far only been used sporadically in patients. PJI is one of the main risk factors for revision surgeries. The aim of the study was to identify novel implant coatings that both exhibit antibacterial properties whilst having optimal biocompatibility. Six different novel implant coatings and surface modifications (EBM TiAl6V4, strontium, TiCuN, TiNbN, gentamicin phosphate (GP), gentamicin phosphate+cationic polymer (GP+CP)) were compared to standard CoCrMo-alloy. The coatings were further characterized with regard to the surface roughness. E. coli and S. capitis were cultured on the modified surfaces to investigate the antibacterial properties. To quantify bacterial proliferation the optical density (OD) was measured and viability was determined using colony forming units (CFU). Murine bone marrow derived macrophages (BMMs) were cultured on the surfaces and differentiated into osteoblasts to quantify the mineralisation using the alizarin red assay. All novel coatings showed reduced bacterial proliferation and viability compared to standard CoCrMo-alloy. A significant reduction was observed for GP and GP+CP coated samples compared to CoCrMo (OD. GP,E.coli. = 0.18±0.4; OD. GP+CP,E.coli. = 0.13±0.3; p≤0.0002; N≥7-8). An increase in osteoblast-mediated mineralisation was observed on all surfaces tested compared to CoCrMo. Furthermore, GP and GP+CP coated samples showed a statistically significant increase (M. GP. = 0.21±0.1; M. GP+CP. = 0.25±0.2; p<0.0001; N≥3-6). The preliminary data indicates that the gentamicin containing surfaces have the most effective antibacterial property and the highest osseointegrative capacity. The use of antibiotic coatings on prostheses could reduce the risk of PJI while being applied on osseointegrative implant surfaces

Abstract. Objective. Short-stem total hip arthroplasty (THA) aims to preserve the proximal bone stock for future revisions, so that the first revision should resemble a primary intervention rather than a revision. This study aimed to compare the clinical and radiological outcomes in revision THA after failed short stem versus after failed conventional stem THA. Methods. This study included forty-five patients with revision THA divided into three groups (15 each); group A: revision after short stem, group B: revision after conventional cementless stem and group C revision after conventional cemented stem. The studied groups were compared regarding 31 variables including demographic data, details of the primary and revision procedures, postoperative radiological subsidence, hospital stay, time for full weight bearing (FWB), preoperative and postoperative clinical scores. Results. Early stem subsidence (40%) was the main indication of revision in group A compared to peri-prosthetic femoral fractures (PFFs) (73.3%) and aseptic loosening (53.3%) in group B and C respectively (P=0.021). The mean time to revision was significantly shorter in group A (15 months) compared to 95.33 and 189.40 months in group B and C respectively. (P=0.005). Sixty % (9 patients) in group A were revised in the first year. The mean operative time, blood loss, postoperative blood transfusion and hospital stay were significantly lower in group A compared to group B and C (P<0.001, <0.001, 0.002 and 0.001 respectively). Revisions in group A were performed using either short stems (13.3%) or conventional stems (86.7%) whilst 80% of patients needed long stems and 20% of patients needed conventional stems in group B and C (P<0.001). The mean postoperative Harris Hip Score (HHS) at the latest follow up was 87.07, 87.53 and 85.47 in group A, B and C respectively. All PFFS had excellent results according to Beal's and Tower's criteria; all fractures healed and the implants were stable. Conclusion. The most common cause of failure of short stems is early stem subsidence. Short stem THA has specific indications and patient selection is very crucial. Preoperative templating for short stems and a detailed analysis of the individual patient anatomy in anteroposterior and lateral views are mandatory to predict the correct implant size more accurately. The use of intraoperative imaging can verify the sizing, implant position, and sufficient contact with the lateral cortex. Revision of short stem THA resembled the primary THA. If a standard implant can be used in a surgical revision instead of a longer revision stem, this can be considered as an advantage for the hip arthroplasty treatment concept. However, this only applies if the longevity of the first treatment with a short stem is comparable with that of a standard stem. Declaration of Interest. (b) declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported:I declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project

Introduction and Objective. In recent years, along with the extending longevity of patients and the increase in their functional demands, the number of annually performed RSA and the incidence of complications are also increasing. When a complication occurs, the patient often needs multiple surgeries to restore the function of the upper limb. Revision implants are directly responsible for the critical reduction of the bone stock, especially in the shoulder. The purpose of this paper is to report the use of allograft bone to restore the bone stock of the glenoid in the treatment of an aseptic glenoid component loosening after a reverse shoulder arthroplasty (RSA). Materials and Methods. An 86-years-old man came to our attention for aseptic glenoid component loosening after RSA. Plain radiographs showed a complete dislocation of the glenoid component with 2 broken screws in the neck of glenoid. CT scans confirmed the severe reduction of the glenoid bone stock and critical bone resorption and were used for the preoperative planning. To our opinion, given the critical bone defect, the only viable option was revision surgery with restoration of bone stock. We planned to use a bone graft harvested from distal bone bank femur as component augmentation. During the revision procedure the baseplate with a long central peg was implanted “on table” on the allograft and an appropriate osteotomy was made to customize the allograft on the glenoid defect according to the CT-based preoperative planning. The Bio-component was implanted with stable screws fixation on residual scapula. We decided not to replace the humeral component since it was stable and showed no signs of mobilization. Results. The new bio-implant was stable, and the patient gained a complete functional recovery of the shoulder. The scheduled radiological assessments up to 12 months showed no signs of bone resorption or mobilization of the glenoid component. Conclusions. The use of bone allograft in revision surgery after a RSA is a versatile and effective technique to treat severe glenoid bone loss and to improve the global stability of the implant. Furthermore, it represents a viable alternative to autologous graft since it requires shorter operative times and reduces graft site complications. There are very few data available regarding the use of allografts and, although the first studies are encouraging, further investigation is needed to determine the biological capabilities of the transplant and its validity in complex revisions after RSA

Abstract. Background. Optimal acetabular component position in Total Hip Arthroplasty is vital for avoiding complications such as dislocation, impingement, abductor muscle strength and range of motion. Transverse acetabular ligament (TAL) and posterior labrum have been shown to be a reliable landmark to guide optimum acetabular cup position. There have been reports of iliopsoas impingement caused by both cemented and uncemented acetabular components. Acetabular component mal-positioning and oversizing of acetabular component are associated with iliopsoas impingement. The Psoas fossa (PF) is not a well-regarded landmark to help with Acetabular Component positioning. Our aim was to assess the relationship of the TAL and PF in relation to Acetabular Component positioning. Methods. A total of 12 cadavers were implanted with the an uncemented acetabular component, their position was initially aligned to TAL. Following optimal seating of the acetabular component the distance of the rim of the shell from the PF was noted. The Acetabular component was then repositioned inside the PF to prevent exposure of the rim of the Acetabular component. This study was performed at Smith & Nephew wet lab in Watford. Results. Out of the twelve acetabular components that were implanted parallel to the TAL, all had the acetabular rim very close or outside to the psoas notch with a potential to cause iliopsoas impingement. Alteration of the acetabular component position was necessary in all cadavers to inside the PF to prevent iliopsoas impingement. It was evident that the edge of PF was not aligned with TAL. Conclusion. Optimal acetabular component position is vital to the longevity and outcome following THA. TAL provides a landmark to guide acetabular component position. We feel the PF is a better landmark to allow appropriate positioning of the acetabular component inside bone without exposure of the component rim and thus preventing iliopsoas impingement at the psoas notch. Declaration of Interest. (b) declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported:I declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project

Abstract. Objectives. Accurate orientation of the acetabular component during a total hip replacement is critical for optimising patient function, increasing the longevity of components, and reducing the risk of complications. This study aimed to determine the validity of a novel VR platform (AescularVR) in assessing acetabular component orientation in a simulated model used in surgical training. Methods. The AescularVR platform was developed using the HTC Vive® VR system hardware, including wireless trackers attached to the surgical instruments and pelvic sawbone. Following calibration, data on the relative position of both trackers are used to determine the acetabular cup orientation (version and inclination). The acetabular cup was manually implanted across a range of orientations representative of those expected intra-operatively. Simultaneous readings from the Vicon® optical motion capture system were used as the ‘gold standard’ for comparison. Correlation and agreement between these two methods was determined using Bland-Altman plots, Pearson's correlation co-efficient, and linear regression modelling. Results. A total of 55 separate orientation readings were obtained. The mean average difference in acetabular cup version and inclination between the Vicon and VR systems was 3.4° (95% CI: −3–9.9°), and −0.005° (95% CI: −4.5–4.5°) respectively. Strong positive correlations were demonstrated between the Vicon and VR systems in both acetabular cup version (Pearson's R = 0.92, 99% CI: 0.84–0.96, p<0.001), and inclination (Pearson's R = 0.94, 99% CI: 0.88–0.97, p<0.001). Using linear regression modelling, the adjusted R. 2. for acetabular version was 0.84, and 0.88 for acetabular inclination. Conclusion. The results of this study indicate that the AescularVR platform is highly accurate and reliable in determining acetabular component orientation in a simulated environment. The AescularVR platform is an adaptable tracking system, which may be modified for use in a range of simulated surgical training and educational purposes, particularly in orthopaedic surgery. Declaration of Interest. (b) declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported:I declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project

Abstract. Objective. Clinical treatments to repair articular cartilage (AC) defects such as autologous cartilage implantation (mosaicplasty) often suffer from poor integration with host tissue, limiting their long-term efficacy. Thus to ensure the longevity of AC repair, understanding natural repair mechanisms that allow for successful integration between cartilaginous surfaces, as has been reported in juvenile tissue, may be key. Here, we evaluated cartilage integration over time in a pig explant model of natural tissue repair by assessing expression and localisation of major ECM proteins, enzymatic cross-linkers including the five isoforms of lysyl oxidase (LOX), small leucine-rich repeat proteoglycans (SLRP's), and proteases (e.g. ADAMTS4). Methods. AC was retrieved from the femoral condyles of 8-week-old pigs. Full thickness 6mmØ AC discs were prepared, defects were induced, and explants cultured for up to 28 days. After fixation, sections were stained using Safranin-O and antibodies against Collagen types I & II, LOX, and ADAMTS4. Gene expression analyses were performed using qPCR. We also cultured devitalized samples, either with or without enzymatic treatment to deplete proteoglycans, for 28 days and similarly assessed repair. Results. Safranin-O staining demonstrated successful integration of cartilage defects over a 28-day period. No significant regulation in the expression of Col1a1, Col2a1, LOX or SLPR genes was observed at any time point. Immunofluorescence staining revealed that only ADAMTS4 localized at the injury surface in integrated samples. Interestingly, we also observed successful spontaneous integration of proteoglycan-depleted devitalized tissue. Conclusion. Cartilage integration in our pig cartilage explant model did not appear to be mediated by upregulation of major cartilage ECM components, enzymatic cross-linkers, or SLRPs. However, spontaneous integration of devitalized, proteoglycan-depleted AC, and localised upregulation of ADAMTS4 at the injured surface in successfully integrated samples, suggest that ADAMTS4 may enhances normal repair in injured AC through local aggrecan depletion, therefore enabling spontaneous cross-linking of collagen fibrils. Declaration of Interest. (b) declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported:I declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project

Poor soft tissue balance in total knee arthroplasty (TKA) is one of the most primary causes of dissatisfaction and reduced joint longevity, which are associated with postoperative instability and early implant failure. 1. Therefore, surgical techniques, including mechanical instruments and 3-D guided navigation systems, in TKA aim to achieve optimum soft tissue balancing in the knee to improve postoperative outcome. 2. Patella-in-Place balancing (PIPB) is a novel technique which aims to restore native collateral ligament behaviour by preserving the original state without any release. Moreover, reduction of the joint laxity compensates for the loss of the visco-elastic properties of the cartilage and meniscus. Following its clinical success, we aimed to evaluate the impact of the PIPB technique on collateral ligament strain and laxity behaviour, with the hypothesis that PIPB would restore strains in the collateral ligaments. 3. . Eight fresh-frozen cadaveric legs were obtained (KU Leuven, Belgium, H019 2015-11-04) and CT images were acquired while rigid marker frames were affixed into the femur, and tibia for testing. After carefully removing the soft tissues around the knee joint, while preserving the joint capsule, ligaments, and tendons, digital extensometers (MTS, Minnesota, USA) were attached along the length of the superficial medial collateral ligament (MCL) and lateral collateral ligament (LCL). A handheld digital dynamometer (Mark-10, Copiague, USA) was used to apply an abduction or adduction moment of 10 Nm at fixed knee flexion angles of 0°, 30°, 60° and 90°. A motion capture system (Vicon Motion Systems, UK) was used to record the trajectories of the rigid marker frames while synchronized strain data was collected for MCL/LCL. All motion protocols were applied following TKA was performed using PIPB with a cruciate retaining implant (Stryker Triathlon, MI, USA). Furthermore, tibiofemoral kinematics were calculated. 4. and combined with the strain data. Postoperative tibial varus/valgus stresses and collateral ligament strains were compared to the native condition using the Wilcoxon Signed-Rank Test (p<0.05). Postoperative tibial valgus laxity was lower than the native condition for all flexion angles. Moreover, tibial valgus of TKA was significantly different than the native condition, except for 0° (p=0.32). Although, tibial varus laxity of TKA was lower than the native at all angles, significant difference was only found at 0° (p=0.03) and 90° (p=0.02). No significant differences were observed in postoperative collateral ligament strains, as compared to the native condition, for all flexion angles, except for MCL strain at 30° (p=0.02) and 60° (p=0.01). Results from this experimental study supported our hypotheses, barring MCL strain in mid-flexion, which might be associated with the implant design. Restored collateral ligament strains with reduced joint laxity, demonstrated by the PIPB technique in TKA in vitro, could potentially restore natural joint kinematics, thereby improving patient outcomes. In conclusion, to further prove the success of PIPB, further biomechanical studies are required to evaluate the success rate of PIPB technique in different implant designs

Crosslinking has been already used for about 80 years to enhance the longevity of polyethylene cables. The polymer alteration has been achieved with peroxide, silane or irradiation. The medical devices industry discovered the benefit of this technology for its tribological applications like hip or knee bearings in the 2000s as crosslinking improves considerably the abrasion resistance of the material. The more current methods used are Gamma and Beta irradiation. On the basis of economical (rising prices of Cobalt), environmental (the radioactive source can not be turned off), technological (low dose rate) drawbacks for Gamma respectively low penetration for Beta irradiation we decided to investigate an alternative technology: the X-Ray irradiation, which provides a homogeneous crosslinking in a relatively short time. We analyzed the wear, mechanical, thermal, oxidative and network properties of two vitamin E doped UHMWPE: first crosslinked with E-Beam, second with X-Ray. There wasn't any significant difference between the X-Ray and the E-Beam crosslinked material

The growth in the popularity of tissue engineering principles in the treatment of musculoskeletal disorders has been complemented greatly with research investment into tissue specific scaffolds. Biological scaffolds produced by means of decellularising native tissues have the advantage of providing the natural complex hierarchical matrix and, in doing so, replicating the specific biomechanical and biological functions of the tissue in question. Decellularisation treatments are multi-faceted, vary considerably between different processes and may involve many lengthy treatment steps. Some of these bio-processes may cause undesirable structural changes to the extracellular matrix of tissues and, by association, their mechanical properties. Thus, it is of paramount importance to ensure that the properties of the scaffolds are not affected to the extent of reducing their integration, biomechanical performance and longevity. This talk consists of a body of work detailing investigations into bio-process optimisation, sterilisation strategies and the regenerative and functional capacity of decellularised xenogeneic and allogeneic tendon, ligament and bone scaffolds. In addition, on-going work concerning advanced pre-clinical assessment, stratification of these products to particular patient populations and the importance of the manufacturing value chain in their translation will be discussed

We have undertaken a series of clinical trials over the last 20 years to look at different bearing surface combinations in young adults. We continue to follow these patients well beyond the planned duration of the trials and new information is constantly becoming available. The first trial compared ceramic-on-ceramic with ceramic-on-standard-polyethylene. These patients have now been followed for 20 years with significant wear in the polyethylene group but virtually identical revision rates. The second trial ceramic-on-ceramic, cobalt-chrome-on-standard-polyethylene and cobalt-chrome-on-cross-linked-polyethylene. In this group the ceramic-on-ceramic patients have the lowest revision rate; the ceramic-on-polyethylene group demonstrates a lower wear rate than cobalt-chrome-on-polyethylene. The third trial looks at cobalt-chrome versus zirconium on either cross-linked polyethylene or conventional polyethylene. At 10 years there remains no evidence of improved performance from the zirconium surface as compared to cobalt-chrome. The cross-linked polyethylene group is clearly outperforming the conventional polyethylene in terms of wear rate but at 10 years the revision rates remain the same in all groups. Cross liked polyethylene appears to be the major determining factor in prosthetic longevity and appears to be more important than the counter face material

Post-surgical infections are still one of the most frequent adverse events in the prosthetic surgery. PMMA-based cements are widely employed in orthopaedic surgery as filler or prosthetic fixing device. The main problems associated with this material are poor bone integration and infection development. Aiming to avoid bacterial adhesion and to extend the longevity of implants, different solutions were proposed, both in terms of operative procedures and new materials development. Regarding the materials advancement, innovative PMMA-based composite bone cements, contemporaneously bioactive and antibacterial (without the use of antibiotics), were developed. The composites are based on a PMMA matrix containing a bioactive glass, doped with antibacterial ions (Ag+ or Cu++); so, the same filler shows at the same time the ability of promoting bone ingrowth and an antibacterial effect. Composite cements were characterized in terms of morphology and composition, curing parameters and mechanical properties; in vitro tests were performed to verify the material ability to release antibacterial ions and to promote the precipitation of hydroxyapatite. Moreover, cytotoxicity and antimicrobial properties were verified. The cements characteristics were tested using different commercial matrix and different viscosities; therefore, the proposed formulations represent an innovative solution for a new family of antibiotic-free, bioactive and antibacterial cements

Pulsed electromagnetic fields (PEMFs) have been considered a potential treatment modality for fracture healing. As bone fracture healing and osseointegration share the same biological events, the application of PEMF stimulation to facilitate the osseointegration process of orthopedic implants has been suggested. However, the mechanism of their action remains unclear. Mammalian target of rapamycin (mTOR) signaling may affect osteoblast proliferation and differentiation. This study aimed to assess the osteogenic differentiation of mesenchymal stem cells (MSCs) under PEMF stimulation and the potential involvement of mTOR signaling pathway in this process. PEMFs were generated by a novel miniaturized electromagnetic device (MED). Potential changes in the expression of mTOR pathway components, including receptors, ligands and nuclear target genes, and their correlation with osteogenic markers and transcription factors were analyzed. PEMF exposure increased cell proliferation, adhesion and osteogenic commitment of MSCs. Osteogenic-related genes were over-expressed following PEMF treatment. Our results confirm that PEMFs contribute to activation of the mTOR pathway via upregulation of the proteins AKT, MAPP kinase, and RRAGA, suggesting that activation of the mTOR pathway is required for PEMF-stimulated osteogenic differentiation. In summary, the findings of the present study revealed that MED-generated PEMFs stimulate osteogenic differentiation and the maturation of the adipose tissue-derived MSCs via activation of the mTOR pathways. Even though further research is required to determine an optimal stimulation timing and flux density both in-vitro and in-vivo, this study results may serve a source for an adjuvant therapy to improve orthopedic implant stability, longevity and enhance fracture healing

Osteoarthritis (OA) affects millions of people and is the fastest growing cause of disability worldwide. In order to address this burden, early intervention strategies have been proposed. Therapies that utilise bone marrow stromal cells (BM-MSCs) to induce cartilage repair, either as a cell therapy or by endogenous release by drilling or microfracture, have proved promising. However, limitations include fibrotic features of the regenerated cartilage that may affect mechanical properties and therefore the longevity of such a repair. In order to improve this regenerative technique, further research is required to understand the key players in the repair mechanism. An interaction, which may be important, is that between BM-MSCs and the resident chondrocytes. The aim of this study is to understand the interplay between BM-MSC and resident chondrocytesisolated from different zonal locations within the human knee. We compared chondrocytes from three different cartilage areas: chondrocytes from 1) the superficial zone (SZ) and 2) the middle-deep (MDZ) zone of non-weight bearing femoral condyles, and from 3) the osteoarthritic zone (OAZ) of patients undergoing knee replacement. First, we evaluated the influence of different chondrocytes on BM-MSCs monolayer in a transwell co-culture, assessing transcript levels of early chondrogenic markers including Sox9 and Col1. Secondly, in a 3D co-culture system, we evaluated how cartilage chips from the three different zones affect the chondrogenic differentiation of BM-MSC pellets. Results indicated that cells from the SZ induce chondrogenic differentiation of BM-MSCs when co-cultured. In contrast, MDZ and OAZ have a negative effect, compared to control conditions. Our findings suggest that chondrocytes from the SZ, a zone which has been reported to reduce with age and may be lost in advanced OA, is important to direct BM-MSCs differentiation towards the chondrogenic fate. This may be relevant to cartilage repair strategies

Summary Statement. Proximal femoral bony deficits present a surgical and biomechanical challenge to implant longevity in revision hip arthroplasty. This work finds comparable primary stability when a distally fixing tapered fluted stem was compared with a conical design in cadaveric tests. Introduction. Proximal bony deficits complicate revision hip surgery and compromise implant survival. Longer distally fixing stems which bypass such defects are therefore required to achieve stability compatible with bony ingrowth and implant longevity. Aims. It is hypothesised that a tapered stem will provide superior rotational stability to a conical design. This work therefore aims to compare the primary stability and biomechanical properties of a new design of tapered fluted modular femoral stem (Redapt®, Smith & Nephew) with that of a conical fluted stem (Restoration®, Stryker). Materials & Methods. 7 Pairs of cadaveric femora were obtained according to strict inclusion/exclusion criteria. Each underwent dual energy x-ray absorptiometry and calibration plain-film radiographs were taken. Digital templating was performed using TraumaCad (Voyant Health, Brainlab) to determine implant sizing. Both stems are fluted, modular and manufactured from titanium. The control stem (Restoration) featured a straight conical design and the investigation stem (Redapt) a straight tapered design. Implantation was performed by a revision arthroplasty surgeon familiar with both systems. Proximal bone deficiency was reproduced using an extended trochanteric osteotomy with removal of metaphyseal bone before reattaching the osteotomy. Primary stability in the axial, sagittal and coronal planes was assessed using micromotion transducers (HBM, Darmstadt, Germany) and also by Radiostereometric Analysis (RSA). RSA employs simultaneous biplanar radiographs to measure relative movement. Two 1mm tantalum beads were mounted on the prosthesis with the centre of the femoral head taken as the third reference point. Beads were placed proximally in the surrounding bone as rigid body markers. Each bone was potted according to the ISO standard for fatigue testing and cyclically loaded at 1Hz for at least 3 increments (750–350N, 1000–350N, 1500–350N) for 1000 cycles. RSA radiographs were taken at baseline and on completion of each cycle. A strain analysis was concurrently performed using a PhotoStress® (Vishay Precision Group, Raleigh, USA) photoelastic coating on the medial femoral cortex. Each bone was loaded intact and then with the prosthesis in-situ at 500N increments until strain fringes were identified. Once testing was completed, the stems were sectioned at the femoral isthmus and data is presented on the cross-sectional fit and fill observed. Results. Both stem designs showed comparable primary stability with all stems achieving clinically acceptable micromotion (<150 μm) when loaded at body weight. A larger proportion of the control stems remained stable as loading increased to x2-3 body weight. Transducer-recorded migration appeared greatest in the axial plane (y axis) with negligible distal movement in the coronal or sagittal planes. Point motion analysis (RSA) indicated most movement to be in the coronal plane (x-axis) whereas segment motion analysis showed rotation about the long axis of the prosthesis to be largest. Photoelastic strain patterns were transferred more distally in both designs, however substantial stress shielding was also observed. Discussion/Conclusion. Both designs achieved adequate distal fixation and primary stability under representative clinical loading conditions. This work supports the continued use of this novel stem design for revision surgery in the presence of extensive proximal bone loss

Background. Increased revision rates and early failure of Metal-on-Metal (MoM) hip replacements are often due to adverse reaction to metal debris (ARMD). ARMD describes numerous symptoms in patients such as pain, osteolysis and soft tissue damage. Cobalt is a major component of MoM joints and can initiate an immune response via activation of the innate immune receptor Toll-like receptor 4 (TLR4). This leads to increased secretion of inflammatory cytokines e.g. interleukin-8 (IL-8). This study investigates whether TLR4-specific antagonists inhibit the inflammatory response to cobalt using IL-8 gene expression and protein secretion as a marker of TLR4 activation. Methods. MonoMac 6 (MM6) cells, a human macrophage cell line, were treated with TLR4-specific antagonists followed by 0.75mM of cobalt chloride. Lipopolysaccharide (LPS), a known TLR4 agonist was used as a positive control. Enzyme-linked immunosorbent assay (ELISA) was used to assess IL-8 protein secretion and real time- polymerase chain reaction (RT-PCR) allowed quantification of IL-8 gene expression. Results. MM6 cells treated with cobalt and LPS up-regulate IL-8 gene expression and protein secretion (n=3). The addition of TLR4-specific antagonists significantly inhibits this up-regulation suggesting the observed effects are TLR4-mediated. MM6 cells stimulated with cobalt (0.75mM) for 16 hours demonstrated a 27-fold increase in IL-8 gene expression (p-value = < 0.0001). When pre-treated with 10μg/ml of a TLR4-specific antagonist fold increase decreased to 6-fold (p-value = < 0.0001). IL-8 secretion decreased from 5000pg/ml to 3000pg/ml (p-value = < 0.0001). Conclusion. TLR4-specific antagonists inhibit cobalt-mediated IL-8 gene expression and protein secretion in MM6 cells. This finding demonstrates the potential to exploit this inhibition in the context of MoM joint replacements by contributing to the development of novel therapeutics designed to improve MoM implant longevity, reduce the incidence of ARMD and prevent subsequent revision surgery