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Several in vitro studies have investigated the biomechanics of reverse total shoulder arthroplasty (RTSA); however, few in vivo studies exist. The purpose of this study was to examine in vivo RTSA contact mechanics in clinically relevant arm positions. Our hypothesis was that contact would preferentially occur in the inferior region of the polyethylene liner. Forty patients receiving a primary RTSA were recruited for a prospective cohort study. All patients received the same implant design with a nonretentive liner. Stereo radiographs were taken at maximal active range of motion. Model-based radiostereometric analysis was used to identify implant position. Contact area between the polyethylene and glenosphere was measured as the geometric intersection of the 2 components and compared with respect to polyethylene liner size, arm position, and relative position within the liner. There were no differences in the proportion of contact area in any arm position between polyethylene liner sizes, ranging from 30% ± 17% to 38% ± 23% for 36-mm liners and 32% ± 21% to 41% ± 25% for 42-mm liners. Contact was equally distributed between the superior and inferior halves of the liner at each arm position (P =.06-.79); however, greater contact area was observed in the outer radius of the liner when the arm was flexed (P =.002). This study highlights that contact mechanics are similar between 36- and 42-mm liners. Contact area is generally equally distributed throughout the liner across the range of motion and not preferentially in the inferior region as hypothesized. [ABSTRACT FROM AUTHOR]

Highlights • Newtonian fluid model underestimates wall shear stress compared to non-Newtonian. • Non-Newtonian fluid models experience reduced disturbed flow compared to Newtonian. • Non-Newtonian fluid predicts reduced exposure to low and oscillatory shear stress. • Regions of high oscillatory shear index demarcate regions of flow recirculation. Abstract The development of atherosclerosis at the carotid bifurcation is impacted by local variations in wall shear stress (WSS) magnitude and direction, as well as flow complexity within the vessel. In this study, stereoscopic particle image velocimetry (PIV) was used to investigate multidirectional WSS and disturbed flow for idealized models of the carotid bifurcation with varying eccentric stenosis of the internal carotid artery (ICA) and both Newtonian (N-fluid) and non-Newtonian (nN-fluid) blood analogues. Turbulence intensity (TI) was reduced with the nN-fluid compared to N-fluid for mild to moderate stenosis, and comparable for more severely stenosed (70%) models. Differences in maximum TI due to viscosity model ranged from 0.02 m/s to 0.06 m/s compared to much larger differences due to geometry of up to 0.29 m/s between mild and severe stenosis. The level of time-averaged WSS (TAWSS) increased with stenosis severity from 5 Pa to 32 Pa, and nN-fluid led to higher WSS on average than N-fluid counterparts. Regions of elevated oscillatory shear index (OSI) demarcated recirculation regions, and mean OSI in the ICA branch was reduced for nN-fluid models by 9–19% compared to N-fluid. Transverse WSS (transWSS) increased with WSS magnitude and again was higher in nN-fluid models. Surface area exposure to shear metrics indicated that a Newtonian viscosity assumption predicted larger regions of low and oscillatory WSS, while predicting reduced regions of high transWSS, in comparison to the more physiological shear thinning fluid. [ABSTRACT FROM AUTHOR]

Introduction: This experiment was undertaken to assess the primary stability of orthodontic miniscrews inserted at different sites in human cadaveric palatal bone for temporary skeletal anchorage, and to determine the effect of bone quality and quantity on their primary stability using microcomputed tomography imaging.Methods: A total of 10 cadaveric maxillary hard palates were used for insertion of 130 orthodontic miniscrews (VectorTAS; Ormco, Orange, Calif; length, 6 mm; diameter, 1.4 mm). Upon insertion, maximal insertion torque (IT) was recorded. Imaging (microcomputed tomography) was performed before and after insertion for assessment of bone quality and quantity parameters (bone mineral density [BMD], bone thickness [BT], and length of screw engagement [LSE]). Differences in each parameter were assessed at the various insertion sites. Correlations between IT and measurements of BMD, BT, and LSE were evaluated.Results: Significant differences (P < 0.001) were found among insertion sites for IT, BT, and LSE, but not for BMD (P = 0.004). Correlations were found between IT and BMD (rs = 0.42; P < 0.001), IT and BT (rs = 0.58; P < 0.001), and IT and LSE (rs = 0.58; P < 0.001). Most perforations of miniscrews into the nasal cavity occurred posterior to the permanent second premolars.Conclusions: The primary stability of orthodontic miniscrews in the palate is affected by bone quality and quantity, with higher primary stability obtained anterior to the second premolars and parasagittally at the level of the permanent first molars. [ABSTRACT FROM AUTHOR]

Objective: Whole-body vibration (WBV) is a popular fitness trend based on claims of increased muscle mass, weight loss and reduced joint pain. Following its original implementation as a treatment to increase bone mass in patients with osteoporosis, WBV has been incorporated into clinical practice for musculoskeletal disorders, including back pain. However, our recent studies revealed damaging effects of WBV on joint health in a murine model. In this report, we examined potential mechanisms underlying disc degeneration following exposure of mice to WBV.Methods: Ten-week-old male mice were exposed to WBV (45 Hz, 0.3 g peak acceleration, 30 min/day, 5 days/week) for 4 weeks, 8 weeks, or 4 weeks WBV followed by 4 weeks recovery. Micro-computed tomography (micro-CT), histological, and gene expression analyses were used to assess the effects of WBV on spinal tissues.Results: Exposure of mice to 4 or 8 weeks of WBV did not alter total body composition or induce significant changes in vertebral bone density. On the other hand, WBV-induced intervertebral disc (IVD) degeneration, associated with decreased disc height and degenerative changes in the annulus fibrosus (AF) that did not recover within 4 weeks after cessation of WBV. Gene expression analysis showed that WBV for 8 weeks induced expression of Mmp3, Mmp13, and Adamts5 in IVD tissues, changes preceded by increased expression of Il-1β.Conclusions: Progressive IVD degeneration induced by WBV was associated with increased expression of Il-1β within the IVD that preceded Mmp and Adamts gene induction. Moreover, WBV-induced IVD degeneration is not reversed following cessation of vibration. [ABSTRACT FROM AUTHOR]

Clinical decision-making for the treatment of patients with diseased carotid artery is mainly based on the severity of the stenosis. However, stenosis severity alone is not a sensitive indicator, and other local factors for the assessment of stroke risk are required. Flow disturbance is of particular interest due to its proven association with increased thromboembolic activities. The objective of this study was to investigate the level of turbulence intensity (TI) with regards to certain geometrical features of the plaque - namely stenosis severity, eccentricity, and ulceration. A family of eight carotid-artery bifurcation models was examined using particle image velocimetry. Results showed a marked difference in turbulence intensity among these models; increasing degree of stenosis severity resulted in increased turbulence intensity, going from 0.12 m/s for mild stenosis to 0.37 m/s for severe stenosis (with concentric geometry). Moreover, independent of stenosis severity, eccentricity led to further elevations in turbulence intensity, increasing TI by 0.05-0.10 m/s over the counterpart concentric plaque. The presence of ulceration (in a 50% eccentric plaque) produced a larger portion of moderate turbulence intensity (~0.10 m/s) compared to the non-ulcerated model, more proximal to the bifurcation apex in the post-stenotic recirculation zone. The effect of plaque eccentricity and ulceration in enhancing the downstream turbulence has potential clinical implications for a more sensitive assessment of stroke risk beyond stenosis severity alone. [ABSTRACT FROM AUTHOR]

Abstract: Geometric wear analysis techniques require unworn geometries to serve as a reference in wear measurement. A method to create a reference geometrical model is described for retrieval studies when the actual unworn geometry is unavailable. Never-implanted tibial inserts were scanned with micro–computed tomography. Two, 3, or 6 insert surfaces were coaligned and averaged to create reference geometries. Individual inserts were compared with each other (manufacturing variability) and with the reference geometries (reference variability). The 3-dimensional deviations between the surfaces were recorded. The reference variability was reduced to 8.3 ± 39 μm, vs manufacturing variability of 15 ± 59 μm. Deviations were smallest on the articular surfaces where most wear occurs and were significantly less than the reported insert wear rate of 20 μm/y. [Copyright &y& Elsevier]

Abstract: There is currently considerable interest in the use of highly cross-linked polyethylene (XLPE) acetabular liners for total hip arthroplasty (THA). In literature, only a single retrieval analysis of one type of XLPE liner implanted for greater than four years exists. The purpose of the present report is to quantify surface deviations in two XLPE liners implanted during revision THA and retrieved between four to five years after implantation. The two XLPE acetabular liners (Reflection, Smith and Nephew Inc., Memphis, TN) were retrieved from patients undergoing their second revision surgery, at 4.90 and 4.07 years. The retrieved liners and a new, non-implanted, unworn liner of the same size were scanned using micro-computed tomography (micro-CT). Articular surface deviation maps were created by comparing the retrievals to the unworn liner, based on the liner geometry obtained from micro-CT. The linear penetration rates were found to be 0.018 and 0.008 mm/year. Localized scratches and pits with deviations greater than 0.205 mm were also found on the articular surfaces of both liners. The XLPE liners retrieved from the two cases demonstrated low linear penetration rates. Regions with greater focal deviations were also apparent, likely due to third-body wear. The results are consistent with previously published clinical follow-ups of other XLPE liners. [Copyright &y& Elsevier]

Purpose: To develop and evaluate a technique for measuring the radial resistive force, chronic outward force, and dimensions of self-expanding stents. Materials and Methods: A Mylar film was looped around the stent, threaded through two carbon fiber rods, and immersed in a 37°C oil bath. A force gauge mounted on a micro-positioning stage was used to measure the applied forces. The apparatus containing the self-expanding nitinol stent (diameter, 40 mm; length, 80 mm) was placed inside a micro-computed tomographic (CT) scanner. At each stent deformation, the load was manually recorded from the force gauge and a micro-CT volume (isotropic voxel spacing, 0.15 mm) obtained. Stent diameter and length were measured from the images, and radial resistive force and chronic outward force were calculated for each deformation. Results: The stress-strain curves indicate that the stents exert much smaller maximum outward forces (1.2 N/cm) than the force that is required to compress them (3.6 N/cm). The forces were measured with a precision of ±3.3% (standard deviation of five repeated measurements). The stent''s diameter was measured with precision better than 0.3% and accuracy of ±0.1 mm. Conclusions: The authors have developed a radiographic technique that enables precise measurements of radial resistive force, chronic outward force, and the dimensions of self-expanding stents during deformation. [Copyright &y& Elsevier]

Abstract: Micro-computed tomography (micro-CT) has previously been validated for measuring wear volume in polyethylene acetabular liners. The creation of 3-dimensional (3D) articular and backside surface deviation maps using micro-CT is described. An acetabular liner was retrieved after 16.7 years of implantation and scanned with micro-CT along with a new, never-implanted liner of the same size and type. The liner surface geometries were reconstructed and co-aligned. A 3D comparison and cross-sectional analysis was performed. Maximum 3D deviation of the articular surface was −2.48 ± 0.02 mm, with maximum backside deviation of 0.46 ± 0.02 mm. Micro-CT can measure surface deviation and therefore calculate the volume of wear plus creep of retrieved acetabular liners, and may be applicable for wear simulator studies and analyzing other polyethylene components including tibial inserts. [Copyright &y& Elsevier]

• Cyclic flexural loading was applied to SLM-built Ti6Al4V porous constructs. • Flexural fatigue strength depended primarily on strut thickness and porosity. • Numerical models predicted flexural fatigue strength with average deviation ≈ 10%. • Fatigue cracks appeared to initiate at the surface of strut junctions. • Simulated bone ingrowth resulted in greater flexural fatigue strength. Porous Ti6Al4V constructs have been developed to replace mandibular bone, however the flexural fatigue properties of these constructs must first be assessed. In this study, porous constructs were built by selective laser melting (SLM) and subjected to cyclic flexural loading using a three-point bending setup and a servo-hydraulic Instron machine. Maximum flexural stress was plotted against the number of cycles. Also, numerical models were developed to predict the fatigue strength of porous constructs. These models were validated using experimental test data and extended to account for bone ingrowth. Scanning electron microscopy was used to study the internal and surface structures of dynamically loaded constructs. We found that numerical models of the SLM-built constructs accurately predicted flexural fatigue strength within ≈10 % deviation. Numerical fatigue models and experimental tests demonstrated that fatigue strength of constructs were ≈30 % of their flexural yield strengths. Numerical models with bone ingrowth revealed that fatigue strength was doubled when compared to models without bone ingrowth. This may have been due to a damping effect of bone, resulting in reduction of fatigue failure. Overall, our study demonstrates the effectiveness of using numerical modeling in estimating the fatigue strength of SLM-built constructs intended for mandibular implant designs. [ABSTRACT FROM AUTHOR]

Objective: Earlier studies have not accounted for continued growth when using the rat calvarial defect model to evaluate bone healing in vivo. The purpose of this study was: 1) to calculate rat cranial vault growth over time; and 2) to determine the effects of accounting for growth on defect healing. Study Design: Bilateral parietal defects were created in 10 adult Wistar rats. Serial microscopic computerized tomography scans were performed. Bone mineral content (BMC) measured according to standard technique and repeated accounting for cranial growth over time was compared with the use of parametric and nonparametric tests. Results: Cranial vault growth continued through 22 weeks of age, increasing 7.5% in width and 9.1% in length, and calvarial defects expanded proportionately. BMC was greater within defects accounting for growth 2-12 weeks postoperatively (P < .003). Conclusions: BMC was underestimated through standard analysis, which demonstrates the importance of accounting for cranial growth given advances in serial imaging techniques. [Copyright &y& Elsevier]

Abstract: In 2002, a patient underwent revision total hip arthroplasty for polyethylene wear. The acetabular cup was well fixed, and it was decided to cement a new polyethylene liner into the existing cup. In 2006, the patient presented with inability to weight bear and easy subluxation of the hip. Revision surgery was performed, and all components were examined postoperatively. Investigation with microcomputed tomography revealed that the liner had plastically deformed at the superior pole resulting in the hip instability. The reasons for this are suspected to be related to the abducted nature of the original cup and an uneven cement mantle. This report suggests that cementation of polyethylene liners into metal cups has limitations and is not appropriate in all circumstances. [Copyright &y& Elsevier]

Laboratory systems for microscopic computed tomography (micro-CT) have recently evolved from specialized prototype tools to become essential components of many research laboratories. The availability of commercial systems with almost microscopic resolution and the capability to image live animals has opened up entirely new applications for micro-CT in laboratory investigation. This review describes the technical aspects of micro-CT and highlights some current research applications. Micro-CT has the potential to replace serial histology as the reference standard in many in vitro studies, and provides a practical approach to obtain quantitative information during some longitudinal investigations in vivo. [Copyright &y& Elsevier]

Abstract: Hemodynamics play a significant role in stroke risk, where thrombus formation may be accelerated in regions of slow or recirculating flow, high shear and increased turbulence. An in vitro investigation was performed with pulsed Doppler ultrasound (DUS) using the complete spectral data to investigate the three-dimensional (3-D) distribution of advanced parameters that may have potential for making a more specific in vivo diagnosis of carotid disease and stroke risk. The effect of stenosis symmetry and the potential of DUS spectral parameters for visualizing regions of recirculation or turbulence were explored. DUS was used to map pulsatile flow in four model geometries representing two different plaque symmetries (eccentricity) and two stenosis severities (mild, severe). Qualitative comparisons were made with flow patterns visualized using digital particle imaging. Color-encoded maps of DUS spectral parameters (mean velocity, spectral-broadening index and turbulence intensity) clearly distinguished regions of slow or recirculating flow and disturbed or turbulent flow. Distinctly different flow patterns resulted from stenoses of equal severity but different eccentricity. Noticeable differences were seen in both the size and location of recirculation zones and in the paths of high-velocity jets. Highly elevated levels of turbulence intensity were seen distal to severe stenosis. Results demonstrated the importance of plaque shape, which is typically not considered in standard diagnosis, in addition to stenosis severity. (E-mail: poepping@uwo.ca). [Copyright &y& Elsevier]

Abstract: Material property assignment is a critical step in developing subject-specific finite element models of bone. Inhomogeneous material properties are often applied using an equation relating density and elastic modulus, with the density information coming from CT scans of the bone. Very few previous studies have investigated which density–elastic modulus relationships from the literature are most suitable for application in long bone. No such studies have been completed for the ulna. The purpose of this study was to investigate six such density–modulus relationships and compare the results to experimental strains from eight cadaveric ulnae. Subject-specific finite element models were developed for each bone using micro-CT scans. Six density–modulus equations were trialed in each bone, resulting in a total of 48 models. Data from a previously completed experimental study in which each bone was instrumented with twelve strain gauges were used for comparison. Although the relationship that best matched experimental strains was somewhat specimen and location dependent, there were two relations which consistently matched the experimental strains most closely. One of these under-estimated and one over-estimated the experimental strain values, by averages of 15% and 31%, respectively. The results of this study suggest that the ideal relationship for the ulna may lie somewhere in between these two relations. [Copyright &y& Elsevier]

• Small dimeter beads are accurately tracked when inserted into soft tissue structures. • Tracked beads can be used to accurately and precisely calculate tissue strains. • A bounding box method is more accurate and precise than a masked based method. The purpose of this work was to assess the resolution to which micro-CT and intra-operative CT systems can quantify distances between radiopaque fiducial markers. Twenty-two markers were cast in a silicone phantom, then imaged at ten random rotations and translations within the field of view of a micro-CT and an intraoperative CT. A bounding box method and a mask-based weighted binary method were used to calculate the location of all markers in an image, then the Euclidian distance between neighbouring marker coordinates was calculated. The standard deviation in the inter-marker distance measurements from each of the marker position methods across the ten repeated trials was calculated for each marker identification method to provide a measure of the precision of the strain measurement with each scanner. The imaging systems measured 3D distances between markers to within 0.007 mm and 0.028 mm in the micro-CT and intra-operative CT, respectively, using the bounding box method, and to within 0.011 mm and 0.040 mm in the micro-CT and intra-operative systems, respectively, using the weighted-mask method. The bounding box method was found to be the most precise and is highly promising for applications in high resolution regional soft-tissue strain measurements. [ABSTRACT FROM AUTHOR]

• Effect of surface finish on corrosion and metal release from Ti6Al4V studied. • Ti6Al4V was produced by laser powder bed fusion using biomedical protocols. • Nitric acid passivation had a negligible effect on metal release and corrosion. • Effect of surface finish (sandblasted, polished) explained by true surface area. • More proteins were adsorbed on rough (sandblasted) surfaces. The biomedical titanium alloy Ti6Al4V has excellent corrosion resistance and biocompatibility and is, therefore, widely used in orthopedic and orthodontic implants. Biomedical implants are increasingly fabricated by additive manufacturing, such as laser powder bed fusion (LPBF). These manufacturing protocols often include sandblasting, surface finish, and passivation. This study aims to investigate the effect of different surface finishes and the commonly used ASTM F86–13 nitric acid passivation for LPBF Ti6Al4V on its corrosion resistance, metal release, and surface changes in benign (bovine serum albumin in a pH 7.4 buffer) and harsh (hydrochloric acid at pH 1.5) solutions using various electrochemical and spectroscopic techniques. Electrochemical, solution and surface analysis showed an insignificant effect of passivation. Smooth surfaces exhibited a slightly better corrosion resistance than rough surfaces due to a 10–20 % smaller true surface area and lower protein adsorption. Implanted ceramic beads from the sandblasting procedure remained on the surface even after the mirror-polishing and passivation procedures. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Metastatic melanoma is highly fatal. Within the tumor microenvironment, the role of cancer-associated fibroblasts (CAFs) in melanoma metastasis and progression is relatively understudied. The matricellular protein CCN2 (formerly termed connective tissue growth factor, CTGF) is overexpressed, in a fashion independent of BRAF mutational status, by CAFs in melanoma. Herein, we find, in human melanoma patients, that CCN2 expression negatively correlates with survival and positively correlates with expression of neovascularization markers. To assess the role of CAFs in melanoma progression, we used C57BL/6 mice expressing a tamoxifen-dependent cre recombinase expressed under the control of a fibroblast-specific promoter/enhancer (COL1A2) to delete CCN2 postnatally in fibroblasts. Mice deleted or not for CCN2 in fibroblasts were injected subcutaneously with B16-F10 melanoma cells. Loss of CCN2 in CAFs resulted in reduced CAF activation, as detected by staining with anti-α-smooth muscle actin antibodies, and reduced tumor-induced neovascularization, as detected by micro-computed tomography (micro-CT) and staining with anti-CD31 antibodies. CCN2-deficient B16(F10) cells were defective in a tubule formation/vasculogenic mimicry assay in vitro. Mice deleted for CCN2 in CAFs also showed impaired vasculogenic mimicry of subcutaneously-injected B16-F10 cells in vivo. Our results provide new insights into the cross-talk among different cell types in the tumor microenvironment and suggest CAFs play a heretofore unappreciated role by being essential for tumor neovascularization via the production of CCN2. Our data are consistent with the hypothesis that activated CAFs are essential for melanoma metastasis and that, due to its role in this process, CCN2 is a therapeutic target for melanoma. Highlights • In human patients, CCN2 negatively correlates with disease-free outcome and positively with expression of angiogenic markers. • Loss of CCN2 in CAFs resulted in reduced CAF activation and tumor-induced neovascularization including impaired vasculogenic mimicry and reduced expression of proangiogenic proteins. • Our results provide suggest CAFs play a heretofore unappreciated role by being essential for tumor neovascularization via the production of CCN2. • Targeting CAF activation, for example by impairing the action of CCN2, represents a novel therapeutic approach for melanoma. • We provide the first genetic evidence linking CCN2 to tumor neovascularization consistent with the notion that CCN2 represents a novel therapeutic approach to treat melanoma. [ABSTRACT FROM AUTHOR]

Introduction Previously, a finite element (FE) model of the proximal tibia was developed and validated against experimentally measured local subchondral stiffness. This model indicated modest predictions of stiffness ( R 2 = 0.77, normalized root mean squared error (RMSE%) = 16.6%). Trabecular bone though was modeled with isotropic material properties despite its orthotropic anisotropy. The objective of this study was to identify the anisotropic FE modeling approach which best predicted (with largest explained variance and least amount of error) local subchondral bone stiffness at the proximal tibia. Methods Local stiffness was measured at the subchondral surface of 13 medial/lateral tibial compartments using in situ macro indentation testing. An FE model of each specimen was generated assuming uniform anisotropy with 14 different combinations of cortical- and tibial-specific density-modulus relationships taken from the literature. Two FE models of each specimen were also generated which accounted for the spatial variation of trabecular bone anisotropy directly from clinical CT images using grey-level structure tensor and Cowin’s fabric-elasticity equations. Stiffness was calculated using FE and compared to measured stiffness in terms of R 2 and RMSE%. Results The uniform anisotropic FE model explained 53–74% of the measured stiffness variance, with RMSE% ranging from 12.4 to 245.3%. The models which accounted for spatial variation of trabecular bone anisotropy predicted 76–79% of the variance in stiffness with RMSE% being 11.2–11.5%. Conclusions Of the 16 evaluated finite element models in this study, the combination of Synder and Schneider (for cortical bone) and Cowin’s fabric-elasticity equations (for trabecular bone) best predicted local subchondral bone stiffness. [ABSTRACT FROM AUTHOR]

Background Quantitative computed tomography based subject-specific finite element modeling has potential to clarify the role of subchondral bone alterations in knee osteoarthritis initiation, progression, and pain. However, it is unclear what density-modulus equation(s) should be applied with subchondral cortical and subchondral trabecular bone when constructing finite element models of the tibia. Using a novel approach applying neural networks, optimization, and back-calculation against in situ experimental testing results, the objective of this study was to identify subchondral-specific equations that optimized finite element predictions of local structural stiffness at the proximal tibial subchondral surface. Methods Thirteen proximal tibial compartments were imaged via quantitative computed tomography. Imaged bone mineral density was converted to elastic moduli using multiple density-modulus equations (93 total variations) then mapped to corresponding finite element models. For each variation, root mean squared error was calculated between finite element prediction and in situ measured stiffness at 47 indentation sites. Resulting errors were used to train an artificial neural network, which provided an unlimited number of model variations, with corresponding error, for predicting stiffness at the subchondral bone surface. Nelder-Mead optimization was used to identify optimum density-modulus equations for predicting stiffness. Findings Finite element modeling predicted 81% of experimental stiffness variance (with 10.5% error) using optimized equations for subchondral cortical and trabecular bone differentiated with a 0.5 g/cm 3 density. Interpretation In comparison with published density-modulus relationships, optimized equations offered improved predictions of local subchondral structural stiffness. Further research is needed with anisotropy inclusion, a smaller voxel size and de-blurring algorithms to improve predictions. [ABSTRACT FROM AUTHOR]

• Laser powder bed fusion (LPBF) manufactured low carbon CoCrMo alloy manufactured. • Perpendicular (XY) and parallel (XZ) to build direction had distinct microstructure. • As-printed surfaces had higher corrosion than abraded surfaces (as-printed XY highest). • Highest corrosion in the presence of citrate species and oxidative conditions. • As-printed, rough surfaces showed better bioactivity and cell survival. Biomedical cobalt-chromium-molybdenum alloys (CoCrMo) are frequently used for orthopedic implant and dental materials exposed to mechanical stressors, such as wear and cyclic load. Due to the high demand for customizable implant shapes, these alloys are increasingly manufactured by additive manufacturing methods such as laser powder bed fusion (LPBF). LPBF results in different microstructures and surface roughness as a function of the building direction. This study investigated the corrosion resistance, bioactivity, biocompatibility, and microstructure of LPBF CoCrMo (low carbon content, heat-treated) in the XY (perpendicular) and XZ (parallel) plane of the building direction for as-printed (as-received) and abraded surfaces. A distinct microstructure and different surface roughness were found for the XY and XZ planes. The as-received XY surface showed the lowest corrosion resistance but was still passive in phosphate-buffered saline (PBS, pH 7.4). As-received surfaces were less corrosion-resistant than abraded surfaces. All specimens exhibited lower corrosion resistance in PBS containing citric acid at pH 7.4 than in PBS and citric acid alone. As-received surfaces showed better hydroxyapatite precipitation and cell viability; however, all surfaces had satisfactory biocompatibility and bioactivity. This study showed that the building direction had a minor effect on the corrosion of LPBF CoCrMo. [Display omitted] [ABSTRACT FROM AUTHOR]

Equilibrative nucleoside transporter 1 (ENT1) mediates passage of adenosine across the plasma membrane. We reported previously that mice lacking ENT1 ( ENT1 − / − ) exhibit progressive ectopic mineralization of spinal tissues resembling diffuse idiopathic skeletal hyperostosis (DISH) in humans. Here, we investigated mechanisms underlying aberrant mineralization in ENT1 − / − mice. Micro-CT revealed ectopic mineralization of spinal tissues in both male and female ENT1 − / − mice, involving the annulus fibrosus of the intervertebral discs (IVDs) of older mice. IVDs were isolated from wild-type and ENT1 − / − mice at 2 months of age (prior to disc mineralization), 4, and 6 months of age (disc mineralization present) and processed for real-time PCR, cell isolation, or histology. Relative to the expression of ENTs in other tissues, ENT1 was the primary nucleoside transporter expressed in wild-type IVDs and mediated the functional uptake of [ 3 H]2-chloroadenosine by annulus fibrosus cells. No differences in candidate gene expression were detected in IVDs from ENT1 − / − and wild-type mice at 2 or 4 months of age. However, at 6 months of age, expression of genes that inhibit biomineralization Mgp , Enpp1 , Ank , and Spp1 were reduced in IVDs from ENT1 − / − mice. To assess whether changes detected in ENT1 − / − mice were cell autonomous, annulus fibrosus cell cultures were established. Compared to wild-type cells, cells isolated from ENT1 − / − IVDs at 2 or 6 months of age demonstrated greater activity of alkaline phosphatase, a promoter of biomineralization. Cells from 2-month-old ENT1 − / − mice also showed greater mineralization than wild-type. Interestingly, altered localization of alkaline phosphatase activity was detected in the inner annulus fibrosus of ENT1 − / − mice in vivo. Alkaline phosphatase activity, together with the marked reduction in mineralization inhibitors, is consistent with the mineralization of IVDs seen in ENT1 − / − mice at older ages. These findings establish that both cell-autonomous and systemic mechanisms contribute to ectopic mineralization in ENT1 − / − mice. [ABSTRACT FROM AUTHOR]

Tendons/ligaments insert into bone via a transitional structure, the enthesis, which is susceptible to injury and difficult to repair. Fibrocartilaginous entheses contain fibrocartilage in their transitional zone, part of which is mineralized. Mineral-associated proteins within this zone have not been adequately characterized. Members of the S mall I ntegrin B inding Li gand N -linked G lycoprotein (SIBLING) family are acidic phosphoproteins expressed in mineralized tissues. Here we show that two SIBLING proteins, bone sialoprotein (BSP) and osteopontin (OPN), are present in the mouse enthesis. Histological analyses indicate that the calcified zone of the quadriceps tendon enthesis is longer in Bsp −/− mice, however no difference is apparent in the supraspinatus tendon enthesis. In an analysis of mineral content within the calcified zone, micro-CT and Raman spectroscopy reveal that the mineral content in the calcified fibrocartilage of the quadriceps tendon enthesis are similar between wild type and Bsp −/− mice. Mechanical testing of the patellar tendon shows that while the tendons fail under similar loads, the Bsp −/− patellar tendon is 7.5% larger in cross sectional area than wild type tendons, resulting in a 16.5% reduction in failure stress. However, Picrosirius Red staining shows no difference in collagen organization. Data collected here indicate that BSP is present in the calcified fibrocartilage of murine entheses and suggest that BSP plays a regulatory role in this structure, influencing the growth of the calcified fibrocartilage in addition to the weakening of the tendon mechanical properties. Based on the phenotype of the Bsp −/− mouse enthesis, and the known in vitro functional properties of the protein, BSP may be a useful therapeutic molecule in the reattachment of tendons and ligaments to bone. [ABSTRACT FROM AUTHOR]

Background Quantitative computed tomography based subject-specific finite element modeling has potential to clarify the role of subchondral bone alterations in knee osteoarthritis initiation, progression, and pain initiation. Calculation of bone elastic moduli from image data is a basic step when constructing finite element models. However, different relationships between elastic moduli and imaged density (known as density–modulus relationships) have been reported in the literature. The objective of this study was to apply seven different trabecular-specific and two cortical-specific density–modulus relationships from the literature to finite element models of proximal tibia subchondral bone, and identify the relationship(s) that best predicted experimentally measured local subchondral structural stiffness with highest explained variance and least error. Methods Thirteen proximal tibial compartments were imaged via quantitative computed tomography. Imaged bone mineral density was converted to elastic moduli using published density–modulus relationships and mapped to corresponding finite element models. Proximal tibial structural stiffness values were compared to experimentally measured stiffness values from in-situ macro-indentation testing directly on the subchondral bone surface (47 indentation points). Findings Regression lines between experimentally measured and finite element calculated stiffness had R 2 values ranging from 0.56 to 0.77. Normalized root mean squared error varied from 16.6% to 337.6%. Interpretation Of the 21 evaluated density–modulus relationships in this study, Goulet combined with Snyder and Schneider or Rho appeared most appropriate for finite element modeling of local subchondral bone structural stiffness. Though, further studies are needed to optimize density–modulus relationships and improve finite element estimates of local subchondral bone structural stiffness. [ABSTRACT FROM AUTHOR]

Abstract: Aim of study: To investigate the role of intra-osseous lesions in advancing the pathogenesis of Osteoarthritis (OA) of the knee, using Finite Element Modeling (FEM) in conjunction with high-resolution imaging techniques. Methods: Twenty early stage OA patients (≤Grade 2 radiographic score) were scanned with a prototype, cone-beam CT system. Scans encompassed the mid-shaft of the femur to the diaphysis of the proximal tibia. Individual bones were segmented to create 3D geometric models that were transferred to FE software for loading experiments. Patient-specific, inhomogeneous material properties were derived from the CT images and mapped directly to the FE models. Duplicate models were also created, with a 3D sphere (range 3–12mm) introduced into a weight-bearing region of the joint, mimicking the size, location, and composition of a subchondral bone cyst (SBC). A spherical shell extending 1mm radially around the SBC served as the sample volume for measurements of von Mises equivalent stress. Both models were vertically loaded with 750N, or approximately 1 body weight during a single-leg stance. Results: All FE models exhibited a physiologically realistic weight-bearing distribution of stress, which initiated at the joint surface and extended to the cortical bone. Models that contained the SBC experienced a nearly two-fold increase in stress (0.934±0.073 and 1.69±0.159MPa, for the non-SBC and SBC models, respectively) within the bone adjacent to the SBC. In addition, there was a positive correlation found between the diameter of the SBC and the resultant intra-osseous stress under load (p=0.004). Conclusions: Our results provide insights into the mechanism by which SBC may accelerate OA, leading to greater pain and disability. Based on these findings, we feel that patient-derived FE models of the OA knee – utilizing in vivo imaging data – present a tremendous potential for monitoring joint mechanics under physiological loads. [Copyright &y& Elsevier]

Abstract: The objective of this investigation was to implement a high-pass frequency filter method to analyze Doppler ultrasound velocity waveforms and quantify turbulence intensity (TI) in vivo. Doppler velocity data were analyzed using two techniques, based on either ensemble averaging or high-pass frequency domain filtering of the periodic waveforms. The accuracy and precision of TI measurements were determined with controlled in vitro experiments, using a pulsatile-flow model of a stenosed carotid bifurcation. The high-pass filter technique was also applied in vivo to determine whether this technique could successfully distinguish between pertinent hemodynamic sites within the carotid artery bifurcation. Twenty-five seconds of Doppler audio data were acquired at three sites (common carotid artery [CCA], internal carotid artery [ICA] stenosis and distal ICA) within 10 human carotid arteries, and repeated three times. Doppler velocity data were analyzed using a ninth-order high-pass Butterworth filter with a 12-Hz inflection point. TI measured within the CCA and distal ICA was found to be significantly different (p < 0.0001) for moderate to nearly occluded carotid artery classifications. Also, TI measured within the distal ICA increased with stenosis severity, with the ability to distinguish between each stenosis class (p < 0.05). This investigation demonstrated the ability to precisely quantify TI using a conventional Doppler ultrasound machine in human subjects, without interfering with normal clinical protocols. (E-mail: david.holdsworth@imaging.robarts.ca) [Copyright &y& Elsevier]

Abstract: Longitudinal bone growth is the result of endochondral bone formation which takes place in the growth plate. The rate of chondrocyte proliferation and hypertrophy, vascular invasion with the formation of primary ossification centers and cartilage replacement by bone tissue are all important processes required for normal growth. We have shown a role for the PI3K signaling pathway in chondrocyte hypertrophy and bone growth in tibia explant cultures. In this current study, we aimed to investigate the role of Akt1, an important target of PI3K, in endochondral ossification. Akt1 KO mice showed reduced size compared to their littermates throughout life, but the largest difference in body size was observed around 1 week of age. Focusing on this specific developmental stage, we discovered delayed secondary ossification in the long bones of Akt1 KO mice. A delay in formation of a structure resembling a secondary ossification center was also seen in tibia organ cultures treated with the PI3K inhibitor LY294002. The expression of matrix metalloproteinase-14 (MMP-14), the main protease responsible for development of secondary ossification centers, was decreased in the epiphysis of Akt1 KO mice, possibly explaining the delay in secondary ossification centers seen in the Akt1 KO mice. Bone mineral density (BMD) and bone mineral content (BMC) measured in the proximal tibia of 1-year-old mice were decreased in Akt1 KO mice, suggesting that the original delay in ossification might affect bone quality in older animals. [Copyright &y& Elsevier]

Abstract: An in vitro investigation of turbulence intensity (TI) associated with a severe carotid stenosis in the presence of physiological cardiac variability is described. The objective of this investigation was to determine if fluctuations due to turbulence could be quantified with conventional Doppler ultrasound (DUS) in the presence of normal physiological cycle-to-cycle cardiac variability. An anthropomorphic model of a 70% stenosed carotid bifurcation was used in combination with a programmable flow pump to generate pulsatile flow with a mean flow rate of 6 mL/s. Utilizing the pump, we studied normal, nonrepetitive cycle-to-cycle cardiac variability (±3.9%) in flow, as well as waveform shapes with standard deviations equal to 0, 2 and 3 times the normal variation. Eighty cardiac cycles of Doppler data were acquired at two regions within the model, representing either laminar or turbulent flow; each measurement was repeated six times. Turbulence intensity values were found to be 11 times higher (p < 0.001), on average, in the turbulent region than in the laminar region, with a mean difference of 24 cm/s. Twenty cardiac cycles were required for confidence in TI values. In conclusion, these results indicate that it is possible to quantify TI in vitro, even in the presence of normal and exaggerated cycle-to-cycle cardiac variability. (E-mail: david.holdsworth@imaging.robarts.ca) [Copyright &y& Elsevier]

Abstract: A technique for the rapid but accurate fabrication of multiple flow phantoms with variations in vascular geometry would be desirable in the investigation of carotid atherosclerosis. This study demonstrates the feasibility and efficacy of implementing numerically controlled direct-machining of vascular geometries into Doppler ultrasound (DUS)–compatible plastic for the easy fabrication of DUS flow phantoms. Candidate plastics were tested for longitudinal speed of sound (SoS) and acoustic attenuation at the diagnostic frequency of 5 MHz. Teflon® was found to have the most appropriate SoS (1376 ± 40 m s–1 compared with 1540 m s–1 in soft tissue) and thus was selected to construct a carotid bifurcation flow model with moderate eccentric stenosis. The vessel geometry was machined directly into Teflon® using a numerically controlled milling technique. Geometric accuracy of the phantom lumen was verified using nondestructive micro-computed tomography. Although Teflon® displayed a higher attenuation coefficient than other tested materials, Doppler data acquired in the Teflon® flow model indicated that sufficient signal power was delivered throughout the depth of the vessel and provided comparable velocity profiles to that obtained in the tissue-mimicking phantom. Our results indicate that Teflon® provides the best combination of machinability and DUS compatibility, making it an appropriate choice for the fabrication of rigid DUS flow models using a direct-machining method. (E-mail: david.holdsworth@imaging.robarts.ca) [Copyright &y& Elsevier]

Abstract: Turbulence is an important factor in the assessment of stenotic disease and a possible causative mechanism for thromboembolism. Previous Doppler studies of turbulence have typically used whole-blood preparations or suspensions of erythrocytes. Recently, a water-glycerol based blood-mimicking fluid (BMF) has been developed for use in Doppler ultrasound studies. This fluid has desirable ultrasound properties but it has not previously been described during in vitro investigations of turbulence intensity. We report on investigations of grid-generated and constrained-jet turbulence in an in vitro test system. The BMF was found to generate significant levels of turbulence during steady flow at physiological flow rates, producing turbulent patterns in the distal region that were consistent with previous studies. Turbulence intensity increased significantly with flow rate (p < 0.005) for both the constrained jet and the constrained grid. Based on our observations, we conclude that a water-glycerol based BMF provides a suitable working fluid during in vitro investigations of turbulence using Doppler ultrasound. (E-mail: david.holdsworth@imaging.robarts.ca) [Copyright &y& Elsevier]

Abstract: In this study, a new radiostereometric analysis (RSA) calibration cage was developed with the aim of improving the accuracy and precision of RSA. This development consisted of three steps: a numerical simulation technique was first used to design the new cage; a synthetic imaging method was then implemented to predict the performance of the designed cage before it was actually fabricated; and an experimental phantom test was finally conducted to verify the actual performance of the new cage and compare with two currently widely used cages. Accuracy was calculated as the 95% prediction intervals from regression analyses between the measured and actual displacements, and precision was defined as the standard deviation of repeated measurements. The final experimental phantom tests showed that the accuracy and precision of the new calibration cage were improved by about 40% over an existing biplanar cage and by about 70% compared to a uniplanar cage design. This new cage can be used with any skeletal joints, in either static or kinematic examination, which is helpful for the standardization of the RSA application. [Copyright &y& Elsevier]

Abstract: As a part of previous computational fluid dynamic (CFD) validation studies, particle image velocimetry (PIV) of two anatomically realistic basilar artery tip aneurysm models revealed two distinct types of flow (one of which has yet to be reported in the literature), characterized by the location and strength of the intra-aneurismal vortex. We hypothesized that these distinct “hemodynamic phenotypes” could be anticipated by a simple geometric parameter: the angle of the aneurysm bulb relative to the parent artery. An idealized basilar tip aneurysm model was constructed to allow independent control of this angle, and CFD simulations were carried out for angles ranging from 2° to 30°, these extremes corresponding to the angles measured from the two anatomically realistic models. The gross hemodynamics predicted by the idealized model for 2° and 30° were consistent with those seen in the corresponding anatomically realistic models. For the idealized model, the flow type switched at an angle between 8° and 12°. Sensitivity studies suggested that, near these angles, the hemodynamic phenotype was sensitive to inflow momentum. Outside this range, however, the parent–bulb angle appeared to be a robust predictor of hemodynamic phenotype. Our findings suggest that blood flow dynamics in basilar artery tip aneurysms fall into one of the two broad phenotypes, each subject to distinct hemodynamic forces. That the general features of these flow types may be anticipated by a relatively simple-to-measure geometric parameter could help ease the introduction of hemodynamic information into routine clinical decision-making. [Copyright &y& Elsevier]

Objectives: The aim of this study was to delineate the temporal profile of adventitial microvessel (Ad-MV) formation after stenting, its relationship to arterial wall hypoxia, and the effects of a tyrosine kinase inhibitor (TKI), SU11218, on Ad-MV and in-stent intimal hyperplasia (IH). Background: Adventitial microvessels have been reported after arterial injury; however, the underlying stimulus for this response and its relationship to IH is unknown. Methods: Coronary stenting was performed in 40 pigs randomized to SU11218 (n = 20) or placebo (n = 20). Vessel wall hypoxia was assessed by pimonidazole adducts and hypoxia-inducible factor (HIF)-1 alpha expression. Adventitial microvessels were quantified by three-dimensional microscopic computed tomography (3D micro CT). Intimal hyperplasia was measured by intravascular ultrasound (IVUS), 3D micro CT, and morphometry. The effects of SU11218 were assessed in vitro on smooth muscle cell (SMC) and endothelial cell (EC) functions and in vivo on Ad-MV and IH. Results: Hypoxia was evident in the vessel wall at 48 h and persisted for four weeks. Adventitial microvessels increased significantly at one week (24 ± 7 microvessels/segment) and four weeks (23 ± 7 microvessels/segment) compared with uninjured arteries (16 ± 2 microvessels/segment; p < 0.001) and correlated with IH (r = 0.77, p < 0.001). The TKI SU11218 inhibited platelet-derived growth factor receptor–beta phosphorylation, EC and SMC DNA synthesis, and migration in a dose-dependent manner in vitro and significantly inhibited Ad-MV (16 ± 5 vs. 23 ± 7 microvessels/segment in placebo, p < 0.001) and produced approximately 80% reduction in IH (0.52 ± 0.51 mm2 vs. 2.47 ± 1.66 mm2 in placebo, p < 0.001) at four weeks in vivo. Conclusions: Arterial stenting causes arterial wall hypoxia followed by Ad-MV formation. The TKI SU11218 inhibits both Ad-MV formation and IH and represents a promising therapeutic agent to prevent in-stent restenosis. [Copyright &y& Elsevier]

Abstract: Numerical simulations of Doppler ultrasound (DUS) relying on computational fluid dynamics (CFD) models of nonaxial flow have traditionally employed detailed (but computationally intensive) models of the DUS physics, or have sacrificed much of the physics in the interest of computational or conceptual simplicity. In this paper, we present a compromise between these extremes, with the objective of simulating the essential characteristics of DUS spectrograms in a real-time manner. Specifically, a precomputed pulsatile CFD velocity field is interrogated at some number, N, of discrete points distributed spatially within a sample volume of prescribed geometry and power distribution and temporally within a prescribed sampling window. Intrinsic spectral broadening is accounted for by convolving each of the point velocities with a semiempirical broadening function. Real-time performance is facilitated through the use of an efficient algorithm for interpolating the unstructured CFD data. A spherical sample volume with Gaussian power distribution, N = 1000 sampling points, and quadratic broadening function are shown to be adequate for simulating, at frame rates of 86 Hz on a 1.5 GHz desktop workstation, realistic-looking spectrograms at representative locations within a stenosed carotid bifurcation model. Via qualitative comparisons with matched in vitro data, these simulated spectrograms are shown to mimic the distinctive spectral envelopes, broadening and power characteristics associated with common carotid, stenotic jet and poststenotic recirculating flows. We conclude that the complex interaction between Doppler ultrasound and complicated clinically relevant blood flow dynamics can be simulated in real time via this relatively straightforward semiempirical approach. (E-mail: steinman@imaging.robarts.ca) [Copyright &y& Elsevier]

A technique is discussed for producing a robust ultrasound (US)-compatible flow phantom that consists of a thin-walled silicone-elastomer vessel with a lumen of arbitrary geometry, embedded in an agar-based tissue-mimicking material (TMM). The TMM has an acoustic attenuation of 0.56 dB cm-1 MHz-1 at 5 MHz, with nearly linear frequency-dependence and acoustic velocity of 1539 ± 4 m s-1. The vessel-mimicking material (VMM) has an acoustic attenuation of 3.5 dB cm-1 MHz-1 with linear frequency-dependence and an acoustic velocity of 1020 ± 20 m s-1. Scattering particles, which are added to the VMM to increase echogenicity and add speckle texture, lead to higher attenuation, depending on particle concentration and frequency. The VMM is stable over time, with a Young’s elastic modulus of 1.3 to 1.7 MPa for strains of up to 10%, which mimics human arteries under typical physiological conditions. The phantom is sealed to prevent TMM exposure to air or water, to avoid changes to the acoustic velocity. [Copyright &y& Elsevier]

The effect of lossy, MP3 compression on spectral parameters derived from Doppler ultrasound (US) signals was investigated. Compression was tested on signals acquired from two sources: 1. phase quadrature and 2. stereo audio directional output. A total of 11, 10-s acquisitions of Doppler US signal were collected from each source at three sites in a flow phantom. Doppler signals were digitized at 44.1 kHz and compressed using four grades of MP3 compression (in kilobits per second, kbps; compression ratios in brackets): 1400 kbps (uncompressed), 128 kbps (11:1), 64 kbps (22:1) and 32 kbps (44:1). Doppler spectra were characterized by peak velocity, mean velocity, spectral width, integrated power and ratio of spectral power between negative and positive velocities. The results suggest that MP3 compression on digital Doppler US signals is feasible at 128 kbps, with a resulting 11:1 compression ratio, without compromising clinically relevant information. Higher compression ratios led to significant differences for both signal sources when compared with the uncompressed signals. (E-mail: david.holdsworth@imaging.robarts.ca) [Copyright &y& Elsevier]

To investigate the correlation between disease severity and Doppler spectral measurements in the carotid artery bifurcation, a unique in vitro system has been developed that mimics the human vasculature with respect to both anatomy and flow perfusion. Agar-based carotid phantoms are perfused with a blood-mimicking fluid using a computer-controlled pump and realistic pulsatile flow waveform. A three-axis translational stage allows the lumen to be interrogated with a 0.6-μL Doppler sample volume at the desired spatial intervals using a semiautomated acquisition system, to collect 10 cardiac cycles of gated quadrature data at each site. Off-line analysis, including a 1024-point FFT, produces a 4-D (i.e., time-varying 3-D) Doppler velocity data set with 1.3-cm/s velocity resolution and 12-ms temporal resolution. Using this system, in vitro flow in bifurcations with both normal and stenosed lumen geometry (from 30% to 80% stenosis by NASCET criteria) can be studied, along with the effect of factors, such as stenosis geometry (concentric vs. eccentric) and flow rate, on the observed Doppler ultrasound (US) spectra and haemodynamic patterns. (E-mail: dholdswo@irus.rri.ca) [Copyright &y& Elsevier]