A multiscale orchestrated computational framework to reveal emergent phenomena in neuroblastoma.

Neuroblastoma is a complex and aggressive type of cancer that affects children. Current treatments involve a combination of surgery, chemotherapy, radiotherapy, and stem cell transplantation. However, treatment outcomes vary due to the heterogeneous nature of the disease. Computational models have been used to analyse data, simulate biological processes, and predict disease progression and treatment outcomes. While continuum cancer models capture the overall behaviour of tumours, and agent-based models represent the complex behaviour of individual cells, multiscale models represent interactions at different organisational levels, providing a more comprehensive understanding of the system. In 2018, the PRIMAGE consortium was formed to build a cloud-based decision support system for neuroblastoma, including a multi-scale model for patient-specific simulations of disease progression. In this work we have developed this multi-scale model that includes data such as patient's tumour geometry, cellularity, vascularization, genetics and type of chemotherapy treatment, and integrated it into an online platform that runs the simulations on a high-performance computation cluster using Onedata and Kubernetes technologies. This infrastructure will allow clinicians to optimise treatment regimens and reduce the number of costly and time-consuming clinical trials. This manuscript outlines the challenging framework's model architecture, data workflow, hypothesis, and resources employed in its development.

Delivering computationally-intensive digital patient applications to the clinic: An exemplar solution to predict femoral bone strength from CT data.

BACKGROUND AND OBJECTIVE: Whilst fragility hip fractures commonly affect elderly people, often causing permanent disability or death, they are rarely addressed in advance through preventive techniques. Quantification of bone strength can help to identify subjects at risk, thus reducing the incidence of fractures in the population. In recent years, researchers have shown that finite element models (FEMs) of the hip joint, derived from computed tomography (CT) images, can predict bone strength more accurately than other techniques currently used in the clinic. The specialised hardware and trained personnel required to perform such analyses, however, limits the widespread adoption of FEMs in clinical contexts. In this manuscript we present CT2S (Computed Tomography To Strength), a system developed in collaboration between The University of Sheffield and Sheffield Teaching Hospitals, designed to streamline access to this complex workflow for clinical end-users. METHODS: The system relies on XNAT and makes use of custom apps based on open source software. Available through a website, it allows doctors in the healthcare environment to benefit from FE based bone strength estimation without being exposed to the technical aspects, which are concealed behind a user-friendly interface. Clinicians request the analysis of CT scans of a patient through the website. Using XNAT functionality, the anonymised images are automatically transferred to the University research facility, where an operator processes them and estimates the bone strength through FEM using a combination of open source and commercial software. Following the analysis, the doctor is provided with the results in a structured report. RESULTS: The platform, currently available for research purposes, has been deployed and fully tested in Sheffield, UK. The entire analysis requires processing times ranging from 3.5 to 8 h, depending on the available computational power. CONCLUSIONS: The short processing time makes the system compatible with current clinical workflows. The use of open source software and the accurate description of the workflow given here facilitates the deployment in other centres.

Evaluation of patient tissue selection methods for deriving equivalent density calibration for femoral bone quantitative CT analyses.

Osteoporosis affects an increasing number of people every year and patient specific finite element analysis of the femur has been proposed to identify patients that could benefit from preventative treatment. The aim of this study was to demonstrate, verify, and validate an objective process for selecting tissues for use as the basis of phantomless calibration to enable patient specific finite element analysis derived hip fracture risk prediction. Retrospective reanalysis of patient computed tomography (CT) scans has the potential to yield insights into more accurate prediction of osteoporotic fracture. Bone mineral density (BMD) specific calibration scans are not typically captured during routine clinical practice. Tissue-based BMD calibration can therefore empower the retrospective study of patient CT scans captured during routine clinical practice. Together the method for selecting tissues as the basis for phantomless calibration coupled with the post-processing steps for deriving a calibration equation using the selected tissues provide an estimation of quantitative equivalent density results derived using calibration phantoms. Patient tissues from a retrospective cohort of 211 patients were evaluated. The best phantomless calibration resulted in a femoral strength (FS) [N] bias of 0.069 ± 0.07% over FS derived from inline calibration and a BMD [kg/cm3] bias of 0.038 ± 0.037% over BMD derived from inline calibration. The phantomless calibration slope for the best method presented was within the range of patient specific calibration curves available for comparison and demonstrated a small bias of 0.028 ± 0.054 HU/(mg/cm3), assuming the Mindways Model 3 BMD inline calibration phantom as the gold standard. The presented method of estimating a calibration equation from tissues showed promise for CT-based femoral fracture analyses of retrospective cohorts without readily available calibration data.

Effect of size and location of simulated lytic lesions on the structural properties of human vertebral bodies, a micro-finite element study.

Currently, the Spinal Instability Neoplastic Score system is used in clinics to evaluate the risk of fracture in patients with spinal metastases. This method, however, does not always provide a clear guideline due to the complexity in accounting for the effect of metastatic lesions on vertebral stability. The aim of this study was to use a validated micro Finite Element (microFE) modelling approach to analyse the effect of the size and location of lytic metastases on the mechanical properties of human vertebral bodies. Micro Computed Tomography based microFE models were generated with and without lytic lesions simulated as holes within a human vertebral body. Single and multiple lytic lesions were simulated with four different sizes and in five different locations. Bone was assumed homogenous, isotropic and linear elastic, and each vertebra was loaded in axial compression. It was observed that the size of lytic lesions was linearly related with the reduction in structural properties of the vertebral body (reduction of stiffness between 3% and 30% for lesion volume between 4% and 35%). The location of lytic lesions did not show a clear effect on predicted structural properties. Single or multiple lesions with the same volume provided similar results. Locally, there was a homogeneous distribution of axial principal strains among the models with and without lytic lesions. This study highlights the potential of microFE models to study the effect of lesions on the mechanical properties of the human vertebral body.

Investigating rolling as mechanism for humeral fractures in non-ambulant infants: a preliminary finite element study.

AIM: To use personalised computed tomography (CT)-based finite element models to quantitatively investigate the likelihood of self-inflicted humeral fracture in non-ambulant infants secondary to rolling. MATERIALS AND METHODS: Three whole-body post-mortem CT examinations of children at the age of rolling (two 4-month-old and one 6-month-old) were used. The mechanical moment needed by each infant to perform a rolling manoeuvre was calculated and applied to the finite element model in order to simulate spontaneous rolling from the prone to the supine position. RESULTS: The maximum predicted strains were found to be substantially lower (with a difference of >80%) than the elastic limit of the bone. CONCLUSION: Results of this study challenge the plausibility of self-inflicted humeral fracture caused by rolling in non-ambulant infants and indicate that it is unlikely for a humeral fracture to result from this mechanism without the assistance of an external force.

Predicting bone strength from CT data: Clinical applications.

In this review we summarise over 15 years of research and development around the prediction of whole bones strength from Computed Tomography data, with particular reference to the prediction of the risk of hip fracture in osteoporotic patients. We briefly discuss the theoretical background, and then provide a summary of the laboratory and clinical validation of these modelling technologies. We then discuss the three current clinical applications: in clinical research, in clinical trials, and in clinical practice. On average the strength predicted with finite element models (QCT-FE) based on computed tomography is 7% more accurate that that predicted with areal bone mineral density from Dual X-ray Absorptiometry (DXA-aBMD), the current standard of care, both in term of laboratory validation on cadaver bones and in terms of stratification accuracy on clinical cohorts of fractured and non-fractured women. This improved accuracy makes QCT-FE superior to DXA-aBMD in clinical research and in clinical trials, where the its use can cut in half the number of patients to be enrolled to get the same statistical power. For routine clinical use to decide who to treat with antiresorptive drugs, QCT-FE is more accurate but less cost-effective than DXA-aBMD, at least when the decision is on first line treatment like bisphosphonates. But the ability to predict skeletal strength from medical imaging is now opening a number of other applications, for example in paediatrics and oncology.

Biomechanical assessment of vertebrae with lytic metastases with subject-specific finite element models.

The assessment of risk of vertebral fracture in patients with lytic metastases is challenging, due to the complexity in modelling the mechanical properties of this heterogeneous material. Currently clinical assessment of patients at high risk of fracture is based on the Spinal Instability Neoplastic Score (SINS), which however in many cases does not provide clear guidelines. The goal of this study was to develop a computational approach to provide a comparative biomechanical assessment of vertebrae with lytic lesions with respect to the adjacent controls and highlight the critical vertebrae. The computed tomography images of the thoracolumbar spine of eight patients suffering of vertebral lytic metastases with SINS between 7 and 12 (indeterminate unstable) were analysed. For each patient one or two vertebrae with lytic lesions were modelled and the closest vertebrae without lesions were considered as control. Metastatic vertebrae (N = 12) and controls (N = 18) were converted to subject-specific, heterogeneous, isotropic, nonlinear finite element models for simulating uniaxial compression. Densitometric and mechanical properties were computed for each vertebra. In average, similar mechanical properties were found for vertebrae with lytic lesions and controls (e.g. ultimate force equal to 6.2 ±â€¯2.7 kN for vertebrae with lytic lesions and to 6.2 ±â€¯3.0 kN for control vertebrae). Only in three patients the vertebrae with lytic lesions were found to be mechanically weaker (-19% to -75% difference for ultimate stress) than the controls. In conclusion, in this study we presented an approach to estimate the mechanical competence of vertebrae with lytic metastases. It remains to be investigated in a clinical study if this method, together with the SINS, can better classify patients with vertebrae with lytic lesions at high risk of fracture.

Effect of integration time on the morphometric, densitometric and mechanical properties of the mouse tibia.

Micro-Computed Tomography (microCT) images are used to measure morphometric and densitometric properties of bone, and to develop finite element (FE) models to estimate mechanical properties. However, there are concerns about the invasiveness of microCT imaging due to the X-rays ionising radiation induced by the repeated scans on the same animal. Therefore, the best compromise between radiation dose and image quality should be chosen for each preclinical application. In this study, we investigated the effect of integration time (time the bone is exposed to radiation at each rotation step during microCT imaging) on measurements performed on the mouse tibia. Four tibiae were scanned at 10.4 µm voxel size using four different procedures, characterized by decreasing integration time (from 200 ms to 50 ms) and therefore decreasing nominal radiation dose (from 513 mGy to 128 mGy). From each image, trabecular and cortical morphometric parameters, spatial distribution of bone mineral content (BMC) in the whole tibia and FE-based estimations of stiffness and strength were obtained. A high-resolution scan (4.3 µm voxel size) was used to quantify measurement errors. Integration time had the largest effect on trabecular morphometric parameters (7-28%). Lower effects were observed on cortical parameters (1-3%), BMC (1-10%) distribution, and FE-based estimations of mechanical properties (1-3%). In conclusion, the effect of integration time on image-based measurements has been quantified. This data should be considered when defining the in vivo microCT scanning protocols in order to find the best compromise between nominal radiation exposure and accuracy in the estimation of bone parameters.

Experimental validation of DXA-based finite element models for prediction of femoral strength.

Osteoporotic fractures are a major clinical problem and current diagnostic tools have an accuracy of only 50%. The aim of this study was to validate dual energy X-rays absorptiometry (DXA)-based finite element (FE) models to predict femoral strength in two loading configurations. Thirty-six pairs of fresh frozen human proximal femora were scanned with DXA and quantitative computed tomography (QCT). For each pair one femur was tested until failure in a one-legged standing configuration (STANCE) and one by replicating the position of the femur in a fall onto the greater trochanter (SIDE). Subject-specific 2D DXA-based linear FE models and 3D QCT-based nonlinear FE models were generated for each specimen and used to predict the measured femoral strength. The outcomes of the models were compared to standard DXA-based areal bone mineral density (aBMD) measurements. For the STANCE configuration the DXA-based FE models (R(2)=0.74, SEE=1473N) outperformed the best densitometric predictor (Neck_aBMD, R(2)=0.66, SEE=1687N) but not the QCT-based FE models (R(2)=0.80, SEE=1314N). For the SIDE configuration both QCT-based FE models (R(2)=0.85, SEE=455N) and DXA neck aBMD (R(2)=0.80, SEE=502N) outperformed DXA-based FE models (R(2)=0.77, SEE=529N). In both configurations the DXA-based FE model provided a good 1:1 agreement with the experimental data (CC=0.87 for SIDE and CC=0.86 for STANCE), with proper optimization of the failure criteria. In conclusion we found that the DXA-based FE models are a good predictor of femoral strength as compared with experimental data ex vivo. However, it remains to be investigated whether this novel approach can provide good predictions of the risk of fracture in vivo.

Patient-specific finite element estimated femur strength as a predictor of the risk of hip fracture: the effect of methodological determinants.

UNLABELLED: A finite element modelling pipeline was adopted to predict femur strength in a retrospective cohort of 100 women. The effects of the imaging protocol and the meshing technique on the ability of the femur strength to classify the fracture and the control groups were analysed. INTRODUCTION: The clinical standard to estimate the risk of osteoporotic hip fracture is based on the areal bone mineral density (aBMD). A few retrospective studies have concluded that finite element (FE)-based femoral strength is a better classifier of fracture and control groups than the aBMD, while others could not find significant differences. We investigated the effect of the imaging protocol and of the FE modelling techniques on the discriminatory power of femoral strength. METHODS: A retrospective cohort of 100 post-menopausal women (50 with hip fracture, 50 controls) was examined. Each subject received a dual-energy absorptiometry (DXA) exam and a computed tomography (CT) scan of the proximal femur region. Each case was modelled a number of times, using different modelling pipelines, and the results were compared in terms of accuracy in discriminating the fracture and the control cases. The baseline pipeline involved local anatomical orientation and mesh morphing. Revised pipelines involved global anatomical orientation using a full-femur atlas registration and an optimised meshing algorithm. Minimum physiological (MPhyS) and pathological (MPatS) strengths were estimated for each subject. Area under the receiver operating characteristic (ROC) curve (AUC) was calculated to compare the ability of MPhyS, MPatS and aBMD to classify the control and the cases. RESULTS: Differences in the modelling protocol were found to considerably affect the accuracy of the FE predictors. For the most optimised protocol, logistic regression showed aBMDNeck, MPhyS and MPatS to be significantly associated with the facture status, with AUC of 0.75, 0.75 and 0.79, respectively. CONCLUSION: The study emphasized the necessity of modelling the whole femur anatomy to develop a robust FE-based tool for hip fracture risk assessment. FE-strength performed only slightly better than the aBMD in discriminating the fracture and control cases. Differences between the published studies can be explained in terms of differences in the modelling protocol and cohort design.

Estimation of local anisotropy of plexiform bone: Comparison between depth sensing micro-indentation and Reference Point Indentation.

The recently developed Reference Point Indentation (RPI) allows the measurements of bone properties at the tissue level in vivo. The goal of this study was to compare the local anisotropic behaviour of bovine plexiform bone measured with depth sensing micro-indentation tests and with RPI. Fifteen plexiform bone specimens were extracted from a bovine femur and polished down to 0.05µm alumina paste for indentations along the axial, radial and circumferential directions (N=5 per group). Twenty-four micro-indentations (2.5µm in depth, 10% of them were excluded for testing problems) and four RPI-indentations (~50µm in depth) were performed on each sample. The local indentation modulus Eind was found to be highest for the axial direction (24.3±2.5GPa) compared to the one for the circumferential indentations (19% less stiff) and for the radial direction (30% less stiff). RPI measurements were also found to be dependent on indentation direction (p<0.001) with the exception of the Indentation Distance Increase (IDI) (p=0.173). In particular, the unloading slope US1 followed similar trends compared to the Eind: 0.47±0.03N/µm for axial, 11% lower for circumferential and 17% lower for radial. Significant correlations were found between US1 and Eind (p=0.001; R(2)=0.58), while no significant relationship was found between IDI and any of the micro-indentation measurements (p>0.157). In conclusion some of the RPI measurements can provide information about local anisotropy but IDI cannot. Moreover, there is a linear relationship between most local mechanical properties measured with RPI and with micro-indentations, but IDI does not correlate with any micro-indentation measurements.

About the inevitable compromise between spatial resolution and accuracy of strain measurement for bone tissue: a 3D zero-strain study.

The accurate measurement of local strain is necessary to study bone mechanics and to validate micro computed tomography (µCT) based finite element (FE) models at the tissue scale. Digital volume correlation (DVC) has been used to provide a volumetric estimation of local strain in trabecular bone sample with a reasonable accuracy. However, nothing has been reported so far for µCT based analysis of cortical bone. The goal of this study was to evaluate accuracy and precision of a deformable registration method for prediction of local zero-strains in bovine cortical and trabecular bone samples. The accuracy and precision were analyzed by comparing scans virtually displaced, repeated scans without any repositioning of the sample in the scanner and repeated scans with repositioning of the samples. The analysis showed that both precision and accuracy errors decrease with increasing the size of the region analyzed, by following power laws. The main source of error was found to be the intrinsic noise of the images compared to the others investigated. The results, once extrapolated for larger regions of interest that are typically used in the literature, were in most cases better than the ones previously reported. For a nodal spacing equal to 50 voxels (498 µm), the accuracy and precision ranges were 425-692 µÎµ and 202-394 µÎµ, respectively. In conclusion, it was shown that the proposed method can be used to study the local deformation of cortical and trabecular bone loaded beyond yield, if a sufficiently high nodal spacing is used.

A comparison between micro-CT and histology for the evaluation of cortical bone: effect of polymethylmethacrylate embedding on structural parameters.

Cortical bone microstructure is an important parameter in the evaluation of bone strength. The aim of this study was to validate the characterization of human cortical bone microarchitecture using microcomputed tomography. In order to do this, microcomputed tomography structural measurements were compared with those obtained through histological examination (the gold standard). Moreover, to calculate structural parameters, microcomputed tomography images have to be binarized with the separation between bone and nonbone structures throughout a global thresholding. As the effect of the surrounding medium on the threshold value is not clear, an easy procedure to find the global uniform threshold for a given acquisition condition is applied. This work also compared the structural parameters of microcomputed tomography cortical sample scan in air or embedded in polymethylmethacrylate; histology was used as a reference. For each acquisition condition, a fixed threshold value was found and was applied on the corresponding microcomputed tomography image for the parameters assessment. Twenty cortical bone samples were collected from human femur and tibia diaphyses. All samples were microcomputed tomography scanned in air, embedded in polymethylmethacrylate, rescanned by microcomputed tomography, examined by histology and finally compared. A good correspondence between the microcomputed tomography images and the histological sections was found. Paired comparisons in cortical porosity, Haversian canal diameter and Haversian canal separation between histological sections and microcomputed tomography cross sections, first in air and then embedded in PolyMethylMethAcrylate, were made: no significant differences were found. None of the comparisons showed significant differences for cortical porosity, Haversian canal diameter and Haversian separation over a three-dimensional volume of interest, between microcomputed tomography scans in air and with samples embedded in PolyMethylMethAcrylate. The very good correlation between bone structural measures obtained from microcomputed tomography datasets and from two-dimensional histological sections confirms that microcomputed tomography may be an efficient tool for the characterization of cortical bone microstructure. Moreover, when the corresponding threshold value for each condition is used, structural parameters determined by microcomputed tomography are not affected by the surrounding medium (PolyMethylMethAcrylate).

Accuracy of finite element predictions in sideways load configurations for the proximal human femur.

Subject-specific finite element models have been used to predict stress-state and fracture risk in individual patients. While many studies analysed quasi-axial loading configurations, only few works simulated sideways load configurations, such as those arising in a fall. The majority among these latter directly predicted bone strength, without assessing elastic strain prediction accuracy. The aim of the present work was to evaluate if a subject-specific finite element modelling technique from CT data that accurately predicted strains in quasi-axial loading configurations is suitable to accurately predict strains also when applying low magnitude loads in sideways configurations. To this aim, a combined numerical-experimental study was performed to compare finite element predicted strains with strain-gauge measurements from three cadaver proximal femurs instrumented with sixteen strain rosettes and tested non-destructively under twelve loading configurations, spanning a wide cone (0-30° for both adduction and internal rotation angles) of sideways fall scenarios. The results of the present study evidenced a satisfactory agreement between experimentally measured and predicted strains (R(2) greater than 0.9, RMSE% lower than 10%) and displacements. The achieved strain prediction accuracy is comparable to those obtained in state of the art studies in quasi-axial loading configurations. Still, the presence of the highest strain prediction errors (around 30%) in the lateral neck aspect would deserve attention in future studies targeting bone failure.

Biomechanical robustness of a new proximal epiphyseal hip replacement to patient variability and surgical uncertainties: a FE study.

The biomechanical behaviour of current hip epiphyseal replacements is notably sensitive to the typical variability of conditions following a standard surgery. The aim of the present study was to assess the biomechanical robustness to the variability of post-operative conditions of an innovative proximal epiphyseal replacement (PER) hip device featuring a short, curved and cemented stem. The risk of femoral neck fractures, prosthesis fractures and aseptic loosening were assessed through a validated finite element procedure following a systematic approach. Risk changes due to anatomical variations were assessed mimicking extreme conditions in terms of femoral size and level of osteoporosis. Failure risks associated with surgical uncertainties were assessed mimicking extreme conditions in terms of uncertainties on the prosthesis position/alignment, cement-bone interdigitation depth, and friction between the prosthesis and the hosting cavity. The femoral neck strength increased after implantation from 9% to 49% and was most sensitive to changes of the anatomo-physiological variables. The risk of stem fractures was low in all studied configurations. The risk of stem loosening was low and most sensitive to surgical uncertainties. In conclusion, the new device can be considered an effective alternative to current epiphyseal replacements. Care is recommended in a proper seating of the prosthesis in the femur.

A new hip epiphyseal prosthesis: design revision driven by a validated numerical procedure.

An innovative epiphyseal device has been recently proposed claiming an effective bone-prosthesis load transfer and a nearly physiological bone stresses distribution. However preliminary experimental tests showed a 23% weakening of the femoral neck after implantation. Aim of this study was to revise the prosthesis geometry with the goal of enhancing the femoral neck strength after implantation, while maintaining unchanged the initial conceptual design. To this aim, the risk of femoral neck fractures, prosthesis fractures, aseptic loosening and excessive bone resorption were addressed through a validated finite element procedure following a systematic approach. The initial prosthesis geometry was revised to reduce each investigated failure risk below the threshold of acceptance (100%). The new geometry was re-assessed to verify the effectiveness of the revision. The first design was predicted to locally induce high bone strains and cement stresses, which translated in a risk of bone and cement failure exceeding the threshold of acceptance (>100%). The revised design preserved a good stability of the device, contemporary reducing the risk for bone (45%) and cement (60%) failure. If results will be confirmed by statistical and clinical experimentations, current clinical indications for hip epiphyseal devices might be extended.

Extensive risk analysis of mechanical failure for an epiphyseal hip prothesis: a combined numerical-experimental approach.

There has been recent renewed interest in proximal femur epiphyseal replacement as an alternative to conventional total hip replacement. In many branches of engineering, risk analysis has proved to be an efficient tool for avoiding premature failures of innovative devices. An extensive risk analysis procedure has been developed for epiphyseal hip prostheses and the predictions of this method have been compared to the known clinical outcomes of a well-established contemporary design, namely hip resurfacing devices. Clinical scenarios leading to revision (i.e. loosening, neck fracture and failure of the prosthetic component) were associated with potential failure modes (i.e. overload, fatigue, wear, fibrotic tissue differentiation and bone remodelling). Driving parameters of the corresponding failure mode were identified together with their safe thresholds. For each failure mode, a failure criterion was identified and studied under the most relevant physiological loading conditions. All failure modes were investigated with the most suitable investigation tool, either numerical or experimental. Results showed a low risk for each failure scenario either in the immediate postoperative period or in the long term. These findings are in agreement with those reported by the majority of clinical studies for correctly implanted devices. Although further work is needed to confirm the predictions of this method, it was concluded that the proposed risk analysis procedure has the potential to increase the efficacy of preclinical validation protocols for new epiphyseal replacement devices.

Integrated friction measurements in hip wear simulations: short-term results.

Hip joint wear simulators are used extensively to simulate the dynamic behaviour of the human hip joint and, through the wear rate, gain a concrete indicator about the overall wear performance of different coupled bearings. Present knowledge of the dynamic behaviour of important concurrent indicators, such as the coefficient of friction, could prove helpful for the continuing improvement in applied biomaterials. A limited number of commercial or custom-made simulators have been designed specifically for friction studies but always separately from wear tests; thus, analysis of these two important parameters has remained unconnected. As a result, a new friction sensor has been designed, built, and integrated in a commercial biaxial rocking motion hip simulator. The aim of this study is to verify the feasibility of an experimental set-up in which the dynamic measurement of the friction factor could effectively be implemented in a standard wear test without compromising its general accuracy and repeatability. A short wear test was run with the new set-up for 1 x 10(6) cycles. In particular, three soft-bearings (metal-on-polyethylene, phi = 28 mm) were tested; during the whole test, axial load and frictional torque about the vertical loading axis were synchronously recorded in order to calculate the friction factor. Additional analyses were performed on the specimens, before and after the test, in order to verify the accuracy of the wear test. The average friction factor was 0.110 +/- 0.025. The friction sensors showed good accuracy and repeatability throughout. This innovative set-up was able to reproduce stable and reliable measurements. The results obtained encourage further investigations of this set-up for long-term assessment and using different combinations of materials.

Quality control protocol for in vitro micro-computed tomography.

The aim of this work was to present and discuss a quality control protocol for in vitro micro-computed tomography (microCT), based on the adaptation of the quality control protocols for medical computed tomography. The importance of establishing a quality control protocol is related to the opportunity to identify problems on time comparing the microCT images acquired in different time points, and in this way to verify the performance of the device. The proposed quality control protocol was applied for a long-time monitoring period to verify the stability of the micro-tomographic system over time. The protocol proposed in this study was applied to the histomorphometric characterization of bone tissue, but it can be used on a wide range of in vitro microCT applications. Noise and uniformity tests, taken and adapted to micro-tomographic system by medical standard guidelines of quality control, were performed by the use of a water phantom. An accuracy test was designed and performed by the use of a morphometric calibrated phantom. All these tests were performed during a long-time monitoring period to control the stability of the system. Specific control charts and monitoring parameters for each test were used to represent the monthly measures collected during 20 months and an out of control condition was defined. The reference values (baseline), calculated to control the stability of micro-tomographic system over time, were calculated during acceptance/status test. During the period, no out of control conditions in noise, uniformity and accuracy tests were recorded. However, a changing condition was found in noise test, as showed by using statistical C (P < 0.01) and Kruskal-Wallis (P < 0.05) tests. In particular, a Wilcoxon rank sum test with Bonferroni correction (P < 0.0125) was applied in noise test to investigate which of the comparisons among first five acquisitions of year 2004 (group B.L.) and each group was significant (P < 0.0125). The noise showed a slight but significant increase over the years compared to baseline value; however, no out of control conditions were recorded. Nonetheless, a maintenance service to control the performance of mechanical components of microCT was required and performed.

Effect of long-term physiological activity on the long-term stem stability of cemented hip arthroplasty: in vitro comparison of three commercial bone cements.

Long-term endurance of the cement mantle is fundamental for the survival of cemented hip prostheses. Current protocols to characterize bone cements are unsuitable to predict the actual clinical outcome. The aim of this study was to assess if it is possible to rank cement types having diverse clinical outcome by using a simplified in vitro physiological test. Composite femurs were implanted with identical stems (Lubinus-SPII), using different commercial cement types: CMW1 to represent cement with poor clinical outcome; Simplex-P and Cemex-RX to represent cements with a positive clinical outcome. Implanted femurs were subjected to a validated protocol that simulated a demanding but physiological loading spectrum. Inducible micromotions and permanent migrations were recorded throughout the test. After test completion, the cement mantles were sectioned and inspected with dye penetrants to quantify the fatigue-induced cracks. Micromotions did not differ significantly between cement types (possibly because a successful prosthesis was chosen that is very stable in the host bone). Significant differences were observed in terms of cement cracks: CMW1 induced significantly more numerous and larger cracks than Simplex-P and Cemex-RX; no difference was observed between Simplex-P and Cemex-RX. This indicates that this protocol: (a) can discriminate between 'good' and 'bad' cements and (b) yields consistent results when comparable cements are tested. The proposed protocol overcomes the limitations of existing standardized material tests for bone cements. New cements can be assessed in comparison with other cements with known (positive/negative) clinical outcome, tested with the same protocol.