In silico clinical trials: how computer simulation will transform the biomedical industry

The term ‘in silico clinical trials indicates the use of individualised computer simulation in the development or regulatory evaluation of a medicinal product, medical device, or medical intervention. This review article summarises the research and technological roadmap developed by the Avicenna Support Action during an 18 month consensus process that involved 577 international experts from academia, the biomedical industry, the simulation industry, the regulatory world, etc. The roadmap documents early examples of in silico clinical trials, identifies relevant use cases for in silico clinical trial technologies over the entire development and assessment cycle for both pharmaceuticals and medical devices, identifies open challenges and barriers to a wider adoption and puts forward 36 recommendations for all relevant stakeholders to consider

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 positon 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 (R²=0.74, SEE=1473N) outperformed the best densitometric predictor (Neck_aBMD, R²=0.66, SEE=1687N) but not the QCT-based FE models (R²=0.80, SEE=1314N). For the SIDE configuration both QCT-based FE models (R²=0.85, SEE=455N) and DXA neck aBMD (R²=0.80, SEE=502N) outperformed DXA-based FE models (R²=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

Development of a protocol to quantify local bone adaptation over space and time: quantification of reproducibility

In vivo micro-computed tomography (μCT) scanning of small rodents is a powerful method for longitudinal monitoring of bone adaptation. However, the life-time bone growth in small rodents makes it a challenge to quantify local bone adaptation. Therefore, the aim of this study was to develop a protocol, which can take into account large bone growth, to quantify local bone adaptations over space and time. The entire right tibiae of eight 14-week-old C57BL/6J female mice were consecutively scanned four times in an in vivo μCT scanner using a nominal isotropic image voxel size of 10.4 μm. The repeated scan image datasets were aligned to the corresponding baseline (first) scan image dataset using rigid registration. 80% of tibia length (starting from the endpoint of the proximal growth plate) was selected as the volume of interest and partitioned into 40 regions along the tibial long axis (10 divisions) and in the cross-section (4 sectors). The bone mineral content (BMC) was used to quantify bone adaptation and was calculated in each region. All local BMCs have precision errors (PE%CV) of less than 3.5% (24 out of 40 regions have PE%CV of less than 2%), least significant changes (LSCs) of less than 3.8%, and 38 out of 40 regions have intraclass correlation coefficients (ICCs) of over 0.8. The proposed protocol allows to quantify local bone adaptations over an entire tibia in longitudinal studies, with a high reproducibility, an essential requirement to reduce the number of animals to achieve the necessary statistical power

Muscle recruitment strategies can reduce joint loading during level walking

Joint inflammation, with consequent cartilage damage and pain, typically reduces functionality and affects activities of daily life in a variety of musculoskeletal diseases. Since mechanical loading is an important determinant of the disease process, a possible conservative treatment is the unloading of joints. In principle, a neuromuscular rehabilitation program aimed to promote alternative muscle recruitments could reduce the loads on the lower-limb joints during walking. The extent of joint load reduction one could expect from this approach remains unknown. Furthermore, assuming significant reductions of the load on the affected joint can be achieved, it is unclear whether, and to what extent, the other joints will be overloaded. Using subject-specific musculoskeletal models of four different participants, we computed the muscle recruitment strategies that minimised the hip, knee and ankle contact force, and predicted the contact forces such strategies induced at the other joints. Significant reductions of the peak force and impulse at the knee and hip were obtained, while only a minimal effect was found at the ankle joint. Adversely, the peak force and the impulse in non-targeted joints increased when aiming to minimize the load in an adjacent joint. These results confirm the potential of alternative muscle recruitment strategies to reduce the loading at the knee and the hip, but not at the ankle. Therefore, neuromuscular rehabilitation can be targeted to reduce the loading at affected joints but must be considered carefully in patients with multiple joints affected due to the potential adverse effects in non-targeted joints

Micro Finite Element models of the vertebral body: Validation of local displacement predictions

The estimation of local and structural mechanical properties of bones with micro Finite Element (microFE) models based on Micro Computed Tomography images depends on the quality bone geometry is captured, reconstructed and modelled. The aim of this study was to validate microFE models predictions of local displacements for vertebral bodies and to evaluate the effect of the elastic tissue modulus on model’s predictions of axial forces. Four porcine thoracic vertebrae were axially compressed in situ, in a step-wise fashion and scanned at approximately 39μm resolution in preloaded and loaded conditions. A global digital volume correlation (DVC) approach was used to compute the full-field displacements. Homogeneous, isotropic and linear elastic microFE models were generated with boundary conditions assigned from the interpolated displacement field measured from the DVC. Measured and predicted local displacements were compared for the cortical and trabecular compartments in the middle of the specimens. Models were run with two different tissue moduli defined from microindentation data (12.0GPa) and a back-calculation procedure (4.6GPa). The predicted sum of axial reaction forces was compared to the experimental values for each specimen. MicroFE models predicted more than 87% of the variation in the displacement measurements (R2 = 0.87–0.99). However, model predictions of axial forces were largely overestimated (80–369%) for a tissue modulus of 12.0GPa, whereas differences in the range 10–80% were found for a back-calculated tissue modulus. The specimen with the lowest density showed a large number of elements strained beyond yield and the highest predictive errors. This study shows that the simplest microFE models can accurately predict quantitatively the local displacements and qualitatively the strain distribution within the vertebral body, independently from the considered bone types

Investigation of the dependence of joint contact forces on musculotendon parameters using a codified workflow for image-based modelling

The generation of subject-specific musculoskeletal models of the lower limb has become a feasible taskthanks to improvements in medical imaging technology and musculoskeletal modelling software.Nevertheless, clinical use of these models in paediatric applications is still limited for what concernsthe estimation of muscle and joint contact forces. Aiming to improve the current state of the art, amethodology to generate highly personalized subject-specific musculoskeletal models of the lower limbbased on magnetic resonance imaging (MRI) scans was codified as a step-by-step procedure and appliedto data from eight juvenile individuals. The generated musculoskeletal models were used to simulate 107gait trials using stereophotogrammetric and force platform data as input. To ensure completeness of themodelling procedure, muscles’ architecture needs to be estimated. Four methods to estimate muscles’maximum isometric force and two methods to estimate musculotendon parameters (optimal fiber lengthand tendon slack length) were assessed and compared, in order to quantify their influence on the models’output. Reported results represent the first comprehensive subject-specific model-based characterizationof juvenile gait biomechanics, including profiles of joint kinematics and kinetics, muscle forces and jointcontact forces. Our findings suggest that, when musculotendon parameters were linearly scaled from areference model and the muscle force-length-velocity relationship was accounted for in the simulations,realistic knee contact forces could be estimated and these forces were not sensitive the method used tocompute muscle maximum isometric force

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

Local displacement and strain uncertainties in different bone types by digital volume correlation of synchrotron microtomograms

Understanding bone mechanics at different hierarchical levels is fundamental to improve preclinical and clinical assessments of bone strength. Digital Volume Correlation (DVC) is the only experimental measurement technique used for measuring local displacements and calculating local strains within bones. To date, its combination with laboratory source micro-computed tomography (LS-microCT) data typically leads to high uncertainties, which limit its application. Here, the benefits of synchrotron radiation micro-computed tomography (SR-microCT) for DVC are reported. Specimens of cortical and trabecular bovine bone and murine tibiae, were each scanned under zero-strain conditions with an effective voxel size of 1.6 μm. In order to consider the effect of the voxel size, analyses were also performed on downsampled images with voxel size of 8 μm. To evaluate displacement and strain uncertainties, each pair of tomograms was correlated using a global DVC algorithm (ShIRT-FE). Displacement random errors for original SR-microCT ranged from 0.024 to 0.226 μm, depending on DVC nodal spacing. Standard deviation of strain errors was below 200 microstrain (ca. 1/10 of the strain associated with physiological loads) for correlations performed with a measurement spatial resolution better than 40 μm for cortical bovine bone (240 μm for downsampled images), 80 μm for trabecular bovine bone (320 μm for downsampled images) and murine tibiae (120 μm for downsampled images). This study shows that the uncertainties of SR-microCT-based DVC, estimated from repeated scans, are lower than those obtained from LS-microCT-based DVC on similar specimens and low enough to measure accurately the local deformation at the tissue level

A new method to monitor bone geometry changes at different spatial scales in the longitudinal in vivo μCT studies of mice bones

Longitudinal studies of bone adaptation in mice using in vivo micro-computed tomography (μCT) have been commonly used for pre-clinical evaluation of physical and pharmacological interventions. The main advantage of this approach is to use each mouse as its own control, reducing considerably the sample size required by statistical power analysis. To date, multi-scale estimation of bone adaptations become essential since the bone activity that takes place at different scales may be associated with different bone mechanisms. Measures of bone adaptations at different time scales have been attempted in a previous study. This paper extends quantification of bone activity at different spatial scales with a proposition of a novel framework. The method involves applying level-set method (LSM) to track the geometric changes from the longitudinal in vivo μCT scans of mice tibia. Bone low- and high-spatial frequency patterns are then estimated using multi-resolution analysis. The accuracy of the framework is quantified by applying it to two times separated scanned images with synthetically manipulated global and/or local activity. The Root Mean Square Deviation (RMSD) was approximately 1.5 voxels or 0.7 voxels for the global low-spatial frequency or local high-spatial frequency changes, respectively. The framework is further applied to the study of bone changes in longitudinal datasets of wild-type mice tibiae over time and space. The results demonstrate the ability for the spatio-temporal quantification and visualisation of bone activity at different spatial scales in longitudinal studies thus providing further insight into bone adaptation mechanisms