Human biventricular electromechanical simulations on the progression of electrocardiographic and mechanical abnormalities in post-myocardial infarction.

AIMS: Develop, calibrate and evaluate with clinical data a human electromechanical modelling and simulation framework for multiscale, mechanistic investigations in healthy and post-myocardial infarction (MI) conditions, from ionic to clinical biomarkers. METHODS AND RESULTS: Human healthy and post-MI electromechanical simulations were conducted with a novel biventricular model, calibrated and evaluated with experimental and clinical data, including torso/biventricular anatomy from clinical magnetic resonance, state-of-the-art human-based membrane kinetics, excitation-contraction and active tension models, and orthotropic electromechanical coupling. Electromechanical remodelling of the infarct/ischaemic region and the border zone were simulated for ischaemic, acute, and chronic states in a fully transmural anterior infarct and a subendocardial anterior infarct. The results were compared with clinical electrocardiogram and left ventricular ejection fraction (LVEF) data at similar states. Healthy model simulations show LVEF 63%, with 11% peak systolic wall thickening, QRS duration and QT interval of 100 ms and 330 ms. LVEF in ischaemic, acute, and chronic post-MI states were 56%, 51%, and 52%, respectively. In linking the three post-MI simulations, it was apparent that elevated resting potential due to hyperkalaemia in the infarcted region led to ST-segment elevation, while a large repolarization gradient corresponded to T-wave inversion. Mechanically, the chronic stiffening of the infarct region had the benefit of improving systolic function by reducing infarct bulging at the expense of reducing diastolic function by inhibiting inflation. CONCLUSION: Our human-based multiscale modelling and simulation framework enables mechanistic investigations into patho-physiological electrophysiological and mechanical behaviour and can serve as testbed to guide the optimization of pharmacological and electrical therapies.

In-silico human electro-mechanical ventricular modelling and simulation for drug-induced pro-arrhythmia and inotropic risk assessment.

Human-based computational modelling and simulation are powerful tools to accelerate the mechanistic understanding of cardiac patho-physiology, and to develop and evaluate therapeutic interventions. The aim of this study is to calibrate and evaluate human ventricular electro-mechanical models for investigations on the effect of the electro-mechanical coupling and pharmacological action on human ventricular electrophysiology, calcium dynamics, and active contraction. The most recent models of human ventricular electrophysiology, excitation-contraction coupling, and active contraction were integrated, and the coupled models were calibrated using human experimental data. Simulations were then conducted using the coupled models to quantify the effects of electro-mechanical coupling and drug exposure on electrophysiology and force generation in virtual human ventricular cardiomyocytes and tissue. The resulting calibrated human electro-mechanical models yielded active tension, action potential, and calcium transient metrics that are in agreement with experiments for endocardial, epicardial, and mid-myocardial human samples. Simulation results correctly predicted the inotropic response of different multichannel action reference compounds and demonstrated that the electro-mechanical coupling improves the robustness of repolarisation under drug exposure compared to electrophysiology-only models. They also generated additional evidence to explain the partial mismatch between in-silico and in-vitro experiments on drug-induced electrophysiology changes. The human calibrated and evaluated modelling and simulation framework constructed in this study opens new avenues for future investigations into the complex interplay between the electrical and mechanical cardiac substrates, its modulation by pharmacological action, and its translation to tissue and organ models of cardiac patho-physiology.

An orthotropic electro-viscoelastic model for the heart with stress-assisted diffusion.

We propose and analyse the properties of a new class of models for the electromechanics of cardiac tissue. The set of governing equations consists of nonlinear elasticity using a viscoelastic and orthotropic exponential constitutive law, for both active stress and active strain formulations of active mechanics, coupled with a four-variable phenomenological model for human cardiac cell electrophysiology, which produces an accurate description of the action potential. The conductivities in the model of electric propagation are modified according to stress, inducing an additional degree of nonlinearity and anisotropy in the coupling mechanisms, and the activation model assumes a simplified stretch-calcium interaction generating active tension or active strain. The influence of the new terms in the electromechanical model is evaluated through a sensitivity analysis, and we provide numerical validation through a set of computational tests using a novel mixed-primal finite element scheme.

Using Non-linear Homogenization to Improve the Performance of Macroscopic Damage Models of Trabecular Bone.

Realistic macro-level finite element simulations of the mechanical behavior of trabecular bone, a cellular anisotropic material, require a suitable constitutive model; a model that incorporates the mechanical response of bone for complex loading scenarios and includes post-elastic phenomena, such as plasticity (permanent deformations) and damage (permanent stiffness reduction), which bone is likely to experience. Some such models have been developed by conducting homogenization-based multiscale finite element simulations on bone micro-structure. While homogenization has been fairly successful in the elastic regime and, to some extent, in modeling the macroscopic plastic response, it has remained a challenge with respect to modeling damage. This study uses a homogenization scheme to upscale the damage behavior from the tissue level (microscale) to the organ level (macroscale) and assesses the suitability of different damage constitutive laws. Ten cubic specimens were each subjected to 21 strain-controlled load cases for a small range of macroscopic post-elastic strains. Isotropic and anisotropic criteria were considered, density and fabric relationships were used in the formulation of the damage law, and a combined isotropic/anisotropic law with tension/compression asymmetry was formulated, based on the homogenized results, as a possible alternative to the currently used single scalar damage criterion. This computational study enhances the current knowledge on the macroscopic damage behavior of trabecular bone. By developing relationships of damage progression with bone's micro-architectural indices (density and fabric) the study also provides an aid for the creation of more precise macroscale continuum models, which are likely to improve clinical predictions.

Effect of including damage at the tissue level in the nonlinear homogenisation of trabecular bone.

Being able to predict bone fracture or implant stability needs a proper constitutive model of trabecular bone at the macroscale in multiaxial, non-monotonic loading modes. Its macroscopic damage behaviour has been investigated experimentally in the past, mostly with the restriction of uniaxial cyclic loading experiments for different samples, which does not allow for the investigation of several load cases in the same sample as damage in one direction may affect the behaviour in other directions. Homogenised finite element models of whole bones have the potential to assess complicated scenarios and thus improve clinical predictions. The aim of this study is to use a homogenisation-based multiscale procedure to upscale the damage behaviour of bone from an assumed solid phase constitutive law and investigate its multiaxial behaviour for the first time. Twelve cubic specimens were each submitted to nine proportional strain histories by using a parallel code developed in-house. Evolution of post-elastic properties for trabecular bone was assessed for a small range of macroscopic plastic strains in these nine load cases. Damage evolution was found to be non-isotropic, and both damage and hardening were found to depend on the loading mode (tensile, compression or shear); both were characterised by linear laws with relatively high coefficients of determination. It is expected that the knowledge of the macroscopic behaviour of trabecular bone gained in this study will help in creating more precise continuum FE models of whole bones that improve clinical predictions.

Nonlinear homogenisation of trabecular bone: Effect of solid phase constitutive model.

Micro-finite element models have been extensively employed to evaluate the elastic properties of trabecular bone and, to a limited extent, its yield behaviour. The macroscopic stiffness tensor and yield surface are of special interest since they are essential in the prediction of bone strength and stability of implants at the whole bone level. While macroscopic elastic properties are now well understood, yield and post-yield properties are not. The aim of this study is to shed some light on what the effect of the solid phase yield criterion is on the macroscopic yield of trabecular bone for samples with different microstructure. Three samples with very different density were subjected to a large set of apparent load cases (which is important since physiological loading is complex and can have multiple components in stress or strain space) with two different solid phase yield criteria: Drucker-Prager and eccentric-ellipsoid. The study found that these two criteria led to small differences in the macroscopic yield strains for most load cases except for those that were compression-dominated; in these load cases, the yield strains for the Drucker-Prager criterion were significantly higher. Higher density samples resulted in higher differences between the two criteria. This work provides a comprehensive assessment of the effect of two different solid phase yield criteria on the macroscopic yield strains of trabecular bone, for a wide range of load cases, and for samples with different morphology.

Time Dependent Behaviour of Trabecular Bone at Multiple Load Levels.

The deformation of bone when subjected to loads is not instantaneous but varies with time. To investigate this time-dependent behaviour sixteen bovine trabecular bone specimens were subjected to compressive loading, creep, unloading and recovery at multiple load levels corresponding to apparent strains of 2000-25,000 µÎµ. We found that: the time-dependent response of trabecular bone comprises of both recoverable and irrecoverable strains; the strain response is nonlinearly related to applied load levels; and the response is linked to bone volume fraction. Although majority of strain is recovered after the load-creep-unload-recovery cycle some residual strain always exists. The analysis of results indicates that trabecular bone becomes stiffer initially and then experiences stiffness degradation with the increasing load levels. Steady state creep rate was found to be dependent on applied stress level and bone volume fraction with a power law relationship.

Nonlinear viscoelastic characterization of bovine trabecular bone.

The time-independent elastic properties of trabecular bone have been extensively investigated, and several stiffness-density relations have been proposed. Although it is recognized that trabecular bone exhibits time-dependent mechanical behaviour, a property of viscoelastic materials, the characterization of this behaviour has received limited attention. The objective of the present study was to investigate the time-dependent behaviour of bovine trabecular bone through a series of compressive creep-recovery experiments and to identify its nonlinear constitutive viscoelastic material parameters. Uniaxial compressive creep and recovery experiments at multiple loads were performed on cylindrical bovine trabecular bone samples ([Formula: see text]). Creep response was found to be significant and always comprised of recoverable and irrecoverable strains, even at low stress/strain levels. This response was also found to vary nonlinearly with applied stress. A systematic methodology was developed to separate recoverable (nonlinear viscoelastic) and irrecoverable (permanent) strains from the total experimental strain response. We found that Schapery's nonlinear viscoelastic constitutive model describes the viscoelastic response of the trabecular bone, and parameters associated with this model were estimated from the multiple load creep-recovery (MLCR) experiments. Nonlinear viscoelastic recovery compliance was found to have a decreasing and then increasing trend with increasing stress level, indicating possible stiffening and softening behaviour of trabecular bone due to creep. The obtained parameters from MLCR tests, expressed as second-order polynomial functions of stress, showed a similar trend for all the samples, and also demonstrate stiffening-softening behaviour with increasing stress.

Evaluating the macroscopic yield behaviour of trabecular bone using a nonlinear homogenisation approach.

Computational homogenisation approaches using high resolution images and finite element (FE) modelling have been extensively employed to evaluate the anisotropic elastic properties of trabecular bone. The aim of this study was to extend its application to characterise the macroscopic yield behaviour of trabecular bone. Twenty trabecular bone samples were scanned using a micro-computed tomography device, converted to voxelised FE meshes and subjected to 160 load cases each (to define a homogenised multiaxial yield surface which represents several possible strain combinations). Simulations were carried out using a parallel code developed in-house. The nonlinear algorithms included both geometrical and material nonlinearities. The study found that for tension-tension and compression-compression regimes in normal strain space, the yield strains have an isotropic behaviour. However, in the tension-compression quadrants, pure shear and combined normal-shear planes, the macroscopic strain norms at yield have a relatively large variation. Also, our treatment of clockwise and counter-clockwise shears as separate loading cases showed that the differences in these two directions cannot be ignored. A quadric yield surface, used to evaluate the goodness of fit, showed that an isotropic criterion adequately represents yield in strain space though errors with orthotropic and anisotropic criteria are slightly smaller. Consequently, although the isotropic yield surface presents itself as the most suitable assumption, it may not work well for all load cases. This work provides a comprehensive assessment of material symmetries of trabecular bone at the macroscale and describes in detail its macroscopic yield and its underlying microscopic mechanics.

Linear viscoelasticity - bone volume fraction relationships of bovine trabecular bone.

Trabecular bone has been previously recognized as time-dependent (viscoelastic) material, but the relationships of its viscoelastic behaviour with bone volume fraction (BV/TV) have not been investigated so far. Therefore, the aim of the present study was to quantify the time-dependent viscoelastic behaviour of trabecular bone and relate it to BV/TV. Uniaxial compressive creep experiments were performed on cylindrical bovine trabecular bone samples ([Formula: see text]) at loads corresponding to physiological strain level of 2000 [Formula: see text]. We assumed that the bone behaves in a linear viscoelastic manner at this low strain level and the corresponding linear viscoelastic parameters were estimated by fitting a generalized Kelvin-Voigt rheological model to the experimental creep strain response. Strong and significant power law relationships ([Formula: see text]) were found between time-dependent creep compliance function and BV/TV of the bone. These BV/TV-based material properties can be used in finite element models involving trabecular bone to predict time-dependent response. For users' convenience, the creep compliance functions were also converted to relaxation functions by using numerical interconversion methods and similar power law relationships were reported between time-dependent relaxation modulus function and BV/TV.

Benefit of cup medialization in total hip arthroplasty is associated with femoral anatomy.

BACKGROUND: Medialization of the cup with a respective increase in femoral offset has been proposed in THA to increase abductor moment arms. Insofar as there are potential disadvantages to cup medialization, it is important to ascertain whether the purported biomechanical benefits of cup medialization are large enough to warrant the downsides; to date, studies regarding this question have disagreed. QUESTIONS/PURPOSES: The purpose of this study was to quantify the effect of cup medialization with a compensatory increase in femoral offset compared with anatomic reconstruction for patients undergoing THA. We tested the hypothesis that there is a (linear) correlation between preoperative anatomic parameters and muscle moment arm increase caused by cup medialization. METHODS: Fifteen patients undergoing THA were selected, covering a typical range of preoperative femoral offsets. For each patient, a finite element model was built based on a preoperative CT scan. The model included the pelvis, femur, gluteus minimus, medius, and maximus. Two reconstructions were compared: (1) anatomic position of the acetabular center of rotation, and (2) cup medialization compensated by an increase in the femoral offset. Passive abduction-adduction and flexion-extension were simulated in the range of normal gait. Muscle moment arms were evaluated and correlated to preoperative femoral offset, acetabular offset, height of the greater trochanter (relative to femoral center of rotation), and femoral antetorsion angle. RESULTS: The increase of muscle moment arms caused by cup medialization varied among patients. Muscle moment arms increase by 10% to 85% of the amount of cup medialization for abduction-adduction and from -35% (decrease) to 50% for flexion-extension. The change in moment arm was inversely correlated (R(2) = 0.588, p = 0.001) to femoral antetorsion (anteversion), such that patients with less femoral antetorsion gained more in terms of hip muscle moments. No linear correlation was observed between changes in moment arm and other preoperative parameters in this series. CONCLUSIONS: The benefit of cup medialization is variable and depends on the individual anatomy. CLINICAL RELEVANCE: Cup medialization with compensatory increase of the femoral offset may be particularly effective in patients with less femoral antetorsion. However, cup medialization must be balanced against its tradeoffs, including the additional loss of medial acetabular bone stock, and eventual proprioceptive implications of the nonanatomic center of rotation and perhaps joint reaction forces. Clinical studies should better determine the relevance of small changes of moment arms on function and joint reaction forces.