Significance of preoperative planning for prophylactic augmentation of osteoporotic hip: A computational modeling study

A potential effective treatment for prevention of osteoporotic hip fractures is augmentation of the mechanical properties of the femur by injecting it with bone cement. This therapy, however, is only in research stage and can benefit substantially from computational simulations to optimize the pattern of cement injection. Some studies have considered a patient-specific planning paradigm for Osteoporotic Hip Augmentation (OHA). Despite their biomechanical advantages, customized plans require advanced surgical systems for implementation. Other studies, therefore, have suggested a more generalized injection strategy. The goal of this study is to investigate as to whether the additional computational overhead of the patient-specific planning can significantly improve the bone strength as compared to the generalized injection strategies attempted in the literature. For this purpose, numerical models were developed from high resolution CT images (n = 4). Through finite element analysis and hydrodynamic simulations, we compared the biomechanical efficiency of the customized cement-based augmentation along with three generalized injection strategies developed previously. Two series of simulations were studied, one with homogeneous and one with inhomogeneous material properties for the osteoporotic bone. The customized cement-based augmentation inhomogeneous models showed that injection of only 10 ml of bone cement can significantly increase the yield load (79.6%, P < 0.01) and yield energy (199%, P < 0.01) of an osteoporotic femur. This increase is significantly higher than those of the generalized injections proposed previously (23.8% on average). Our findings suggest that OHA can significantly benefit from a patient-specific plan that determines the pattern and volume of the injected cement.     

Subject-specific modeling of the scapula bone tissue adaptation

Adaptation of the scapula bone tissue to mechanical loading is simulated in the current study using a subject-specific three-dimensional finite element model of an intact cadaveric scapula. The loads experienced by the scapula during different types of movements are determined using a subject-specific large-scale musculoskeletal model of the shoulder joint. The obtained density distributions are compared with the CT-measured density distribution of the same scapula. Furthermore, it is assumed that the CT-measured density distribution can be estimated as a weighted linear combination of the density distributions calculated for different loads experienced during daily life. An optimization algorithm is used to determine the weighting factors of fourteen different loads such that the difference between the weighted linear combination of the calculated density distributions and the CT-measured density is minimal. It is shown that the weighted linear combination of the calculated densities matches the CT-measured density distribution better than every one of the density distributions calculated for individual movements. The weighting factors of nine out of fourteen loads were estimated to be zero or very close to zero. The five loads that had larger weighting factors were associated with either one of the following categories: (1) small-load small-angle abduction or flexion movements that occur frequently during our daily lives or (2) large-load large-angle abduction or flexion movements that occur infrequently during our daily lives.     

3D finite element model of the diabetic neuropathic foot: A gait analysis driven approach

Diabetic foot is an invalidating complication of diabetes that can lead to foot ulcers. Three-dimensional (3D) finite element analysis (FEA) allows characterizing the loads developed in the different anatomical structures of the foot in dynamic conditions. The aim of this study was to develop a subject specific 3D foot FE model (FEM) of a diabetic neuropathic (DNS) and a healthy (HS) subject, whose subject specificity can be found in term of foot geometry and boundary conditions. Kinematics, kinetics and plantar pressure (PP) data were extracted from the gait analysis trials of the two subjects with this purpose. The FEM were developed segmenting bones, cartilage and skin from MRI and drawing a horizontal plate as ground support. Materials properties were adopted from previous literature. FE simulations were run with the kinematics and kinetics data of four different phases of the stance phase of gait (heel strike, loading response, midstance and push off). FEMs were then driven by group gait data of 10 neuropathic and 10 healthy subjects. Model validation focused on agreement between FEM-simulated and experimental PP.     

A modelling approach demonstrating micromechanical changes in the tibial cemented interface due to in vivo service

Post-operative changes in trabecular bone morphology at the cement-bone interface can vary depending on time in service. This study aims to investigate how micromotion and bone strains change at the tibial bone-cement interface before and after cementation. This work discusses whether the morphology of the post-mortem interface can be explained by studying changes in these mechanical quantities. Three post-mortem cement-bone interface specimens showing varying levels of bone resorption (minimal, extensive and intermediate) were selected for this study Using image segmentation techniques, masks of the post-mortem bone were dilated to fill up the mould spaces in the cement to obtain the immediately post-operative situation. Finite element (FE) models of the post-mortem and post-operative situation were created from these segmentation masks. Subsequent removal of the cement layer resulted in the pre-operative situation. FE micromotion and bone strains were analyzed for the interdigitated trabecular bone. For all specimens micromotion increased from the post-operative to the post-mortem models (distally, in specimen 1: 0.1 to 0.5 µm; specimen 2: 0.2 to 0.8 µm; specimen 3: 0.27 to 1.62 µm). Similarly bone strains were shown to increase from post-operative to post-mortem (distally, in specimen 1: −185 to −389 µε; specimen 2: −170 to −824 µε; specimen 3: −216 to −1024 µε). Post-mortem interdigitated bone was found to be strain shielded in comparison with supporting bone indicating that failure of bone would occur distal to the interface. These results indicate that stress shielding of interdigitated trabeculae is a plausible explanation for resorption patterns observed in post-mortem specimens.     

Combining specimen-specific finite-element models and optimization in cortical-bone material characterization improves prediction accuracy in three-point bending tests

Although the beam theory is widely used for calculating material parameters in three-point bending test, it cannot accurately describe the biomechanical properties of specimens after the yield. Hence, we propose a finite element (FE) based optimization method to obtain accurate bone material parameters from three-point bending test. We tested 80 machined bovine cortical bone specimens at both longitudinal and transverse directions using three-point bending. We then adopted the beam theory and the FE-based optimization method combined with specimen-specific FE models to derive the material parameters of cortical bone. We compared data obtained using these two methods and further evaluated two groups of parameters with three-point bending simulations. Our data indicated that the FE models with material properties from the FE-based optimization method showed best agreements with experimental data for the entire force-displacement responses, including the post-yield region. Using the beam theory, the yield stresses derived from 0.0058% strain offset for the longitudinal specimen and 0.0052% strain offset for the transverse specimen are closer to those derived from the FE-based optimization method, compared to yield stresses calculated without strain offset. In brief, we conclude that the optimization FE method is more appropriate than the traditional beam theory in identifying the material parameters of cortical bone for improving prediction accuracy in three-point bending mode. Given that the beam theory remains as a popular method because of its efficiency, we further provided correction functions to adjust parameters calculated from the beam theory for accurate FE simulation.     

The influence of nano MgO and BaSO4 particle size additives on properties of PMMA bone cement

A common technique to aid in implant fixation into surrounding bone is to inject bone cement into the space between the implant and surrounding bone. The most common bone cement material used clinically today is poly(methyl methacrylate), or PMMA. Although promising, there are numerous disadvantages of using PMMA in bone fixation applications which has limited its wide spread use. Specifically, the PMMA polymerization reaction is highly exothermic in situ, thus, damaging surrounding bone tissue while curing. In addition, PMMA by itself is not visible using typical medical imaging techniques (such as X-rays required to assess new bone formation surrounding the implant). Lastly, although PMMA does support new bone growth, studies have highlighted decreased osteoblast (bone forming cell) functions on PMMA compared to other common orthopedic coating materials, such as calcium phosphates and hydroxyapatite. For these reasons, the goal of this study was to begin to investigate novel additives to PMMA which can enhance its cytocompatibility properties with osteoblasts, decrease its exothermic reaction when curing, and increase its radiopacity. Results of this study demonstrated that compared to conventional (or micron) equivalents, PMMA with nanoparticles of MgO and BaSO4 reduced harmful exothermic reactions of PMMA during solidification and increased radiopacity, respectively. Moreover, osteoblast adhesion increased on PMMA with nanoparticles of MgO and BaSO4 compared with PMMA alone. This study, thus, suggests that nanoparticles of MgO and BaSO4 should be further studied for improving properties of PMMA for orthopedic applications.     

A combined passive and active musculoskeletal model study to estimate L4-L5 load sharing

A number of geometrically-detailed passive finite element (FE) models of the lumbar spine have been developed and validated under in vitro loading conditions. These models are devoid of muscles and thus cannot be directly used to simulate in vivo loading conditions acting on the lumbar joint structures or spinal implants. Gravity loads and muscle forces estimated by a trunk musculoskeletal (MS) model under twelve static activities were applied to a passive FE model of the L4-L5 segment to estimate load sharing among the joint structures (disc, ligaments, and facets) under simulated in vivo loading conditions. An equivalent follower (FL), that generates IDP equal to that generated by muscle forces, was computed in each task. Results indicated that under in vivo loading conditions, the passive FE model predicted intradiscal pressures (IDPs) that closely matched those measured under the simulated tasks (R² = 0.98 and root-mean-squared-error, RMSE = 0.18 MPa). The calculated equivalent FL compared well with the resultant force of all muscle forces and gravity loads acting on the L4-L5 segment (R² = 0.99 and RMSE = 58 N). Therefore, as an alternative approach to represent in vivo loading conditions in passive FE model studies, this FL can be estimated by available in-house or commercial MS models. In clinical applications and design of implants, commonly considered in vitro loading conditions on the passive FE models do not adequately represent the in vivo loading conditions under muscle exertions. Therefore, more realistic in vivo loading conditions should instead be used.     

A hierarchical approach to ecosystem assessment of restoration planning at regional,catchment and local scales in Japan

A hierarchical approach to restoration planning at the regional, catchment and local scales is proposed and examined. Restoration projects limited to a local scale and focused on habitat improvement for individual species ended in failure, which has led to the recognition that there is a need for ecosystem-based management at the landscape level. The first landscape-level restoration in Japan is under way in the Kushiro and Shibetsu River Basins, in northern Japan. However, public consensus on these large-scale restoration projects has not yet matured and there are very few projects that have progressed even as far as mapping to classify intact and disturbed ecosystems. Classification of habitat quality using physical and biological indicators appears to be the core element of analysis of ecological degradation at the regional scale (100–1,000 km²). This mass-screening process is critical to identify areas in potential need of restoration. The causes and mechanisms of ecosystem degradation are then examined at the catchment scale (10–100 km²) by linking material flows and habitat conditions. Direct environmental gradient analysis is useful to determine cause and effect relationships between species and habitat quality. Finally, we recommend implementation of field experiments with a clear hypothesis at the local scale (0.01–1 km²). At this stage, key variables causing degradation of the target ecosystem are manipulated to verify the hypothesis. Based on the results of local-scale analyses, the possibility of restoration success can be evaluated, which directs us to practical schemes for future restoration projects at larger scales.     

Anisometry Anterior Cruciate Ligament Sport Injury Mechanism Study: A Finite Element Model with Optimization Method

ACL damage is one the most frequent causes of knee injuries and thus has long been the focus of research in biomechanics and sports medicine. Due to the anisometric geometry and functional complexity of the ACL in the knee joint, it is usually difficult to experimentally study the biomechanics of ACLs. Anatomically ACL geometry was obtained from both MR images and anatomical observations. The optimal material parameters of the ACL were obtained by using an optimization-based material identification method that minimized the differences between experimental results from ACL specimens and FE simulations. The optimal FE model simulated biomechanical responses of the ACL during complex combined injury-causing knee movements, it predicted stress concentrations on the top and middle side of the posterolateral (PL) bundles. This model was further validated by a clinical case of ACL injury diagnosed by MRI and arthroscope, it demonstrated that the locations of rupture in the patient’s knee corresponded to those where the stresses and moments were predicted to be concentrated. The result implies that varus rotation played a contributing but secondary role in injury under combined movements, the ACL elevation angle, is positive correlated with the tensional loading tolerance of the ACL.     

A model-based approach for estimation of changes in lumbar segmental kinematics associated with alterations in trunk muscle forces

The kinematics information from imaging, if combined with optimization-based biomechanical models, may provide a unique platform for personalized assessment of trunk muscle forces (TMFs). Such a method, however, is feasible only if differences in lumbar spine kinematics due to differences in TMFs can be captured by the current imaging techniques. A finite element model of the spine within an optimization procedure was used to estimate segmental kinematics of lumbar spine associated with five different sets of TMFs. Each set of TMFs was associated with a hypothetical trunk neuromuscular strategy that optimized one aspect of lower back biomechanics. For each set of TMFs, the segmental kinematics of lumbar spine was estimated for a single static trunk flexed posture involving, respectively, 40° and 10° of thoracic and pelvic rotations. Minimum changes in the angular and translational deformations of a motion segment with alterations in TMFs ranged from 0° to 0.7° and 0 mm to 0.04 mm, respectively. Maximum changes in the angular and translational deformations of a motion segment with alterations in TMFs ranged from 2.4° to 7.6° and 0.11 mm to 0.39 mm, respectively. The differences in kinematics of lumbar segments between each combination of two sets of TMFs in 97% of cases for angular deformation and 55% of cases for translational deformation were within the reported accuracy of current imaging techniques. Therefore, it might be possible to use image-based kinematics of lumbar segments along with computational modeling for personalized assessment of TMFs.     

A simplified model of scar contraction

The healing of wounds is a complex process and the contraction of the resulting scar can have a negative impact on the neighbouring skin. A finite element model of skin simulating the contraction of a scar and deformation of the surrounding skin is presented. The skin is represented by an orthotropic–viscoelastic constitutive law, which is validated against experimental data in the literature. A simplified experimental model of a contracting scar in real skin is also developed. The pattern and size of the wrinkles formed around the contracting scar in the finite element model compare favourably with those formed in the experimental model. The orthotropic nature of skin plays a significant role in the behaviour of skin around scars—the wrinkles have a preferential orientation that corresponds to a direction perpendicular to the Langer's lines in the skin. The pre-stress in skin (a property that is ignored in many skin models) is shown to be an important factor in wrinkle formation around scars. The proposed model can be used to analyse the suturing and closure of wounds of various shapes.     

Automatic VMAT planning for post-operative prostate cancer cases using particle swarm optimization: A proof of concept study

ObjectiveTo investigate the potential of Particle Swarm Optimization (PSO) for fully automatic VMAT radiotherapy (RT) treatment planning.Material and MethodsIn PSO a solution space of planning constraints is searched for the best possible RT plan in an iterative, statistical method, optimizing a population of candidate solutions. To identify the best candidate solution and for final evaluation a plan quality score (PQS), based on dose volume histogram (DVH) parameters, was introduced.Automatic PSO-based RT planning was used for N = 10 postoperative prostate cancer cases, retrospectively taken from our clinical database, with a prescribed dose of EUD = 66 Gy in addition to two constraints for rectum and one for bladder. Resulting PSO-based plans were compared dosimetrically to manually generated VMAT plans.ResultsPSO successfully proposed treatment plans comparable to manually optimized ones in 9/10 cases. The median (range) PTV EUD was 65.4 Gy (64.7–66.0) for manual and 65.3 Gy (62.5–65.5) for PSO plans, respectively. However PSO plans achieved significantly lower doses in rectum D_2% 67.0 Gy (66.5–67.5) vs. 66.1 Gy (64.7–66.5, p = 0.016). All other evaluated parameters (PTV D_98% and D_2%, rectum V_40Gy and V_60Gy, bladder D_2% and V_60Gy) were comparable in both plans. Manual plans had lower PQS compared to PSO plans with −0.82 (−16.43–1.08) vs. 0.91 (−5.98–6.25).ConclusionPSO allows for fully automatic generation of VMAT plans with plan quality comparable to manually optimized plans. However, before clinical implementation further research is needed concerning further adaptation of PSO-specific parameters and the refinement of the PQS.     

A topology optimization based model of bone adaptation

A novel topology optimization model based on homogenization methods was developed for predicting bone density distribution and anisotropy, assuming the bone structure to be a self-optimizing biological material which maximizes its own structural stiffness. The feasibility and efficiency of this method were tested on a 2D model for a proximal femur under single and multiple loading conditions. The main aim was to compute homogenized optimal designs using an optimal laminated microstructure. The computational results showed that high bone density levels are distributed along the diaphysis and form arching struts within the femoral head. The pattern of bone density distribution and the anisotropic bone behavior predicted by the model in the multiple load case were both in good agreement with the structural architecture and bone density distribution occurring in natural femora. This approach provides a novel means of understanding the remodeling processes involved in fracture repair and the treatment of bone diseases.     

A biomechanical model of Peyronie's disease

Peyronie's disease is a pathological condition of the penis which is characterized by localized ossification of the tunica albuginea. A common symptom of the chronic stage is penile deformity during erection, which is frequently associated with pain and erectile dysfunction. A two-dimensional biomechanical model of the penis was applied to study the development of Peyronie’s disease by simulating the mechanical stress distribution which would result from the interaction of the ossified tunical tissue with other penile soft tissues. The model was solved by using commercial finite element software for a characteristic erectile pressure. The results demonstrate that Peyronie’s plaques may induce intensified stresses around the penile nerves and blood vessels, up to double those in the normal penis. These elevated stresses may cause a painful sensation of neural origin or ischemia in regions of compressed vascular tissue. Severe penile deformities have been shown to develop if Peyronie’s plaques develop only around one of the corpora cavernosa due to the non-homogeneous resistance of the tunica to expansion during erection. The present model can be clinically applied as an aid in the planning process of reconstructive surgery or insertion of a prosthesis.     

A combined experimental and mathematical approach for molecular-based optimization of irinotecan circadian delivery

Circadian timing largely modifies efficacy and toxicity of many anticancer drugs. Recent findings suggest that optimal circadian delivery patterns depend on the patient genetic background. We present here a combined experimental and mathematical approach for the design of chronomodulated administration schedules tailored to the patient molecular profile. As a proof of concept we optimized exposure of Caco-2 colon cancer cells to irinotecan (CPT11), a cytotoxic drug approved for the treatment of colorectal cancer. CPT11 was bioactivated into SN38 and its efflux was mediated by ATP-Binding-Cassette (ABC) transporters in Caco-2 cells. After cell synchronization with a serum shock defining Circadian Time (CT) 0, circadian rhythms with a period of 26 h 50 (SD 63 min) were observed in the mRNA expression of clock genes REV-ERBα, PER2, BMAL1, the drug target topoisomerase 1 (TOP1), the activation enzyme carboxylesterase 2 (CES2), the deactivation enzyme UDP-glucuronosyltransferase 1, polypeptide A1 (UGT1A1), and efflux transporters ABCB1, ABCC1, ABCC2 and ABCG2. DNA-bound TOP1 protein amount in presence of CPT11, a marker of the drug PD, also displayed circadian variations. A mathematical model of CPT11 molecular pharmacokinetics-pharmacodynamics (PK-PD) was designed and fitted to experimental data. It predicted that CPT11 bioactivation was the main determinant of CPT11 PD circadian rhythm. We then adopted the therapeutics strategy of maximizing efficacy in non-synchronized cells, considered as cancer cells, under a constraint of maximum toxicity in synchronized cells, representing healthy ones. We considered exposure schemes in the form of an initial concentration of CPT11 given at a particular CT, over a duration ranging from 1 to 27 h. For any dose of CPT11, optimal exposure durations varied from 3h40 to 7h10. Optimal schemes started between CT2h10 and CT2h30, a time interval corresponding to 1h30 to 1h50 before the nadir of CPT11 bioactivation rhythm in healthy cells.     

A multiscale model for eccentric and concentric cardiac growth through sarcomerogenesis

We present a novel computational model for maladaptive cardiac growth in which kinematic changes of the cardiac chambers are attributed to alterations in cytoskeletal architecture and in cellular morphology. We adopt the concept of finite volume growth characterized through the multiplicative decomposition of the deformation gradient into an elastic part and a growth part. The functional form of its growth tensor is correlated to sarcomerogenesis, the creation and deposition of new sarcomere units. In response to chronic volume-overload, an increased diastolic wall strain leads to the addition of sarcomeres in series, resulting in a relative increase in cardiomyocyte length, associated with eccentric hypertrophy and ventricular dilation. In response to chronic pressure-overload, an increased systolic wall stress leads to the addition of sacromeres in parallel, resulting in a relative increase in myocyte cross sectional area, associated with concentric hypertrophy and ventricular wall thickening. The continuum equations for both forms of maladaptive growth are discretized in space using a nonlinear finite element approach, and discretized in time using the implicit Euler backward scheme. We explore a generic bi-ventricular heart model in response to volume- and pressure-overload to demonstrate how local changes in cellular morphology translate into global alterations in cardiac form and function.     

A combined molecular dynamics and diffusion model of single proton conduction through gramicidin

We develop a model for proton conduction through gramicidin based on the molecular dynamics simulations of Pomès and Roux (Biophys. J. 72:A246, 1997). The transport of a single proton through the gramicidin pore is described by a potential of mean force and diffusion coefficient obtained from the molecular dynamics. In addition, the model incorporates the dynamics of a defect in the hydrogen bonding structure of pore waters without an excess proton. Proton entrance and exit were not simulated by the molecular dynamics. The single proton conduction model includes a simple representation of these processes that involves three free parameters. A reasonable value can be chosen for one of these, and the other two can be optimized to yield a good fit to the proton conductance data of, Ann. N.Y. Acad. Sci. 339:8-20) for pH > or = 1.7. A sensitivity analysis shows the significance of this fit.     

A new cell-based FE model for the mechanics of embryonic epithelia

In order to overcome a significant stiffening artefact associated with current finite element (FE) models for the mechanics of embryonic epithelia, two new FE formulations were developed. Cell–cell interfacial tensions γ are represented by constant-force rod elements as in previous models. However, the viscosity of the cytoplasm with its embedded organelles and filament networks is modeled using viscous triangular elements, it is modeled using either radial and circumferential dashpots or an orthogonal dashpot system rather than the viscous triangular elements typical of previous two-dimensional FE models. The models are tested against tissue (epithelium) stretching because it gives rise to significant changes in cell shape and against cell sorting because it involves high rates of cell rearrangement. The orthogonal dashpot system is found to capture cell size and shape effects well, give the model cells characteristics that are consistent with those of real cells, provide high computational efficiency and hold promise for future three-dimensional analyses.