What Has Finite Element Analysis Taught Us about Diabetic Foot Disease and Its Management? A Systematic Review

Background

Over the past two decades finite element (FE) analysis has become a popular tool for researchers seeking to simulate the biomechanics of the healthy and diabetic foot. The primary aims of these simulations have been to improve our understanding of the foot’s complicated mechanical loading in health and disease and to inform interventions designed to prevent plantar ulceration, a major complication of diabetes. This article provides a systematic review and summary of the findings from FE analysis-based computational simulations of the diabetic foot.

Methods

A systematic literature search was carried out and 31 relevant articles were identified covering three primary themes: methodological aspects relevant to modelling the diabetic foot; investigations of the pathomechanics of the diabetic foot; and simulation-based design of interventions to reduce ulceration risk.

Results

Methodological studies illustrated appropriate use of FE analysis for simulation of foot mechanics, incorporating nonlinear tissue mechanics, contact and rigid body movements. FE studies of pathomechanics have provided estimates of internal soft tissue stresses, and suggest that such stresses may often be considerably larger than those measured at the plantar surface and are proportionally greater in the diabetic foot compared to controls. FE analysis allowed evaluation of insole performance and development of new insole designs, footwear and corrective surgery to effectively provide intervention strategies. The technique also presents the opportunity to simulate the effect of changes associated with the diabetic foot on non-mechanical factors such as blood supply to local tissues.

Discussion

While significant advancement in diabetic foot research has been made possible by the use of FE analysis, translational utility of this powerful tool for routine clinical care at the patient level requires adoption of cost-effective (both in terms of labour and computation) and reliable approaches with clear clinical validity for decision making.     

A multibody knee model with discrete cartilage prediction of tibio-femoral contact mechanics

Combining musculoskeletal simulations with anatomical joint models capable of predicting cartilage contact mechanics would provide a valuable tool for studying the relationships between muscle force and cartilage loading. As a step towards producing multibody musculoskeletal models that include representation of cartilage tissue mechanics, this research developed a subject-specific multibody knee model that represented the tibia plateau cartilage as discrete rigid bodies that interacted with the femur through deformable contacts. Parameters for the compliant contact law were derived using three methods: (1) simplified Hertzian contact theory, (2) simplified elastic foundation contact theory and (3) parameter optimisation from a finite element (FE) solution. The contact parameters and contact friction were evaluated during a simulated walk in a virtual dynamic knee simulator, and the resulting kinematics were compared with measured in vitro kinematics. The effects on predicted contact pressures and cartilage–bone interface shear forces during the simulated walk were also evaluated. The compliant contact stiffness parameters had a statistically significant effect on predicted contact pressures as well as all tibio-femoral motions except flexion–extension. The contact friction was not statistically significant to contact pressures, but was statistically significant to medial–lateral translation and all rotations except flexion–extension. The magnitude of kinematic differences between model formulations was relatively small, but contact pressure predictions were sensitive to model formulation. The developed multibody knee model was computationally efficient and had a computation time 283 times faster than a FE simulation using the same geometries and boundary conditions.     

A finite element model of myocardial infarction using a composite material approach

Computational models are effective tools to study cardiac mechanics under normal and pathological conditions. They can be used to gain insight into the physiology of the heart under these conditions while they are adaptable to computer assisted patient-specific clinical diagnosis and therapeutic procedures. Realistic cardiac mechanics models incorporate tissue active/passive response in conjunction with hyperelasticity and anisotropy. Conventional formulation of such models leads to mathematically-complex problems usually solved by custom-developed non-linear finite element (FE) codes. With a few exceptions, such codes are not available to the research community. This article describes a computational cardiac mechanics model developed such that it can be implemented using off-the-shelf FE solvers while tissue pathologies can be introduced in the model in a straight-forward manner. The model takes into account myocardial hyperelasticity, anisotropy, and active contraction forces. It follows a composite tissue modeling approach where the cardiac tissue is decomposed into two major parts: background and myofibers. The latter is modelled as rebars under initial stresses mimicking the contraction forces. The model was applied in silico to study the mechanics of infarcted left ventricle (LV) of a canine. End-systolic strain components, ejection fraction, and stress distribution attained using this LV model were compared quantitatively and qualitatively to corresponding data obtained from measurements as well as to other corresponding LV mechanics models. This comparison showed very good agreement.     

Subject-specific geometry affects acetabular contact pressure during gait more than subject-specific loading patterns

Abstract

Finite element modeling (FEM) can predict hip cartilage contact mechanics. This study investigated how subject-specific boundary conditions and joint geometry affect acetabular cartilage contact mechanics using a multi-scale workflow. For two healthy subjects, musculoskeletal models calculated subject-specific hip kinematics and loading, which were used as boundary conditions for FEM. Cartilage contact mechanics were predicted using either generic or subject-specific FEM and boundary conditions. A subject-specific mesh resulted in a more lateral contact. Effects of subject-specific boundary conditions varied between both subjects. Results highlight the complex interplay between loading and kinematics and their effect on cartilage contact mechanics.     

Implantable sensor technology: measuring bone and joint biomechanics of daily life in vivo

Stresses and strains are major factors influencing growth, remodeling and repair of musculoskeletal tissues. Therefore, knowledge of forces and deformation within bones and joints is critical to gain insight into the complex behavior of these tissues during development, aging, and response to injury and disease. Sensors have been used in vivo to measure strains in bone, intraarticular cartilage contact pressures, and forces in the spine, shoulder, hip, and knee. Implantable sensors have a high impact on several clinical applications, including fracture fixation, spine fixation, and joint arthroplasty. This review summarizes the developments in strain-measurement-based implantable sensor technology for musculoskeletal research.     

Specimen-specific predictions of contact stress under physiological loading in the human hip: validation and sensitivity studies

Hip osteoarthritis may be initiated and advanced by abnormal cartilage contact mechanics, and finite element (FE) modeling provides an approach with the potential to allow the study of this process. Previous FE models of the human hip have been limited by single specimen validation and the use of quasi-linear or linear elastic constitutive models of articular cartilage. The effects of the latter assumptions on model predictions are unknown, partially because data for the instantaneous behavior of healthy human hip cartilage are unavailable. The aims of this study were to develop and validate a series of specimen-specific FE models, to characterize the regional instantaneous response of healthy human hip cartilage in compression, and to assess the effects of material nonlinearity, inhomogeneity and specimen-specific material coefficients on FE predictions of cartilage contact stress and contact area. Five cadaveric specimens underwent experimental loading, cartilage material characterization and specimen-specific FE modeling. Cartilage in the FE models was represented by average neo-Hookean, average Veronda Westmann and specimen- and region-specific Veronda Westmann hyperelastic constitutive models. Experimental measurements and FE predictions compared well for all three cartilage representations, which was reflected in average RMS errors in contact stress of less than 25 %. The instantaneous material behavior of healthy human hip cartilage varied spatially, with stiffer acetabular cartilage than femoral cartilage and stiffer cartilage in lateral regions than in medial regions. The Veronda Westmann constitutive model with average material coefficients accurately predicted peak contact stress, average contact stress, contact area and contact patterns. The use of subject- and region-specific material coefficients did not increase the accuracy of FE model predictions. The neo-Hookean constitutive model underpredicted peak contact stress in areas of high stress. The results of this study support the use of average cartilage material coefficients in predictions of cartilage contact stress and contact area in the normal hip. The regional characterization of cartilage material behavior provides the necessary inputs for future computational studies, to investigate other mechanical parameters that may be correlated with OA and cartilage damage in the human hip. In the future, the results of this study can be applied to subject-specific models to better understand how abnormal hip contact stress and contact area contribute to OA.     

Functional conservation of MBD proteins: MeCP2 and Drosophila MBD proteins alter sleep

Proteins containing a methyl‐CpG‐binding domain (MBD) bind 5mC and convert the methylation pattern information into appropriate functional cellular states. The correct readout of epigenetic marks is of particular importance in the nervous system where abnormal expression or compromised MBD protein function, can lead to disease and developmental disorders. Recent evidence indicates that the genome of Drosophila melanogaster is methylated and two MBD proteins, dMBD2/3 and dMBD‐R2, are present. Are Drosophila MBD proteins required for neuronal function, and as MBD‐containing proteins have diverged and evolved, does the MBD domain retain the molecular properties required for conserved cellular function across species? To address these questions, we expressed the human MBD‐containing protein, hMeCP2, in distinct amine neurons and quantified functional changes in sleep circuitry output using a high throughput assay in Drosophila. hMeCP2 expression resulted in phase‐specific sleep loss and sleep fragmentation with the hMeCP2‐mediated sleep deficits requiring an intact MBD domain. Reducing endogenous dMBD2/3 and dMBD‐R2 levels also generated sleep fragmentation, with an increase in sleep occurring upon dMBD‐R2 reduction. To examine if hMeCP2 and dMBD‐R2 are targeting common neuronal functions, we reduced dMBD‐R2 levels in combination with hMeCP2 expression and observed a complete rescue of sleep deficits. Furthermore, chromosomal binding experiments indicate MBD‐R2 and MeCP2 associate on shared genomic loci. Our results provide the first demonstration that Drosophila MBD‐containing family members are required for neuronal function and suggest that the MBD domain retains considerable functional conservation at the whole organism level across species.     

Cost-effectiveness of total hip and knee replacements for the Australian population with osteoarthritis: discrete-event simulation model

Background

Osteoarthritis constitutes a major musculoskeletal burden for the aged Australians. Hip and knee replacement surgeries are effective interventions once all conservative therapies to manage the symptoms have been exhausted. This study aims to evaluate the cost-effectiveness of hip and knee replacements in Australia. To our best knowledge, the study is the first attempt to account for the dual nature of hip and knee osteoarthritis in modelling the severities of right and left joints separately.

Methodology/Principal Findings

We developed a discrete-event simulation model that follows up the individuals with osteoarthritis over their lifetimes. The model defines separate attributes for right and left joints and accounts for several repeat replacements. The Australian population with osteoarthritis who were 40 years of age or older in 2003 were followed up until extinct. Intervention effects were modelled by means of disability-adjusted life-years (DALYs) averted. Both hip and knee replacements are highly cost effective (AUD 5,000 per DALY and AUD 12,000 per DALY respectively) under an AUD 50,000/DALY threshold level. The exclusion of cost offsets, and inclusion of future unrelated health care costs in extended years of life, did not change the findings that the interventions are cost-effective (AUD 17,000 per DALY and AUD 26,000 per DALY respectively). However, there was a substantial difference between hip and knee replacements where surgeries administered for hips were more cost-effective than for knees.

Conclusions/Significance

Both hip and knee replacements are cost-effective interventions to improve the quality of life of people with osteoarthritis. It was also shown that the dual nature of hip and knee OA should be taken into account to provide more accurate estimation on the cost-effectiveness of hip and knee replacements.     

Evaluating knee replacement mechanics during ADL with PID-controlled dynamic finite element analysis

Validated computational knee simulations are valuable tools for design phase development of knee replacement devices. Recently, a dynamic finite element (FE) model of the Kansas knee simulator was kinematically validated during gait and deep flexion cycles. In order to operate the computational simulator in the same manner as the experiment, a proportional–integral–derivative (PID) controller was interfaced with the FE model to control the quadriceps actuator excursion and produce a target flexion profile regardless of implant geometry or alignment conditions. The controller was also expanded to operate multiple actuators simultaneously in order to produce in vivo loading conditions at the joint during dynamic activities. Subsequently, the fidelity of the computational model was improved through additional muscle representation and inclusion of relative hip–ankle anterior–posterior (A–P) motion. The PID-controlled model was able to successfully recreate in vivo loading conditions (flexion angle, compressive joint load, medial–lateral load distribution or varus-valgus torque, internal–external torque, A–P force) for deep knee bend, chair rise, stance-phase gait and step-down activities.     

Methyl-CpG binding domain 1 gene polymorphisms and lung cancer risk in a Chinese population

Polymorphisms of the methyl-CpG binding domain 1 (MBD1) gene may influence MBD1 activity on gene expression profiles, thereby modulating individual susceptibility to lung cancer. To test this hypothesis, we investigated the associations of four MBD1 polymorphisms and lung cancer risk in a Chinese population. Single locus analysis revealed significant associations between two polymorphisms (rs125555 and rs140689) and lung cancer risk (p=0.011 and p=0.005, respectively). Since the two polymorphisms were in linkage disequilibrium, further haplotype analyses were performed and revealed a significant association with lung cancer (global test p-value=0.0041). Our results suggested that MBD1 polymorphisms might be involved in the development of lung cancer. Validation of these findings in larger studies of other populations is needed.     

Determination of elastomeric foam parameters for simulations of complex loading

Background: Finite element (FE) analysis has shown promise for the evaluation of elastomeric foam personal protection devices. Although appropriate representation of foam materials is necessary in order to obtain realistic simulation results, material definitions used in the literature vary widely and often fail to account for the multi-mode loading experienced by these devices. This study aims to provide a library of elastomeric foam material parameters that can be used in FE simulations of complex loading scenarios.

Method of Approach: Twelve foam materials used in footwear were tested in uni-axial compression, simple shear and volumetric compression. For each material, parameters for a common compressible hyperelastic material model used in FE analysis were determined using: (a) compression; (b) compression and shear data; and (c) data from all three tests.

Results: Material parameters and Drucker stability limits for the best fits are provided with their associated errors. The material model was able to reproduce deformation modes for which data was provided during parameter determination but was unable to predict behavior in other deformation modes.

Conclusions: Simulation results were found to be highly dependent on the extent of the test data used to determine the parameters in the material definition. This finding calls into question the many published results of simulations of complex loading that use foam material parameters obtained from a single mode of testing. The library of foam parameters developed here presents associated errors in three deformation modes that should provide for a more informed selection of material parameters.     

Application of neural networks for the prediction of cartilage stress in a musculoskeletal system

Traditional finite element (FE) analysis is computationally demanding. The computational time becomes prohibitively long when multiple loading and boundary conditions need to be considered such as in musculoskeletal movement simulations involving multiple joints and muscles. Presented in this study is an innovative approach that takes advantage of the computational efficiency of both the dynamic multibody (MB) method and neural network (NN) analysis. A NN model that captures the behavior of musculoskeletal tissue subjected to known loading situations is built, trained, and validated based on both MB and FE simulation data. It is found that nonlinear, dynamic NNs yield better predictions over their linear, static counterparts. The developed NN model is then capable of predicting stress values at regions of interest within the musculoskeletal system in only a fraction of the time required by FE simulation.     

Regional variations of in vivo surface stiffness of soft tissue layers of musculoskeletal extremities

Surface stiffness of bulk soft tissue in musculoskeletal extremities is important to consider in the design of prosthetics, exoskeletons, and protective gear. This knowledge is also foundational for surgical simulation and clinical interventions leveraging manipulation of the musculoskeletal surfaces. Injuries to musculoskeletal extremities are common and surgical and preventive interventions require interactions between various objects such as surgical tools and support surfaces with tissue boundaries. While a handful of investigations examined the variations in indentation mechanics due to pathology or injury specific sites, a comprehensive analysis across the surfaces of musculoskeletal extremities has not been completed. In this study we examine variations of surface stiffness across 8 sites of the upper and lower arms and legs for 95 subjects using an instrumented ultrasound device. Differences in surface stiffness were observed between gender, activity level, and indentation location groups. The lower arm posterior location had the highest average stiffness (3.89 × 10⁻³ MPa/mm), while the lowest stiffness was observed at the upper leg posterior location (0.98 × 10⁻³ MPa/mm). The differences between indentation sites were larger in magnitude when compared to differences due to demographics (gender and activity level). However the large ranges of the 95% confidence intervals suggest that an aggregated metric based on population or sub-group may not capture individual variations. This study implicates the motivation to explore tissue composition variations within the indentation sites as well as the potential importance to include variations in surface stiffness during surgical simulations.     

Ethical issues in implementation research: a discussion of the problems in achieving informed consent

Background

Implementation of research into practice in health care systems is a challenging and often unsuccessful endeavor. The United States Department of Veterans Affairs (VA) Quality Enhancement Research Initiative (QUERI) research teams include formative evaluations (FE) in their action-oriented VA implementation projects to identify critical information about the processes of implementation that can guide adjustments to project activities, in order to better meet project goals. This article describes the development and use of FE in an action-oriented implementation research project.

Methods

This two-year action-oriented implementation research project was conducted at 23 VA Spinal Cord Injury (SCI) Centers, and targeted patients, staff and the system of care, such as administration and information technology. Data for FE were collected by electronic and paper surveys, semi-structured and open-ended interviews, notes during conference calls, and exchange of e-mail messages. Specific questions were developed for each intervention (designed to improve vaccination rates for influenza in veterans with spinal cord injury and disorder); informants were selected for their knowledge of interventions and their use in SCI Centers.

Results

Data from FE were compiled separately for each intervention to describe barriers to progress and guide adjustments to implementation activities. These data addressed the processes of implementing the interventions, problem-solving activities and the status of interventions at SCI Centers.

Conclusion

Formative evaluations provided the project team with a broad view of the processes of implementing multi-targeted interventions as well as the evolving status of the related best practice. Using FE was useful, although the challenges of conducting FE for non-field researchers should be addressed. Work is needed to develop methods for conducting FE across multiple sites, as well as acknowledging variations in local contexts that affect implementation of interventions.     

Interactive graph-cut segmentation for fast creation of finite element models from clinical ct data for hip fracture prediction

In this study, we propose interactive graph cut image segmentation for fast creation of femur finite element (FE) models from clinical computed tomography scans for hip fracture prediction. Using a sample of N = 48 bone scans representing normal, osteopenic and osteoporotic subjects, the proximal femur was segmented using manual (gold standard) and graph cut segmentation. Segmentations were subsequently used to generate FE models to calculate overall stiffness and peak force in a sideways fall simulations. Results show that, comparable FE results can be obtained with the graph cut method, with a reduction from 20 to 2–5 min interaction time. Average differences between segmentation methods of 0.22 mm were not significantly correlated with differences in FE derived stiffness (R² = 0.08, p = 0.05) and weakly correlated to differences in FE derived peak force (R² = 0.16, p = 0.01). We further found that changes in automatically assigned boundary conditions as a consequence of small segmentation differences were significantly correlated with FE derived results. The proposed interactive graph cut segmentation software MITK-GEM is freely available online at https://simtk.org/home/mitk-gem.     

Physical sensor difference-based method and virtual sensor difference-based method for visual and quantitative estimation of lower limb 3D gait posture using accelerometers and magnetometers

An approach using a physical sensor difference-based algorithm and a virtual sensor difference-based algorithm to visually and quantitatively confirm lower limb posture was proposed. Three accelerometers and two MAG³s (inertial sensor module) were used to measure the accelerations and magnetic field data for the calculation of flexion/extension (FE) and abduction/adduction (AA) angles of hip joint and FE, AA and internal/external rotation (IE) angles of knee joint; then, the trajectories of knee and ankle joints were obtained with the joint angles and segment lengths. There was no integration of acceleration or angular velocity for the joint rotations and positions, which is an improvement on the previous method in recent literature. Compared with the camera motion capture system, the correlation coefficients in five trials were above 0.91 and 0.92 for the hip FE and AA, respectively, and higher than 0.94, 0.93 and 0.93 for the knee joint FE, AA and IE, respectively.     

An intrinsically disordered region of methyl-CpG binding domain protein 2 (MBD2) recruits the histone deacetylase core of the NuRD complex

The MBD2-NuRD (Nucleosome Remodeling and Deacetylase) complex is an epigenetic reader of DNA methylation that regulates genes involved in normal development and neoplastic diseases. To delineate the architecture and functional interactions of the MBD2-NuRD complex, we previously solved the structures of MBD2 bound to methylated DNA and a coiled-coil interaction between MBD2 and p66α that recruits the CHD4 nucleosome remodeling protein to the complex. The work presented here identifies novel structural and functional features of a previously uncharacterized domain of MBD2 (MBD2_IDR). Biophysical analyses show that the MBD2_IDR is an intrinsically disordered region (IDR). However, despite this inherent disorder, MBD2_IDR increases the overall binding affinity of MBD2 for methylated DNA. MBD2_IDR also recruits the histone deacetylase core components (RbAp48, HDAC2 and MTA2) of NuRD through a critical contact region requiring two contiguous amino acid residues, Arg²⁸⁶ and Leu²⁸⁷. Mutating these residues abrogates interaction of MBD2 with the histone deacetylase core and impairs the ability of MBD2 to repress the methylated tumor suppressor gene PRSS8 in MDA-MB-435 breast cancer cells. These findings expand our knowledge of the multi-dimensional interactions of the MBD2-NuRD complex that govern its function.     

Effects of idealized joint geometry on finite element predictions of cartilage contact stresses in the hip

Computational models may have the ability to quantify the relationship between hip morphology, cartilage mechanics and osteoarthritis. Most models have assumed the hip joint to be a perfect ball and socket joint and have neglected deformation at the bone-cartilage interface. The objective of this study was to analyze finite element (FE) models of hip cartilage mechanics with varying degrees of simplified geometry and a model with a rigid bone material assumption to elucidate the effects on predictions of cartilage stress. A previously validated subject-specific FE model of a cadaveric hip joint was used as the basis for the models. Geometry for the bone-cartilage interface was either: (1) subject-specific (i.e. irregular), (2) spherical, or (3) a rotational conchoid. Cartilage was assigned either a varying (irregular) or constant thickness (smoothed). Loading conditions simulated walking, stair-climbing and descending stairs. FE predictions of contact stress for the simplified models were compared with predictions from the subject-specific model. Both spheres and conchoids provided a good approximation of native hip joint geometry (average fitting error ～0.5 mm). However, models with spherical/conchoid bone geometry and smoothed articulating cartilage surfaces grossly underestimated peak and average contact pressures (50% and 25% lower, respectively) and overestimated contact area when compared to the subject-specific FE model. Models incorporating subject-specific bone geometry with smoothed articulating cartilage also underestimated pressures and predicted evenly distributed patterns of contact. The model with rigid bones predicted much higher pressures than the subject-specific model with deformable bones. The results demonstrate that simplifications to the geometry of the bone-cartilage interface, cartilage surface and bone material properties can have a dramatic effect on the predicted magnitude and distribution of cartilage contact pressures in the hip joint.     

Validation of an HR-pQCT-based homogenized finite element approach using mechanical testing of ultra-distal radius sections

Osteoporotic (Colles’ type) fractures of the distal radius occur relatively early in lifetime and could estimate risk of fracture of other, more endangered anatomical sites. High-resolution peripheral quantitative computed tomography (HR-pQCT) based micro finite element (μFE) analysis was shown to better predict fracture load of the distal radius than densitometry or histomorphometric measures. As an alternative to μFE, homogenization-based FE (hFE) approach may provide at least equivalent predictive power with reduced computational needs. The aim of this study was to validate the hFE approach with compression tests of 25 distal radius sections extracted at the location which is relevant in Colles’ fractures. HR-pQCT-based input parameters of the hFE models were calibrated with respect to μCT. HR-pQCT-based hFE models were then built and their ability to predict experimental stiffness and ultimate load was compared to those of the density-based parameters, histomorphometric indices and μFE models assessed from the same input images. Bone mineral content was the best non-FE-based predictor (R ² = 0.86) of ultimate force. Both FE methods were not only the strongest predictors, but provided quantitatively correct fracture loads. The calibrated hFE approach provided closely as strong prediction (R ² = 0.94) as μFE (R ² = 0.95), but the former was computationally cheaper. The results of this validation study suggest that FE simulation could be used as an efficient and precise tool to predict Colles’ fracture load.