Showing papers in "Journal of Biomechanical Engineering-transactions of The Asme in 2015"

Is My Model Good Enough? Best Practices for Verification and Validation of Musculoskeletal Models and Simulations of Movement

Abstract: Computational modeling and simulation of neuromusculoskeletal (NMS) systems enables researchers and clinicians to study the complex dynamics underlying human and animal movement. NMS models use equations derived from physical laws and biology to help solve challenging real-world problems, from designing prosthetics that maximize running speed to developing exoskeletal devices that enable walking after a stroke. NMS modeling and simulation has proliferated in the biomechanics research community over the past 25 years, but the lack of verification and validation standards remains a major barrier to wider adoption and impact. The goal of this paper is to establish practical guidelines for verification and validation of NMS models and simulations that researchers, clinicians, reviewers, and others can adopt to evaluate the accuracy and credibility of modeling studies. In particular, we review a general process for verification and validation applied to NMS models and simulations, including careful formulation of a research question and methods, traditional verification and validation steps, and documentation and sharing of results for use and testing by other researchers. Modeling the NMS system and simulating its motion involves methods to represent neural control, musculoskeletal geometry, muscle-tendon dynamics, contact forces, and multibody dynamics. For each of these components, we review modeling choices and software verification guidelines; discuss variability, errors, uncertainty, and sensitivity relationships; and provide recommendations for verification and validation by comparing experimental data and testing robustness. We present a series of case studies to illustrate key principles. In closing, we discuss challenges the community must overcome to ensure that modeling and simulation are successfully used to solve the broad spectrum of problems that limit human mobility.

Biomechanics and Mechanobiology of Trabecular Bone: A Review

Abstract: Trabecular bone is a highly porous, heterogeneous, and anisotropic material which can be found at the epiphyses of long bones and in the vertebral bodies. Studying the mechanical properties of trabecular bone is important, since trabecular bone is the main load bearing bone in vertebral bodies and also transfers the load from joints to the compact bone of the cortex of long bones. This review article highlights the high dependency of the mechanical properties of trabecular bone on species, age, anatomic site, loading direction, and size of the sample under consideration. In recent years, high resolution micro finite element methods have been extensively used to specifically address the mechanical properties of the trabecular bone and provide unique tools to interpret and model the mechanical testing experiments. The aims of the current work are to first review the mechanobiology of trabecular bone and then present classical and new approaches for modeling and analyzing the trabecular bone microstructure and macrostructure and corresponding mechanical properties such as elastic properties and strength.

A Subject-Specific Musculoskeletal Modeling Framework to Predict In Vivo Mechanics of Total Knee Arthroplasty

Abstract: Musculoskeletal (MS) models should be able to integrate patient-specific MS architecture and undergo thorough validation prior to their introduction into clinical practice. We present a methodology to develop subject-specific models able to simultaneously predict muscle, ligament, and knee joint contact forces along with secondary knee kinematics. The MS architecture of a generic cadaver-based model was scaled using an advanced morphing technique to the subject-specific morphology of a patient implanted with an instrumented total knee arthroplasty (TKA) available in the fifth “grand challenge competition to predict in vivo knee loads” dataset. We implemented two separate knee models, one employing traditional hinge constraints, which was solved using an inverse dynamics technique, and another one using an 11-degree-of-freedom (DOF) representation of the tibiofemoral (TF) and patellofemoral (PF) joints, which was solved using a combined inverse dynamic and quasi-static analysis, called force-dependent kinematics (FDK). TF joint forces for one gait and one right-turn trial and secondary knee kinematics for one unloaded leg-swing trial were predicted and evaluated using experimental data available in the grand challenge dataset. Total compressive TF contact forces were predicted by both hinge and FDK knee models with a root-mean-square error (RMSE) and a coefficient of determination (R2) smaller than 0.3 body weight (BW) and equal to 0.9 in the gait trial simulation and smaller than 0.4 BW and larger than 0.8 in the right-turn trial simulation, respectively. Total, medial, and lateral TF joint contact force predictions were highly similar, regardless of the type of knee model used. Medial (respectively lateral) TF forces were over- (respectively, under-) predicted with a magnitude error of M −0.4) in the gait trial, and under- (respectively, over-) predicted with a magnitude error of M > −0.4 (respectively < 0.3) in the right-turn trial. Secondary knee kinematics from the unloaded leg-swing trial were overall better approximated using the FDK model (average Sprague and Geers' combined error C = 0.06) than when using a hinged knee model (C = 0.34). The proposed modeling approach allows detailed subject-specific scaling and personalization and does not contain any nonphysiological parameters. This modeling framework has potential applications in aiding the clinical decision-making in orthopedics procedures and as a tool for virtual implant design.

Development and Validation of a Musculoskeletal Model of the Fully Articulated Thoracolumbar Spine and Rib Cage

Abstract: We developed and validated a fully articulated model of the thoracolumbar spine in opensim that includes the individual vertebrae, ribs, and sternum. To ensure trunk muscles in the model accurately represent muscles in vivo, we used a novel approach to adjust muscle cross-sectional area (CSA) and position using computed tomography (CT) scans of the trunk sampled from a community-based cohort. Model predictions of vertebral compressive loading and trunk muscle tension were highly correlated to previous in vivo measures of intradiscal pressure (IDP), vertebral loading from telemeterized implants and trunk muscle myoelectric activity recorded by electromyography (EMG).

Collagen structure and mechanical properties of the human sclera: Analysis for the effects of age

Abstract: The objective of this study was to measure the collagen fiber structure and estimate the material properties of 7 human donor scleras, from age 53 to 91. The specimens were subjected to inflation testing, and the full-field displacement maps were measured by digital image correlation (DIC). After testing, the collagen fiber structure was mapped using wide-angle x-ray scattering (WAXS). A specimen-specific inverse finite element method was applied to calculate the material properties of the collagen fibers and inter-fiber matrix by minimizing the difference between the experimental displacements and model predictions. Age effects on the fiber structure and material properties were estimated using multivariate models accounting for spatial autocorrelation. Older age was associated with a larger matrix stiffness (p=0.001), a lower degree of fiber alignment in the peripapillary sclera (p=0.01), and a lower mechanical anisotropy in the peripapillary sclera (p=0.03)

The Computational Fluid Dynamics Rupture Challenge 2013--Phase II: Variability of Hemodynamic Simulations in Two Intracranial Aneurysms.

Abstract: With the increased availability of computational resources, the past decade has seen a rise in the use of computational fluid dynamics (CFD) for medical applications. There has been an increase in the application of CFD to attempt to predict the rupture of intracranial aneurysms, however, while many hemodynamic parameters can be obtained from these computations, to date, no consistent methodology for the prediction of the rupture has been identified. One particular challenge to CFD is that many factors contribute to its accuracy; the mesh resolution and spatial/temporal discretization can alone contribute to a variation in accuracy. This failure to identify the importance of these factors and identify a methodology for the prediction of ruptures has limited the acceptance of CFD among physicians for rupture prediction. The International CFD Rupture Challenge 2013 seeks to comment on the sensitivity of these various CFD assumptions to predict the rupture by undertaking a comparison of the rupture and blood-flow predictions from a wide range of independent participants utilizing a range of CFD approaches. Twenty-six groups from 15 countries took part in the challenge. Participants were provided with surface models of two intracranial aneurysms and asked to carry out the corresponding hemodynamics simulations, free to choose their own mesh, solver, and temporal discretization. They were requested to submit velocity and pressure predictions along the centerline and on specified planes. The first phase of the challenge, described in a separate paper, was aimed at predicting which of the two aneurysms had previously ruptured and where the rupture site was located. The second phase, described in this paper, aims to assess the variability of the solutions and the sensitivity to the modeling assumptions. Participants were free to choose boundary conditions in the first phase, whereas they were prescribed in the second phase but all other CFD modeling parameters were not prescribed. In order to compare the computational results of one representative group with experimental results, steady-flow measurements using particle image velocimetry (PIV) were carried out in a silicone model of one of the provided aneurysms. Approximately 80% of the participating groups generated similar results. Both velocity and pressure computations were in good agreement with each other for cycle-averaged and peak-systolic predictions. Most apparent "outliers" (results that stand out of the collective) were observed to have underestimated velocity levels compared to the majority of solutions, but nevertheless identified comparable flow structures. In only two cases, the results deviate by over 35% from the mean solution of all the participants. Results of steady CFD simulations of the representative group and PIV experiments were in good agreement. The study demonstrated that while a range of numerical schemes, mesh resolution, and solvers was used, similar flow predictions were observed in the majority of cases. To further validate the computational results, it is suggested that time-dependent measurements should be conducted in the future. However, it is recognized that this study does not include the biological aspects of the aneurysm, which needs to be considered to be able to more precisely identify the specific rupture risk of an intracranial aneurysm.

Decreased Elastic Energy Storage, Not Increased Material Stiffness, Characterizes Central Artery Dysfunction in Fibulin-5 Deficiency Independent of Sex

Abstract: Central artery stiffness has emerged over the past 15 years as a clinically significant indicator of cardiovascular function and initiator of disease. Loss of elastic fiber integrity is one of the primary contributors to increased arterial stiffening in aging, hypertension, and related conditions. Elastic fibers consist of an elastin core and multiple glycoproteins; hence defects in any of these constituents can adversely affect arterial wall mechanics. In this paper, we focus on mechanical consequences of the loss of fibulin-5, an elastin-associated glycoprotein involved in elastogenesis. Specifically, we compared the biaxial mechanical properties of five central arteries-the ascending thoracic aorta, descending thoracic aorta, suprarenal abdominal aorta, infrarenal abdominal aorta, and common carotid artery-from male and female wild-type and fibulin-5 deficient mice. Results revealed that, independent of sex, all five regions in the fibulin-5 deficient mice manifested a marked increase in structural stiffness but also a marked decrease in elastic energy storage and typically an increase in energy dissipation, with all differences being most dramatic in the ascending and abdominal aortas. Given that the primary function of large arteries is to store elastic energy during systole and to use this energy during diastole to work on the blood, fibulin-5 deficiency results in a widespread diminishment of central artery function that can have significant effects on hemodynamics and cardiac function.

Rotational Acceleration, Brain Tissue Strain, and the Relationship to Concussion

Abstract: The mechanisms of concussion have been investigated by many researchers using a variety of methods. However, there remains much debate over the relationships between head kinematics from an impact and concussion. This review presents the links between research conducted in different disciplines to better understand the relationship between linear and rotational acceleration and brain strains that have been postulated as the root cause of concussion. These concepts are important when assigning performance variables for helmet development, car design, and protective innovation research.

Three-Dimensional Local Measurements of Bone Strain and Displacement: Comparison of Three Digital Volume Correlation Approaches

Abstract: Different digital volume correlation (DVC) approaches are currently available or under development for bone tissue micromechanics. The aim of this study was to compare accuracy and precision errors of three DVC approaches for a particular three-dimensional (3D) zero-strain condition. Trabecular and cortical bone specimens were repeatedly scanned with a micro-computed tomography (CT). The errors affecting computed displacements and strains were extracted for a known virtual translation, as well as for repeated scans. Three DVC strategies were tested: two local approaches, based on fast-Fourier-transform (DaVis-FFT) or direct-correlation (DaVis-DC), and a global approach based on elastic registration and a finite element (FE) solver (ShIRT-FE). Different computation subvolume sizes were tested. Much larger errors were found for the repeated scans than for the virtual translation test. For each algorithm, errors decreased asymptotically for larger subvolume sizes in the range explored. Considering this particular set of images, ShIRT-FE showed an overall better accuracy and precision (a few hundreds microstrain for a subvolume of 50 voxels). When the largest subvolume (50-52 voxels) was applied to cortical bone, the accuracy error obtained for repeated scans with ShIRT-FE was approximately half of that for the best local approach (DaVis-DC). The difference was lower (250 microstrain) in the case of trabecular bone. In terms of precision, the errors shown by DaVis-DC were closer to the ones computed by ShIRT-FE (differences of 131 microstrain and 157 microstrain for cortical and trabecular bone, respectively). The multipass computation available for DaVis software improved the accuracy and precision only for the DaVis-FFT in the virtual translation, particularly for trabecular bone. The better accuracy and precision of ShIRT-FE, followed by DaVis-DC, were obtained with a higher computational cost when compared to DaVis-FFT. The results underline the importance of performing a quantitative comparison of DVC methods on the same set of samples by using also repeated scans, other than virtual translation tests only. ShIRT-FE provides the most accurate and precise results for this set of images. However, both DaVis approaches show reasonable results for large nodal spacing, particularly for trabecular bone. Finally, this study highlights the importance of using sufficiently large subvolumes, in order to achieve better accuracy and precision.

Effect of Hydration on Healthy Intervertebral Disk Mechanical Stiffness

Abstract: The intervertebral disk has an excellent swelling capacity to absorb water, which is thought to be largely due to the high proteoglycan composition. Injury, aging, degeneration, and diurnal loading are all noted by a significant decrease in water content and tissue hydration. The objective of this study was to evaluate the effect of hydration, through osmotic loading, on tissue swelling and compressive stiffness of healthy intervertebral disks. The wet weight of nucleus pulposus (NP) and annulus fibrosus (AF) explants following swelling was 50% or greater, demonstrating significant ability to absorb water under all osmotic loading conditions (0.015 M-3.0 M phosphate buffered saline (PBS)). Estimated NP residual strains, calculated from the swelling ratio, were approximately 1.5 × greater than AF residual strains. Compressive stiffness increased with hyperosmotic loading, which is thought to be due to material compaction from osmotic-loading and the nonlinear mechanical behavior. Importantly, this study demonstrated that residual strains and material properties are greatly dependent on osmotic loading. The findings of this study support the notion that swelling properties from osmotic loading will be important for accurately describing the effect of degeneration and injury on disk mechanics. Furthermore, the tissue swelling will be an important consideration for developing biological repair strategies aimed at restoring mechanical behavior toward a healthy disk.

A Novel Paradigm for Engineering Education: Virtual Internships With Individualized Mentoring and Assessment of Engineering Thinking

Abstract: Engineering virtual internships are a novel paradigm for providing authentic engineering experiences in the first-year curriculum. They are both individualized and accommodate large numbers of students. As we describe in this report, this approach can (a) enable students to solve complex engineering problems in a mentored, collaborative environment; (b) allow educators to assess engineering thinking; and (c) provide an introductory experience that students enjoy and find valuable. Furthermore, engineering virtual internships have been shown to increase students'-and especially women's-interest in and motivation to pursue engineering degrees. When implemented in first-year engineering curricula more broadly, the potential impact of engineering virtual internships on the size and diversity of the engineering workforce could be dramatic.

Hemodynamics in the Left Atrium and Its Effect on Ventricular Flow Patterns

Abstract: In the present study, we investigate the hemodynamics inside left atrium (LA) and understand its impact on the development of ventricular flow patterns. We construct the heart model using dynamic-computed tomographic images and perform simulations using an immersed boundary method based flow solver. We show that the atrial hemodynamics is characterized by a circulatory flow generated by the left pulmonary veins (LPVs) and a direct stream from the right pulmonary veins (RPVs). The complex interaction of the vortex rings formed from each of the PVs leads to vortex breakup and annihilation, thereby producing a regularized flow at the mitral annulus. A comparison of the ventricular flow velocities between the physiological and a simplified pipe-based atrium model shows that the overall differences are limited to about 10% of the peak mitral flow velocity. The implications of this finding on the functional morphology of the left heart as well the computational and experimental modeling of ventricular hemodynamics are discussed.

The In Situ Mechanics of Trabecular Bone Marrow: The Potential for Mechanobiological Response

Abstract: Bone adapts to habitual loading through mechanobiological signaling. Osteocytes are the primary mechanical sensors in bone, upregulating osteogenic factors and downregulating osteoinhibitors, and recruiting osteoclasts to resorb bone in response to microdamage accumulation. However, most of the cell populations of the bone marrow niche,which are intimately involved with bone remodeling as the source of bone osteoblast and osteoclast progenitors, are also mechanosensitive. We hypothesized that the deformation of trabecular bone would impart mechanical stress within the entrapped bone marrow consistent with mechanostimulation of the constituent cells. Detailed fluid-structure interaction models of porcine femoral trabecular bone and bone marrow were created using tetrahedral finite element meshes. The marrow was allowed to flow freely within the bone pores, while the bone was compressed to 2000 or 3000 microstrain at the apparent level.Marrow properties were parametrically varied from a constant 400 mPas to a power law rule exceeding 85 Pas. Deformation generated almost no shear stress or pressure in the marrow for the low viscosity fluid, but exceeded 5 Pa when the higher viscosity models were used. The shear stress was higher when the strain rate increased and in higher volume fraction bone. The results demonstrate that cells within the trabecular bone marrow could be mechanically stimulated by bone deformation, depending on deformation rate, bone porosity, and bone marrow properties. Since the marrow contains many mechanosensitive cells, changes in the stimulatory levels may explain the alterations in bone marrow morphology with aging and disease, which may in turn affect the trabecular bone mechanobiology and adaptation.

Deconstructing the anterior cruciate ligament: what we know and do not know about function, material properties, and injury mechanics.

Abstract: Anterior cruciate ligament (ACL) injury is a common and potentially catastrophic knee joint injury, afflicting a large number of males and particularly females annually. Apart from the obvious acute injury events, it also presents with significant long-term morbidities, in which osteoarthritis (OA) is a frequent and debilitative outcome. With these facts in mind, a vast amount of research has been undertaken over the past five decades geared toward characterizing the structural and mechanical behaviors of the native ACL tissue under various external load applications. While these efforts have afforded important insights, both in terms of understanding treating and rehabilitating ACL injuries; injury rates, their well-established sex-based disparity, and long-term sequelae have endured. In reviewing the expanse of literature conducted to date in this area, this paper identifies important knowledge gaps that contribute directly to this long-standing clinical dilemma. In particular, the following limitations remain. First, minimal data exist that accurately describe native ACL mechanics under the extreme loading rates synonymous with actual injury. Second, current ACL mechanical data are typically derived from isolated and oversimplified strain estimates that fail to adequately capture the true 3D mechanical response of this anatomically complex structure. Third, graft tissues commonly chosen to reconstruct the ruptured ACL are mechanically suboptimal, being overdesigned for stiffness compared to the native tissue. The net result is an increased risk of rerupture and a modified and potentially hazardous habitual joint contact profile. These major limitations appear to warrant explicit research attention moving forward in order to successfully maintain/restore optimal knee joint function and long-term life quality in a large number of otherwise healthy individuals.

Allometry of the Tendon Enthesis: Mechanisms of Load Transfer Between Tendon and Bone

Abstract: Several features of the tendon-to-bone attachment were examined allometrically to determine load transfer mechanisms. The humeral head diameter increased geometrically with animal mass. Area of the attachment site exhibited a near isometric increase with muscle physiological cross section. In contrast, the interfacial roughness as well as the mineral gradient width demonstrated a hypoallometric relationship with physiologic cross-sectional area (PCSA). The isometric increase in attachment area indicates that as muscle forces increase, the attachment area increases accordingly, thus maintaining a constant interfacial stress. Due to the presence of constant stresses at the attachment, the micrometer-scale features may not need to vary with increasing load.

Contribution of Collagen Fiber Undulation to Regional Biomechanical Properties Along Porcine Thoracic Aorta

Abstract: As major extracellular matrix components, elastin, and collagen play crucial roles in regulating the mechanical properties of the aortic wall and, thus, the normal cardiovascular function. The mechanical properties of aorta, known to vary with age and multitude of diseases as well as the proximity to the heart, have been attributed to the variations in the content and architecture of wall constituents. This study is focused on the role of layer-specific collagen undulation in the variation of mechanical properties along the porcine descending thoracic aorta. Planar biaxial tensile tests are performed to characterize the hyperelastic anisotropic mechanical behavior of tissues dissected from four locations along the thoracic aorta. Multiphoton microscopy is used to image the associated regional microstructure. Exponential-based and recruitment-based constitutive models are used to account for the observed mechanical behavior while considering the aortic wall as a composite of two layers with independent properties. An elevated stiffness is observed in distal regions compared to proximal regions of thoracic aorta, consistent with sharper and earlier collagen recruitment estimated for medial and adventitial layers in the models. Multiphoton images further support our prediction that higher stiffness in distal regions is associated with less undulation in collagen fibers. Recruitment-based models further reveal that regardless of the location, collagen in the media is recruited from the onset of stretching, whereas adventitial collagen starts to engage with a delay. A parameter sensitivity analysis is performed to discriminate between the models in terms of the confidence in the estimated model parameters.

Mechanical Platelet Activation Potential in Abdominal Aortic Aneurysms

Abstract: Intraluminal thrombus (ILT) in abdominal aortic aneurysms (AAA) has potential implications to aneurysm growth and rupture risk; yet, the mechanisms underlying its development remain poorly understood. Some researchers have proposed that ILT development may be driven by biomechanical platelet activation within the AAA, followed by adhesion in regions of low wall shear stress. Studies have investigated wall shear stress levels within AAA, but platelet activation potential (AP) has not been quantified. In this study, patient-specific computational fluid dynamic (CFD) models were used to analyze stress-induced AP within AAA under rest and exercise flow conditions. The analysis was conducted using Lagrangian particle-based and Eulerian continuum-based approaches, and the results were compared. Results indicated that biomechanical platelet activation is unlikely to play a significant role for the conditions considered. No consistent trend was observed in comparing rest and exercise conditions, but the functional dependence of AP on stress magnitude and exposure time can have a large impact on absolute levels of anticipated platelet AP. The Lagrangian method obtained higher peak AP values, although this difference was limited to a small percentage of particles that falls below reported levels of physiologic background platelet activation.

A Technique for Quantifying Wrist Motion Using Four-Dimensional Computed Tomography: Approach and Validation

Abstract: The wrist joint is an articulation consisting of many bones and ligamentous structures which, during normal function, allows complex motions while still maintaining stability. The wrist is the most frequently injured upper extremity joint, with wrist ligament injuries being subject to a high rate of misdiagnosis [1–3]. Accurate diagnosis is crucial for providing the most effective interventions that, if not implemented early enough, can lead to significant pain and suffering for patients and limit the spectrum of treatment options [4–8]. Magnetic resonance imaging (MRI) cannot accurately detect rupture of the scapholunate interosseous ligament [9,10]. Further, since standard MRI and CT imaging are static in nature, only abnormal carpal bone position can be detected, without the possibility to analyze abnormal motion. These dynamic changes can be assessed occasionally with fluoroscopy [11–13], but more commonly, especially in patients with mild or early injuries, a definitive diagnosis is made during surgery. Prior investigations of carpal motion have focused on understanding normal and pathological motion patterns in vitro and in vivo. Considerable knowledge has been gained about basic biomechanics of wrist function including carpal bone motion [14–25], the effect of ligamentous constraints [26–33], and bilateral symmetry [17,34,35]. However, these studies have been limited by their inability to capture dynamic four-dimensional (4D) (three spatial dimensions + time) data during unconstrained movements in vivo. Recently, our research team and others [36–44] have noted the utility of four-dimensional (4D) CT image sequences as a visualization and clinical tool for assessing dynamic movements in various joints. 4DCT is an imaging technique whereby joint motion is acquired using a dynamic sequential scanning mode similar to CT perfusion. In this mode, images of a moving joint are continuously acquired. Therefore, it holds promise to detect injuries earlier when only subtle bony motion changes are occurring. Due to the complex geometry and motions, this data are best viewed volumetrically. Volume-rendered dynamic image sequences can be rotated and viewed with varying bone opacities to assist in clinical decision-making. The next step in successful clinical implementation of the tool is quantification and validation of measures from the 4DCT image sequences that will enable selection of appropriate and timely interventions for these patients. This includes quantification of measures that we call imaging biomarkers, including joint proximity which approximates the articular joint contact which is known to be affected by wrist instability and osteoarthritis. The purpose of this manuscript is to describe a 4DCT approach for quantifying wrist motion and validate the accuracy in two cadaveric specimens during motion induced using an in vitro wrist simulator.

The Effect of Quantitative Computed Tomography Acquisition Protocols on Bone Mineral Density Estimation

Abstract: Osteoporosis is characterized by bony material loss and decreased bone strength leading to a significant increase in fracture risk. Patient-specific quantitative computed tomography (QCT) finite element (FE) models may be used to predict fracture under physiological loading. Material properties for the FE models used to predict fracture are obtained by converting grayscale values from the CT into volumetric bone mineral density (vBMD) using calibration phantoms. If there are any variations arising from the CT acquisition protocol, vBMD estimation and material property assignment could be affected, thus, affecting fracture risk prediction. We hypothesized that material property assignments may be dependent on scanning and postprocessing settings including voltage, current, and reconstruction kernel, thus potentially having an effect in fracture risk prediction. A rabbit femur and a standard calibration phantom were imaged by QCT using different protocols. Cortical and cancellous regions were segmented, their average Hounsfield unit (HU) values obtained and converted to vBMD. Estimated vBMD for the cortical and cancellous regions were affected by voltage and kernel but not by current. Our study demonstrated that there exists a significant variation in the estimated vBMD values obtained with different scanning acquisitions. In addition, the large noise differences observed utilizing different scanning parameters could have an important negative effect on small subregions containing fewer voxels.

A Thick-Walled Fluid–Solid-Growth Model of Abdominal Aortic Aneurysm Evolution: Application to a Patient-Specific Geometry

Abstract: We propose a novel thick-walled fluid-solid-growth (FSG) computational framework for modeling vascular disease evolution. The arterial wall is modeled as a thick-walled nonlinearly elastic cylindrical tube consisting of two layers corresponding to the media-intima and adventitia, where each layer is treated as a fiber-reinforced material with the fibers corresponding to the collagenous component. Blood is modeled as a Newtonian fluid with constant density and viscosity; no slip and no-flux conditions are applied at the arterial wall. Disease progression is simulated by growth and remodeling (G&R) of the load bearing constituents of the wall. Adaptions of the natural reference configurations and mass densities of constituents are driven by deviations of mechanical stimuli from homeostatic levels. We apply the novel framework to model abdominal aortic aneurysm (AAA) evolution. Elastin degradation is initially prescribed to create a perturbation to the geometry which results in a local decrease in wall shear stress (WSS). Subsequent degradation of elastin is driven by low WSS and an aneurysm evolves as the elastin degrades and the collagen adapts. The influence of transmural G&R of constituents on the aneurysm development is analyzed. We observe that elastin and collagen strains evolve to be transmurally heterogeneous and this may facilitate the development of tortuosity. This multiphysics framework provides the basis for exploring the influence of transmural metabolic activity on the progression of vascular disease.

Device-Based In Vitro Techniques for Mechanical Stimulation of Vascular Cells: A Review

Abstract: The most common cause of death in the developed world is cardiovascular disease. For decades, this has provided a powerful motivation to study the effects of mechanical forces on vascular cells in a controlled setting, since these cells have been implicated in the development of disease. Early efforts in the 1970 s included the first use of a parallel-plate flow system to apply shear stress to endothelial cells (ECs) and the development of uniaxial substrate stretching techniques (Krueger et al., 1971, "An in Vitro Study of Flow Response by Cells," J. Biomech., 4(1), pp. 31-36 and Meikle et al., 1979, "Rabbit Cranial Sutures in Vitro: A New Experimental Model for Studying the Response of Fibrous Joints to Mechanical Stress," Calcif. Tissue Int., 28(2), pp. 13-144). Since then, a multitude of in vitro devices have been designed and developed for mechanical stimulation of vascular cells and tissues in an effort to better understand their response to in vivo physiologic mechanical conditions. This article reviews the functional attributes of mechanical bioreactors developed in the 21st century, including their major advantages and disadvantages. Each of these systems has been categorized in terms of their primary loading modality: fluid shear stress (FSS), substrate distention, combined distention and fluid shear, or other applied forces. The goal of this article is to provide researchers with a survey of useful methodologies that can be adapted to studies in this area, and to clarify future possibilities for improved research methods.

Predicting Complete Ground Reaction Forces and Moments During Gait With Insole Plantar Pressure Information Using a Wavelet Neural Network.

Abstract: In general, three-dimensional ground reaction forces (GRFs) and ground reaction moments (GRMs) that occur during human gait are measured using a force plate, which are expensive and have spatial limitations. Therefore, we proposed a prediction model for GRFs and GRMs, which only uses plantar pressure information measured from insole pressure sensors with a wavelet neural network (WNN) and principal component analysis-mutual information (PCA-MI). For this, the prediction model estimated GRFs and GRMs with three different gait speeds (slow, normal, and fast groups) and healthy/pathological gait patterns (healthy and adolescent idiopathic scoliosis (AIS) groups). Model performance was validated using correlation coefficients (r) and the normalized root mean square error (NRMSE%) and was compared to the prediction accuracy of the previous methods using the same dataset. As a result, the performance of the GRF and GRM prediction model proposed in this study (slow group: r = 0.840-0.989 and NRMSE% = 10.693-15.894%; normal group: r = 0.847-0.988 and NRMSE% = 10.920-19.216%; fast group: r = 0.823-0.953 and NRMSE% = 12.009-20.182%; healthy group: r = 0.836-0.976 and NRMSE% = 12.920-18.088%; and AIS group: r = 0.917-0.993 and NRMSE% = 7.914-15.671%) was better than that of the prediction models suggested in previous studies for every group and component (p < 0.05 or 0.01). The results indicated that the proposed model has improved performance compared to previous prediction models.

Harnessing Biomechanics to Develop Cartilage Regeneration Strategies

Abstract: As this review was prepared specifically for the American Society of Mechanical Engineers H.R. Lissner Medal, it primarily discusses work toward cartilage regeneration performed in Dr. Kyriacos A. Athanasiou's laboratory over the past 25 years. The prevalence and severity of degeneration of articular cartilage, a tissue whose main function is largely biomechanical, have motivated the development of cartilage tissue engineering approaches informed by biomechanics. This article provides a review of important steps toward regeneration of articular cartilage with suitable biomechanical properties. As a first step, biomechanical and biochemical characterization studies at the tissue level were used to provide design criteria for engineering neotissues. Extending this work to the single cell and subcellular levels has helped to develop biochemical and mechanical stimuli for tissue engineering studies. This strong mechanobiological foundation guided studies on regenerating hyaline articular cartilage, the knee meniscus, and temporomandibular joint (TMJ) fibrocartilage. Initial tissue engineering efforts centered on developing biodegradable scaffolds for cartilage regeneration. After many years of studying scaffold-based cartilage engineering, scaffoldless approaches were developed to address deficiencies of scaffold-based systems, resulting in the self-assembling process. This process was further improved by employing exogenous stimuli, such as hydrostatic pressure, growth factors, and matrix-modifying and catabolic agents, both singly and in synergistic combination to enhance neocartilage functional properties. Due to the high cell needs for tissue engineering and the limited supply of native articular chondrocytes, costochondral cells are emerging as a suitable cell source. Looking forward, additional cell sources are investigated to render these technologies more translatable. For example, dermis isolated adult stem (DIAS) cells show potential as a source of chondrogenic cells. The challenging problem of enhanced integration of engineered cartilage with native cartilage is approached with both familiar and novel methods, such as lysyl oxidase (LOX). These diverse tissue engineering strategies all aim to build upon thorough biomechanical characterizations to produce functional neotissue that ultimately will help combat the pressing problem of cartilage degeneration. As our prior research is reviewed, we look to establish new pathways to comprehensively and effectively address the complex problems of musculoskeletal cartilage regeneration.

A generalized method for the analysis of planar biaxial mechanical data using tethered testing configurations

Abstract: Simulation of the mechanical behavior of soft tissues is critical for many physiological and medical device applications. Accurate mechanical test data is crucial for both obtaining the form and robust parameter determination of the constitutive model. For incompressible soft tissues that are either membranes or thin sections, planar biaxial mechanical testing configurations can provide much information about the anisotropic stress-strain behavior. However, the analysis of soft biological tissue planar biaxial mechanical test data can be complicated by in-plane shear, tissue heterogeneities, and inelastic changes in specimen geometry that commonly occur during testing. These inelastic effects, without appropriate corrections, alter the stress-traction mapping and violates equilibrium so that the stress tensor is incorrectly determined. To overcome these problems, we presented an analytical method to determine the Cauchy stress tensor from the experimentally derived tractions for tethered testing configurations. We accounted for the measured testing geometry and compensate for run-time inelastic effects by enforcing equilibrium using small rigid body rotations. To evaluate the effectiveness of our method, we simulated complete planar biaxial test configurations that incorporated actual device mechanisms, specimen geometry, and heterogeneous tissue fibrous structure using a finite element (FE) model. We determined that our method corrected the errors in the equilibrium of momentum and correctly estimated the Cauchy stress tensor. We also noted that since stress is applied primarily over a subregion bounded by the tethers, an adjustment to the effective specimen dimensions is required to correct the magnitude of the stresses. Simulations of various tether placements demonstrated that typical tether placements used in the current experimental setups will produce accurate stress tensor estimates. Overall, our method provides an improved and relatively straightforward method of calculating the resulting stresses for planar biaxial experiments for tethered configurations, which is especially useful for specimens that undergo large shear and exhibit substantial inelastic effects.

Improving Accuracy in Arrhenius Models of Cell Death: Adding a Temperature-Dependent Time Delay

Abstract: The Arrhenius formulation for single-step irreversible unimolecular reactions has been used for many decades to describe the thermal damage and cell death processes. Arrhenius predictions are acceptably accurate for structural proteins, for some cell death assays, and for cell death at higher temperatures in most cell lines, above about 55 °C. However, in many cases--and particularly at hyperthermic temperatures, between about 43 and 55 °C--the particular intrinsic cell death or damage process under study exhibits a significant "shoulder" region that constant-rate Arrhenius models are unable to represent with acceptable accuracy. The primary limitation is that Arrhenius calculations always overestimate the cell death fraction, which leads to severely overoptimistic predictions of heating effectiveness in tumor treatment. Several more sophisticated mathematical model approaches have been suggested and show much-improved performance. But simpler models that have adequate accuracy would provide useful and practical alternatives to intricate biochemical analyses. Typical transient intrinsic cell death processes at hyperthermic temperatures consist of a slowly developing shoulder region followed by an essentially constant-rate region. The shoulder regions have been demonstrated to arise chiefly from complex functional protein signaling cascades that generate delays in the onset of the constant-rate region, but may involve heat shock protein activity as well. This paper shows that acceptably accurate and much-improved predictions in the simpler Arrhenius models can be obtained by adding a temperature-dependent time delay. Kinetic coefficients and the appropriate time delay are obtained from the constant-rate regions of the measured survival curves. The resulting predictions are seen to provide acceptably accurate results while not overestimating cell death. The method can be relatively easily incorporated into numerical models. Additionally, evidence is presented to support the application of compensation law behavior to the cell death processes--that is, the strong correlation between the kinetic coefficients, ln{A} and E(a), is confirmed.

A Coupled Lumped-Parameter and Distributed Network Model for Cerebral Pulse-Wave Hemodynamics

Abstract: The cerebral circulation is unique in its ability to maintain blood flow to the brain under widely varying physiologic conditions. Incorporating this autoregulatory response is necessary for cerebral blood flow (CBF) modeling, as well as investigations into pathological conditions. We discuss a one-dimensional (1D) nonlinear model of blood flow in the cerebral arteries coupled to autoregulatory lumped-parameter (LP) networks. The LP networks incorporate intracranial pressure (ICP), cerebrospinal fluid (CSF), and cortical collateral blood flow models. The overall model is used to evaluate changes in CBF due to occlusions in the middle cerebral artery (MCA) and common carotid artery (CCA). Velocity waveforms at the CCA and internal carotid artery (ICA) were examined prior and post MCA occlusion. Evident waveform changes due to the occlusion were observed, providing insight into cerebral vasospasm monitoring by morphological changes of the velocity or pressure waveforms. The role of modeling of collateral blood flows through cortical pathways and communicating arteries was also studied. When the MCA was occluded, the cortical collateral flow had an important compensatory role, whereas the communicating arteries in the circle of Willis (CoW) became more important when the CCA was occluded. To validate the model, simulations were conducted to reproduce a clinical test to assess dynamic autoregulatory function, and results demonstrated agreement with published measurements.

Mechanical and Microstructural Investigation of the Cyclic Behavior of Human Amnion

Abstract: The structural and mechanical integrity of amnion is essential to prevent preterm premature rupture (PPROM) of the fetal membrane. In this study, the mechanical response of human amnion to repeated loading and the microstructural mechanisms determining its behavior were investigated. Inflation and uniaxial cyclic tests were combined with corresponding in situ experiments in a multiphoton microscope (MPM). Fresh unfixed amnion was imaged during loading and changes in thickness and collagen orientation were quantified. Mechanical and in situ experiments revealed differences between the investigated configurations in the deformation and microstructural mechanisms. Repeated inflation induces a significant but reversible volume change and is characterized by high energy dissipation. Under uniaxial tension, volume reduction is associated with low energy, unrecoverable in-plane fiber reorientation.

Multiscale Modeling of Trabecular Bone Marrow: Understanding the Micromechanical Environment of Mesenchymal Stem Cells During Osteoporosis

Abstract: Mechanical loading directs the differentiation of mesenchymal stem cells (MSCs) in vitro and it has been hypothesized that the mechanical environment plays a role in directing the cellular fate of MSCs in vivo. However, the complex multicellular composition of trabecular bone marrow means that the precise nature of mechanical stimulation that MSCs experience in their native environment is not fully understood. In this study, we developed a multiscale model that discretely represents the cellular constituents of trabecular bone marrow and applied this model to characterize mechanical stimulation of MCSs in vivo.We predicted that cell-level strains in certain locations of the trabecular marrow microenvironment were greater in magnitude (maximum e12¼24,000 le) than levels that have been found to result in osteogenic differentiation of MSCs in vitro (>8000 le),which may indicate that the native mechanical environment of MSCs could direct cellular fate in vivo. The results also showed that cell–cell adhesions could play an important role in mediating mechanical stimulation within the MSC population in vivo. The model was applied to investigate how changes that occur during osteoporosis affected mechanical stimulation in the cellular microenvironment of trabecular bone marrow. Specifically,a reduced bone volume (BV) resulted in an overall increase in bone deformation, leading to greater cell-level mechanical stimulation in trabecular bone marrow (maximume12¼48,000 le). An increased marrow adipocyte content resulted in slightly lower levels of stimulation within the adjacent cell population due to a shielding effect caused by the more compliant behavior of adipocytes (maximum e12¼41,000 le). Despite this reduction, stimulation levels in trabecular bone marrow during osteoporosis remained much higher than those predicted to occur under healthy conditions. It was found that compensatory mechanobiological responses that occur during osteoporosis, such as increased trabecular stiffness and axial alignment of trabeculae, would be effective in returning MSC stimulation in trabecular marrow to normal levels. These results have provided novel insight into the mechanical stimulation of the trabecular marrow MSC population in both healthy and osteoporotic bone, and could inform the design three dimensional(3D) in vitro bioreactor strategies techniques, which seek to emulate physiological conditions.

Biomechanical Properties of Human Ascending Thoracic Aortic Dissections

Abstract: Thoracic aortic dissections are associated with a significant risk of morbidity and mortality, and currently challenge our understanding of the biomechanical factors leading to their initiation and propagation. We quantified the biaxial mechanical properties of human type A dissections (n = 16) and modeled the stress-strain data using a microstructurally motivated form of strain energy function. Our results show significantly higher stiffness for dissected tissues as compared to control aorta without arterial disease. Higher stiffness of dissected tissues did not, however, correlate with greater aortic diameter measured prior to surgery nor were there any age dependent differences in the tissue properties.

Effects of age and diabetes on scleral stiffness.

Abstract: The effects of diabetes on the collagen structure and material properties of the sclera are unknown but may be important to elucidate whether diabetes is a risk factor for major ocular diseases such as glaucoma. This study provides a quantitative assessment of the changes in scleral stiffness and collagen fiber alignment associated with diabetes. Posterior scleral shells from five diabetic donors and seven non-diabetic donors were pressurized to 30 mm Hg. Three-dimensional surface displacements were calculated during inflation testing using digital image correlation (DIC). After testing, each specimen was subjected to wide-angle X-ray scattering (WAXS) measurements of its collagen organization. Specimen-specific finite element models of the posterior scleras were generated from the experimentally measured geometry. An inverse finite element analysis was developed to determine the material properties of the specimens, i.e., matrix and fiber stiffness, by matching DIC-measured and finite element predicted displacement fields. Effects of age and diabetes on the degree of fiber alignment, matrix and collagen fiber stiffness, and mechanical anisotropy were estimated using mixed effects models accounting for spatial autocorrelation. Older age was associated with a lower degree of fiber alignment and larger matrix stiffness for both diabetic and non-diabetic scleras. However, the age-related increase in matrix stiffness was 87% larger in diabetic specimens compared to non-diabetic controls and diabetic scleras had a significantly larger matrix stiffness (p = 0.01). Older age was associated with a nearly significant increase in collagen fiber stiffness for diabetic specimens only (p = 0.06), as well as a decrease in mechanical anisotropy for non-diabetic scleras only (p = 0.04). The interaction between age and diabetes was not significant for all outcomes. This study suggests that the age-related increase in scleral stiffness is accelerated in eyes with diabetes, which may have important implications in glaucoma.