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### Research Papers

J Biomech Eng. 2017;140(1):011001-011001-11. doi:10.1115/1.4037791.

Stair ascent is an activity of daily living and necessary for maintaining independence in community environments. One challenge to improving an individual's ability to ascend stairs is a limited understanding of how lower-limb muscles work in synergy to perform stair ascent. Through dynamic coupling, muscles can perform multiple functions and require contributions from other muscles to perform a task successfully. The purpose of this study was to identify the functional roles of individual muscles during stair ascent and the mechanisms by which muscles work together to perform specific subtasks. A three-dimensional (3D) muscle-actuated simulation of stair ascent was generated to identify individual muscle contributions to the biomechanical subtasks of vertical propulsion, anteroposterior (AP) braking and propulsion, mediolateral control and leg swing. The vasti and plantarflexors were the primary contributors to vertical propulsion during the first and second halves of stance, respectively, while gluteus maximus and hamstrings were the primary contributors to forward propulsion during the first and second halves of stance, respectively. The anterior and posterior components of gluteus medius were the primary contributors to medial control, while vasti and hamstrings were the primary contributors to lateral control during the first and second halves of stance, respectively. To control leg swing, antagonistic muscles spanning the hip, knee, and ankle joints distributed power from the leg to the remaining body segments. These results compliment previous studies analyzing stair ascent and provide further rationale for developing targeted rehabilitation strategies to address patient-specific deficits in stair ascent.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2017;140(1):011002-011002-14. doi:10.1115/1.4037857.

Computational fluid dynamics (CFD) provides a noninvasive method to functionally assess aortic hemodynamics. The thoracic aorta has an anatomically complex inlet comprising of the aortic valve and root, which is highly prone to different morphologies and pathologies. We investigated the effect of using patient-specific (PS) inflow velocity profiles compared to idealized profiles based on the patient's flow waveform. A healthy 31 yo with a normally functioning tricuspid aortic valve (subject A), and a 52 yo with a bicuspid aortic valve (BAV), aortic valvular stenosis, and dilated ascending aorta (subject B) were studied. Subjects underwent MR angiography to image and reconstruct three-dimensional (3D) geometric models of the thoracic aorta. Flow-magnetic resonance imaging (MRI) was acquired above the aortic valve and used to extract the patient-specific velocity profiles. Subject B's eccentric asymmetrical inflow profile led to highly complex velocity patterns, which were not replicated by the idealized velocity profiles. Despite having identical flow rates, the idealized inflow profiles displayed significantly different peak and radial velocities. Subject A's results showed some similarity between PS and parabolic inflow profiles; however, other parameters such as Flowasymmetry were significantly different. Idealized inflow velocity profiles significantly alter velocity patterns and produce inaccurate hemodynamic assessments in the thoracic aorta. The complex structure of the aortic valve and its predisposition to pathological change means the inflow into the thoracic aorta can be highly variable. CFD analysis of the thoracic aorta needs to utilize fully PS inflow boundary conditions in order to produce truly meaningful results.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2017;140(1):011003-011003-8. doi:10.1115/1.4037854.

Pedestrians represent one of the most vulnerable road users and comprise nearly 22% the road crash-related fatalities in the world. Therefore, protection of pedestrians in car-to-pedestrian collisions (CPC) has recently generated increased attention with regulations involving three subsystem tests. The development of a finite element (FE) pedestrian model could provide a complementary component that characterizes the whole-body response of vehicle–pedestrian interactions and assesses the pedestrian injuries. The main goal of this study was to develop and to validate a simplified full body FE model corresponding to a 50th male pedestrian in standing posture (M50-PS). The FE model mesh and defined material properties are based on a 50th percentile male occupant model. The lower limb-pelvis and lumbar spine regions of the human model were validated against the postmortem human surrogate (PMHS) test data recorded in four-point lateral knee bending tests, pelvic\abdomen\shoulder\thoracic impact tests, and lumbar spine bending tests. Then, a pedestrian-to-vehicle impact simulation was performed using the whole pedestrian model, and the results were compared to corresponding PMHS tests. Overall, the simulation results showed that lower leg response is mostly within the boundaries of PMHS corridors. In addition, the model shows the capability to predict the most common lower extremity injuries observed in pedestrian accidents. Generally, the validated pedestrian model may be used by safety researchers in the design of front ends of new vehicles in order to increase pedestrian protection.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2017;140(1):011004-011004-12. doi:10.1115/1.4037916.

This paper is concerned with proposing a suitable structurally motivated strain energy function, denoted by $Weelastin network$, for modeling the deformation of the elastin network within the aortic valve (AV) tissue. The AV elastin network is the main noncollagenous load-bearing component of the valve matrix, and therefore, in the context of continuum-based modeling of the AV, the $Weelastin network$ strain energy function would essentially serve to model the contribution of the “isotropic matrix.” To date, such a function has mainly been considered as either a generic neo-Hookean term or a general exponential function. In this paper, we take advantage of the established structural analogy between the network of elastin chains and the freely jointed molecular chain networks to customize a structurally motivated $Weelastin network$ function on this basis. The ensuing stress–strain (force-stretch) relationships are thus derived and fitted to the experimental data points reported by (Vesely, 1998, “The Role of Elastin in Aortic Valve Mechanics,” J. Biomech., 31, pp. 115–123) for intact AV elastin network specimens under uniaxial tension. The fitting results are then compared with those of the neo-Hookean and the general exponential models, as the frequently used models in the literature, as well as the “Arruda–Boyce” model as the gold standard of the network chain models. It is shown that our proposed $Weelastin network$ function, together with the general exponential and the Arruda–Boyce models provide excellent fits to the data, with R2 values in excess of 0.98, while the neo-Hookean function is entirely inadequate for modeling the AV elastin network. However, the general exponential function may not be amenable to rigorous interpretation, as there is no structural meaning attached to the model. It is also shown that the parameters estimated by the Arruda–Boyce model are not mathematically and structurally valid, despite providing very good fits. We thus conclude that our proposed strain energy function $Weelastin network$ is the preferred choice for modeling the behavior of the AV elastin network and thereby the isotropic matrix. This function may therefore be superimposed onto that of the anisotropic collagen fibers family in order to develop a structurally motivated continuum-based model for the AV.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2017;140(1):011005-011005-8. doi:10.1115/1.4037406.

This study focuses on thermal analysis of the problem of scaling up from the vitrification of rabbit kidneys to the vitrification of human kidneys, where vitrification is the preservation of biological material in the glassy state. The basis for this study is a successful cryopreservation protocol for a rabbit kidney model, based on using a proprietary vitrification solution known as M22. Using the finite element analysis (FEA) commercial code ANSYS, heat transfer simulations suggest that indeed the rabbit kidney unquestionably cools rapidly enough to be vitrified based on known intrarenal concentrations of M22. Scaling up 21-fold, computer simulations suggest less favorable conditions for human kidney vitrification. In this case, cooling rates below −100 °C are sometimes slower than 1 °C/min, a rate that provides a clear-cut margin of safety at all temperatures based on the stability of rabbit kidneys in past studies. Nevertheless, it is concluded in this study that vitrifying human kidneys is possible without significant ice damage, assuming that human kidneys can be perfused with M22 as effectively as rabbit kidneys. The thermal analysis suggests that cooling rates can be further increased by a careful design of the cryogenic protocol and by tailoring the container to the shape of the kidney, in contrast to the present cylindrical container. This study demonstrates the critical need for the thermal analysis of experimental cryopreservation and highlights the unmet need for measuring the thermophysical properties of cryoprotective solutions under conditions relevant to realistic thermal histories.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2017;140(1):011006-011006-10. doi:10.1115/1.4037945.

Quantized dynamical entropy (QDE) has recently been proposed as a new measure to quantify the complexity of dynamical systems with the purpose of offering a better computational efficiency. This paper further investigates the viability of this method using five different human gait signals. These signals are recorded while normal walking and while performing secondary tasks among two age groups (young and older age groups). The results are compared with the outcomes of previously established sample entropy (SampEn) measure for the same signals. We also study how analyzing segmented and spatially and temporally normalized signal differs from analyzing whole data. Our findings show that human gait signals become more complex as people age and while they are cognitively loaded. Center of pressure (COP) displacement in mediolateral direction is the best signal for showing the gait changes. Moreover, the results suggest that by segmenting data, more information about intrastride dynamical features are obtained. Most importantly, QDE is shown to be a reliable measure for human gait complexity analysis.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2017;140(1):011007-011007-9. doi:10.1115/1.4038147.

With the onset and progression of osteoarthritis (OA), articular cartilage (AC) mechanical properties are altered. These alterations can serve as an objective measure of tissue degradation. Although the mouse is a common and useful animal model for studying OA, it is extremely challenging to measure the mechanical properties of murine AC due to its small size (thickness < 50 μm). In this study, we developed novel and direct approach to independently quantify two quasi-static mechanical properties of mouse AC: the load-dependent (nonlinear) solid matrix Young's modulus (E) and drained Poisson's ratio (ν). The technique involves confocal microscope-based multiaxial strain mapping of compressed, intact murine AC followed by inverse finite element analysis (iFEA) to determine E and ν. Importantly, this approach yields estimates of E and ν that are independent of the initial guesses used for iterative optimization. As a proof of concept, mechanical properties of AC on the medial femoral condyles of wild-type mice were obtained for both trypsin-treated and control specimens. After proteolytic tissue degradation induced through trypsin treatment, a dramatic decrease in E was observed (compared to controls) at each of the three tested loading conditions. A significant decrease in ν due to trypsin digestion was also detected. These data indicate that the method developed in this study may serve as a valuable tool for comparative studies evaluating factors involved in OA pathogenesis using experimentally induced mouse OA models.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2017;140(1):011008-011008-12. doi:10.1115/1.4038157.

Quantitative animal models are critically needed to provide proof of concept for the investigation of rehabilitative balance therapies (e.g., invasive vestibular prostheses) and treatment response prior to, or in conjunction with, human clinical trials. This paper describes a novel approach to modeling the nonhuman primate postural control system. Our observation that rhesus macaques and humans have even remotely similar postural control motivates the further application of the rhesus macaque as a model for studying the effects of vestibular dysfunction, as well as vestibular prosthesis-assisted states, on human postural control. Previously, system identification methodologies and models were only used to describe human posture. However, here we utilized pseudorandom, roll-tilt balance platform stimuli to perturb the posture of a rhesus monkey in normal and mild vestibular (equilibrium) loss states. The relationship between rhesus monkey trunk sway and platform roll-tilt was determined via stimulus–response curves and transfer function results. A feedback controller model was then used to explore sensory reweighting (i.e., changes in sensory reliance), which prevented the animal from falling off of the tilting platform. Conclusions involving sensory reweighting in the nonhuman primate for a normal sensory state and a state of mild vestibular loss led to meaningful insights. This first-phase effort to model the balance control system in nonhuman primates is essential for future investigations toward the effects of invasive rehabilitative (balance) technologies on postural control in primates, and ultimately, humans.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2017;140(1):011009-011009-10. doi:10.1115/1.4037915.

Availability of essential species like oxygen is critical in shaping the dynamics of tumor growth. When the intracellular oxygen level falls below normal, it initiates major cascades in cellular dynamics leading to tumor cell survival. In a cellular block with cells growing away from the blood vessel, the scenario can be aggravated for the cells further inside the block. In this study, the dynamics of intracellular species inside a colony of tumor cells are investigated by varying the cell-block thickness and cell types in a microfluidic cell culture device. The oxygen transport across the cell block is modeled through diffusion, while ascorbate (AS) transport from the extracellular medium is addressed by a concentration-dependent uptake model. The extracellular and intracellular descriptions were coupled through the consumption and traffic of species from the microchannel to the cell block. Our model shows that the onset of hypoxia is possible in HeLa cell within minutes depending on the cell location, although the nutrient supply inside the channel is maintained in normoxic levels. This eventually leads to total oxygen deprivation inside the cell block in the extreme case, representing the development of a necrotic core that maintains a dynamic balance with growing cells and scarce supply. The numerical model reveals that species concentration and hypoxic response are different for HeLa and HelaS3 cells. Results also indicate that the long-term hypoxic response from a microfluidic cellular block stays within 5% of the values of a tissue with the basal layer. The hybrid model can be very useful in designing microfluidic experiments to satisfactorily predict the tissue-level response in cancer research.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2017;140(1):011010-011010-13. doi:10.1115/1.4038163.

The aim of this study was to investigate and quantify contributions of kinetic energy and viscous dissipation to airway resistance during inspiration and expiration at various flow rates in airway models of different bifurcation angles. We employed symmetric airway models up to the 20th generation with the following five different bifurcation angles at a tracheal flow rate of 20 L/min: 15 deg, 25 deg, 35 deg, 45 deg, and 55 deg. Thus, a total of ten computational fluid dynamics (CFD) simulations for both inspiration and expiration were conducted. Furthermore, we performed additional four simulations with tracheal flow rate values of 10 and 40 L/min for a bifurcation angle of 35 deg to study the effect of flow rate on inspiration and expiration. Using an energy balance equation, we quantified contributions of the pressure drop associated with kinetic energy and viscous dissipation. Kinetic energy was found to be a key variable that explained the differences in airway resistance on inspiration and expiration. The total pressure drop and airway resistance were larger during expiration than inspiration, whereas wall shear stress and viscous dissipation were larger during inspiration than expiration. The dimensional analysis demonstrated that the coefficients of kinetic energy and viscous dissipation were strongly correlated with generation number. In addition, the viscous dissipation coefficient was significantly correlated with bifurcation angle and tracheal flow rate. We performed multiple linear regressions to determine the coefficients of kinetic energy and viscous dissipation, which could be utilized to better estimate the pressure drop in broader ranges of successive bifurcation structures.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2017;140(1):011011-011011-10. doi:10.1115/1.4038199.

Accurate prediction of muscle and joint contact forces during human movement could improve treatment planning for disorders such as osteoarthritis, stroke, Parkinson's disease, and cerebral palsy. Recent studies suggest that muscle synergies, a low-dimensional representation of a large set of muscle electromyographic (EMG) signals (henceforth called “muscle excitations”), may reduce the redundancy of muscle excitation solutions predicted by optimization methods. This study explores the feasibility of using muscle synergy information extracted from eight muscle EMG signals (henceforth called “included” muscle excitations) to accurately construct muscle excitations from up to 16 additional EMG signals (henceforth called “excluded” muscle excitations). Using treadmill walking data collected at multiple speeds from two subjects (one healthy, one poststroke), we performed muscle synergy analysis on all possible subsets of eight included muscle excitations and evaluated how well the calculated time-varying synergy excitations could construct the remaining excluded muscle excitations (henceforth called “synergy extrapolation”). We found that some, but not all, eight-muscle subsets yielded synergy excitations that achieved >90% extrapolation variance accounted for (VAF). Using the top 10% of subsets, we developed muscle selection heuristics to identify included muscle combinations whose synergy excitations achieved high extrapolation accuracy. For 3, 4, and 5 synergies, these heuristics yielded extrapolation VAF values approximately 5% lower than corresponding reconstruction VAF values for each associated eight-muscle subset. These results suggest that synergy excitations obtained from experimentally measured muscle excitations can accurately construct unmeasured muscle excitations, which could help limit muscle excitations predicted by muscle force optimizations.

Commentary by Dr. Valentin Fuster

### Technical Brief

J Biomech Eng. 2017;140(1):014501-014501-6. doi:10.1115/1.4037949.

The mechanical response of intact blood vessels to applied loads can be delineated into passive and active components using an isometric decomposition approach. Whereas the passive response is due predominantly to the extracellular matrix (ECM) proteins and amorphous ground substance, the active response depends on the presence of smooth muscle cells (SMCs) and the contractile machinery activated within those cells. To better understand determinants of active stress generation within the vascular wall, we subjected porcine common carotid arteries (CCAs) to biaxial inflation–extension testing under maximally contracted or passive SMC conditions and semiquantitatively measured two known markers of the contractile SMC phenotype: smoothelin and smooth muscle-myosin heavy chain (SM-MHC). Using isometric decomposition and established constitutive models, an intuitive but novel correlation between the magnitude of active stress generation and the relative abundance of smoothelin and SM-MHC emerged. Our results reiterate the importance of stretch-dependent active stress generation to the total mechanical response. Overall these findings can be used to decouple the mechanical contribution of SMCs from the ECM and is therefore a powerful tool in the analysis of disease states and potential therapies where both constituent are altered.

Commentary by Dr. Valentin Fuster

### Errata

J Biomech Eng. 2017;140(1):017001-017001-1. doi:10.1115/1.4038262.

Devyn Rice has been removed as an author and removed from the Acknowledgment.

Commentary by Dr. Valentin Fuster

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