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IN THIS ISSUE

### Research Papers

J Biomech Eng. 2019;141(8):081001-081001-17. doi:10.1115/1.4043442.

Although tremor is the most common movement disorder, there are few noninvasive treatment options. Creating effective tremor suppression devices requires a knowledge of where tremor originates mechanically (which muscles) and how it propagates through the limb (to which degrees-of-freedom (DOF)). To simulate tremor propagation, we created a simple model of the upper limb, with tremorogenic activity in the 15 major superficial muscles as inputs and tremulous joint displacement in the seven major DOF as outputs. The model approximated the muscle excitation–contraction dynamics, musculoskeletal geometry, and mechanical impedance of the limb. From our simulations, we determined fundamental principles for tremor propagation: (1) The distribution of tremor depends strongly on musculoskeletal dynamics. (2) The spreading of tremor is due to inertial coupling (primarily) and musculoskeletal geometry (secondarily). (3) Tremorogenic activity in a given muscle causes significant tremor in only a small subset of DOF, though these affected DOF may be distant from the muscle. (4) Assuming uniform distribution of tremorogenic activity among muscles, tremor increases proximal-distally, and the contribution from muscles increases proximal-distally. (5) Although adding inertia (e.g., with weighted utensils) is often used to suppress tremor, it is possible to increase tremor by adding inertia to the wrong DOF. (6) Similarly, adding viscoelasticity to the wrong DOF can increase tremor. Based solely on the musculoskeletal system, these principles indicate that tremor treatments targeting muscles should focus first on the distal muscles, and devices targeting DOF should focus first on the distal DOF.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2019;141(8):081002-081002-8. doi:10.1115/1.4043208.

During chondrogenesis, tissue organization changes dramatically. We previously showed that the compressive moduli of chondrocytes increase concomitantly with extracellular matrix (ECM) stiffness, suggesting cells were remodeling to adapt to the surrounding environment. Due to the difficulty in analyzing the mechanical response of cells in situ, we sought to create an in silico model that would enable us to investigate why cell and ECM stiffness increased in tandem. The goal of this study was to establish a methodology to segment, quantify, and generate mechanical models of developing cartilage to explore how variations in geometry and material properties affect strain distributions. Multicellular geometries from embryonic day E16.5 and postnatal day P3 murine cartilage were imaged in three-dimensional (3D) using confocal microscopy. Image stacks were processed using matlab to create geometries for finite element analysis using ANSYS. The geometries based on confocal images and isolated, single cell models were compressed 5% and the equivalent von Mises strain of cells and ECM were compared. Our simulations indicated that cells had similar strains at both time points, suggesting that the stiffness and organization of cartilage changes during development to maintain a constant strain profile within cells. In contrast, the ECM at P3 took on more strain than at E16.5. The isolated, single-cell geometries underestimated both cell and ECM strain and were not able to capture the similarity in cell strain at both time points. We expect this experimental and computational pipeline will facilitate studies investigating other model systems to implement physiologically derived geometries.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2019;141(8):081003-081003-7. doi:10.1115/1.4043443.

Multifidus function is important for active stabilization of the spine, but it can be compromised in patients with chronic low back pain and other spine pathologies. Force production and strength of back muscles are often evaluated using isometric or isokinetic tests, which lack the ability to quantify multifidi contribution independent of the erector spinae and adjacent hip musculature. The objective of this study is to evaluate localized force production capability in multifidus muscle using ultrasound shear wave elastography (SWE) in healthy individuals. Three different body positions were considered: lying prone, sitting up, and sitting up with the right arm lifted. These positions were chosen to progressively increase multifidus contraction and to minimize body motion during measurements. Shear modulus was measured at the superficial and deeper layers of the multifidus. Repeatability and possible sources of error of the shear modulus measurements were analyzed. Multifidus shear modulus (median (interquartile range)) increased from prone, i.e., 16.15 (6.69) kPa, to sitting up, i.e., 27.28 (15.72) kPa, to sitting up with the right arm lifted position, i.e., 45.02 (25.27) kPa. Multifidi shear modulus in the deeper layer of the multifidi was lower than the superficial layer, suggesting lower muscle contraction. Intraclass correlation coefficients (ICCs) for evaluation of shear modulus by muscle layer were found to be excellent (ICC = 0.76–0.80). Results suggest that the proposed protocol could quantify local changes in spinal muscle function in healthy adults; further research in patients with spine pathology is warranted.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2019;141(8):081004-081004-9. doi:10.1115/1.4043322.

Arterial stiffening is a hallmark of aging, but how aging affects the arterial response to pressure is still not completely understood, especially with regard to specific matrix metalloproteinases (MMPs). Here, we performed biaxial inflation–extension tests on C57BL/6 mice to study the effects of age and MMP12, a major arterial elastase, on arterial biomechanics. Aging from 2 to 24 months leads to both circumferential and axial stiffening with stretch, and these changes are associated with an increased wall thickness, a decreased inner radius–wall thickness ratio, and a decreased in vivo axial stretch. Analysis of in vivo stretch and stress–stretch curves with arteries from age- and sex-matched wild-type (WT) and MMP12-null arteries demonstrates that MMP12 deletion attenuates age-dependent arterial stiffening, mostly in the axial direction. MMP12 deletion also prevents the aging-associated decrease in the in vivo stretch and, in general, leads to an axial mechanics phenotype characteristic of much younger mice. Circumferential arterial mechanics were much less affected by deletion of MMP12. We conclude that the induction of MMP12 during aging preferentially promotes axial arterial stiffening.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2019;141(8):081005-081005-10. doi:10.1115/1.4043253.

Cell mechanics has been shown to regulate stem cell differentiation. We have previously reported that altered cell stiffness of mesenchymal stem cells can delay or facilitate biochemically directed differentiation. One of the factors that can affect the cell stiffness is cholesterol. However, the effect of cholesterol on differentiation of human mesenchymal stem cells remains elusive. In this paper, we demonstrate that cholesterol is involved in the modulation of the cell stiffness and subsequent adipogenic differentiation. Rapid cytoskeletal actin reorganization was evident and correlated with the cell's Young's modulus measured using atomic force microscopy. In addition, the level of membrane-bound cholesterol was found to increase during adipogenic differentiation and inversely varied with the cell stiffness. Furthermore, cholesterol played a key role in the regulation of the cell morphology and biomechanics, suggesting its crucial involvement in mechanotransduction. To better understand the underlying mechanisms, we investigated the effect of cholesterol on the membrane–cytoskeleton linker proteins (ezrin and moesin). Cholesterol depletion was found to upregulate the ezrin expression which promoted cell spreading, increased Young's modulus, and hindered adipogenesis. In contrast, cholesterol enrichment increased the moesin expression, decreased Young's modulus, and induced cell rounding and facilitated adipogenesis. Taken together, cholesterol appears to regulate the stem cell mechanics and adipogenesis through the membrane-associated linker proteins.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2019;141(8):081006-081006-16. doi:10.1115/1.4043038.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2019;141(8):081007-081007-6. doi:10.1115/1.4043358.

The purpose of this study is to quantify the impact of enzyme activity on the vitreous humor structure over time to understand the mechanical characteristics of the vitreous humor gel. Changes in the mechanical behavior of the vitreous occur due to many reasons including aging, which may lead to many vitreoretinal diseases. The degeneration process of the vitreous has been studied; however, in situ experimental procedures to validate the existing hypotheses are limited. We examined thirty-eight porcine eyes using in situ rheological creep tests to measure the mechanical properties of the vitreous humor of the eyes prior to, 1 h and 24 h after the intravitreal injection. Eyes in one group were injected with collagenase type II solution and eyes in the control group were injected with phosphate buffered saline solution (PBS) with calcium and magnesium chloride. Prior to the injection, viscosity and creep compliance intercept values between both groups were not statistically different. At 1 h and 24 h after the injection, vitreous properties in the eyes from the first group showed a statistically significant increase in the J intercept values (representing the inverse of elasticity) compared to the control group. In addition, 1 h and 24 h after the injection, vitreous viscosity was lower in the eyes from the first group than in the eyes from the control group. These findings are a foundation for future studies on the effectiveness of intravitreal drugs that modify the mechanical properties of the vitreous humor.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2019;141(8):081008-081008-10. doi:10.1115/1.4043032.

This work aims to provide a contribution to determine a proper model for the study of fluid film lubrication for the reduction of knee prostheses failure due to polyethylene wear. The Phan-Thien and Tanner (PTT) rheological law and the elastic deformation of the articular surfaces were considered in this modeling. The governing equations were solved numerically for different geometries and different Weissenberg numbers. The lubrication approximation applied to the PTT rheological law leads to an expression for the apparent viscosity similar to the Cross model. The results attest the importance of considering the non-Newtonian behavior of the synovial fluid, the elastic deformation, and the geometrical features of the prostheses to obtain quantitative information.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2019;141(8):081009-081009-8. doi:10.1115/1.4043558.

Understanding low back muscle morphology is critical to understanding spinal loading and the underlying injury mechanisms, which help in characterizing risk and, therefore, minimize low back pain injuries. Individualized erector spinae muscle mass (ESMM) cross-sectional area (CSA) allows biomechanics practitioners to calculate individualized force generating capacities and spinal loadings for given tasks. The objective is to perform morphological analyses and then provide regression models to estimate the ESMM CSA of an individual with his/her subject characteristics. Thirty-five subjects (13 females and 22 males) without low back pain (LBP) history were included in this magnetic resonance imaging (MRI) study. Axial-oblique scans of low back region were used to measure the ESMM CSA. Subject demographics and anthropometrics were obtained and regressed over the ESMM CSA. Best-subset regression analyses were performed. Lean body mass (LBM) and the ankle, wrist, and head indexes were the most frequent predictive variables. Regression models with easy-to-measure variables showed smaller predictive power and increased estimation error compared to other regression models. Practitioners should consider this trade-off between model accuracy and complexity. An individual's ESMM CSA could be estimated by his/her individual characteristics, which enables biomechanical practitioners to estimate individualized low back force capacity and spinal loading.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2019;141(8):081010-081010-10. doi:10.1115/1.4043449.

Pre-impact fall detection can send alarm service faster to reduce long-lie conditions and decrease the risk of hospitalization. Detecting various types of fall to determine the impact site or direction prior to impact is important because it increases the chance of decreasing the incidence or severity of fall-related injuries. In this study, a robust pre-impact fall detection model was developed to classify various activities and falls as multiclass and its performance was compared with the performance of previous developed models. Twelve healthy subjects participated in this study. All subjects were asked to place an inertial measuring unit module by fixing on a belt near the left iliac crest to collect accelerometer data for each activity. Our novel proposed model consists of feature calculation and infinite latent feature selection (ILFS) algorithm, auto labeling of activities, and application of machine learning classifiers for discrete and continuous time series data. Nine machine-learning classifiers were applied to detect falls prior to impact and derive final detection results by sorting the classifier. Our model showed the highest classification accuracy. Results for the proposed model that could classify as multiclass showed significantly higher average classification accuracy of 99.57 ± 0.01% for discrete data-based classifiers and 99.84 ± 0.02% for continuous time series-based classifiers than previous models (p < 0.01). In the future, multiclass pre-impact fall detection models can be applied to fall protector devices by detecting various activities for sending alerts or immediate feedback reactions to prevent falls.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2019;141(8):081011-081011-8. doi:10.1115/1.4043521.

Freezing of the aqueous solutions that comprise biological materials, such as isotonic physiological saline, results in the formation of ice crystals and the generation of a hypertonic solution, both of which prove deleterious to biological matter. The field of modern cryopreservation, or preservation of biological matter at subfreezing temperatures, emerged from the 1948 discovery that certain chemical additives such as glycerol, known as cryoprotectants, can protect cells from freeze-related damage by depressing the freezing point of water in solution. This gave rise to a slew of important medical applications, from the preservation of sperm and blood cells to the recent preservation of an entire liver, and current cryopreservation protocols thus rely heavily on the use of additive cryoprotectants. However, high concentrations of cryoprotectants themselves prove toxic to cells, and thus there is an ongoing effort to minimize cryoprotectant usage while maintaining protection from ice-related damage. Herein, we conceive from first principles a new, purely thermodynamic method to eliminate ice formation and hypertonicity during the freezing of a physiological solution: multiphase isochoric freezing. We develop a comprehensive thermodynamic model to predict the equilibrium behaviors of multiphase isochoric systems of arbitrary composition and validate these concepts experimentally in a simple device with no moving parts, providing a baseline from which to design tailored cryopreservation protocols using the multiphase isochoric technique.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2019;141(8):081012-081012-7. doi:10.1115/1.4043562.
FREE TO VIEW

Accurate joint kinematics plays an important role in estimating joint kinetics in musculoskeletal simulations. Biplanar fluoroscopic (BPF) systems have been introduced to measure skeletal kinematics with six degrees-of-freedom. The purpose of this study was to model knee kinematic coupling using knee kinematics during walking, as measured by the BPF system. Seven healthy individuals (mean age, 23 ± 2 yr) performed treadmill walking trials at 1.2 m/s. Knee kinematics was regressed separately for the swing and stance phases using a generalized mixed effects model. Tibial anterior translation function was $y=0.20x−3.09$ for the swing phase and $y=0.31x−0.54$ for the stance phase, where $x$ was the flexion angle and $y$ was the tibial anterior translation. Tibial lateral and inferior translation were also regressed separately for the stance phase and the swing phase. Tibial external rotation was $y=−0.002x2+0.19x−0.64$ for the swing phase and $y=−0.19x−1.22$ for the stance phase. The tibial adduction rotation function was also calculated separately for the stance and swing phase. The study presented three-dimensional coupled motion in the knee during the stance and swing phases of walking, and demonstrated the lateral pivoting motion found in previous studies. This expanded understanding of secondary knee motion functions will benefit musculoskeletal simulation and help improve the accuracy of calculated kinetics.

Topics: Kinematics , Knee
Commentary by Dr. Valentin Fuster

### Technical Brief

J Biomech Eng. 2019;141(8):084501-084501-7. doi:10.1115/1.4043447.

Characterization of muscle mechanism through the torque-angle and torque–velocity relationships is critical for human movement evaluation and simulation. in vivo determination of these relationships through dynamometric measurements and modeling is based on physiological and mathematical aspects. However, no investigation regarding the effects of the mathematical model and the physiological parameters underneath these models was found. The purpose of the current study was to compare the capacity of various torque-angle and torque–velocity models to fit experimental dynamometric measurement of the elbow and provide meaningful mechanical and physiological information. Therefore, varying mathematical function and physiological muscle parameters from the literature were tested. While a quadratic torque-angle model seemed to increase predicted to measured elbow torque fitting, a new power-based torque–velocity parametric model gave meaningful physiological values to interpret with similar fitting results to a classical torque–velocity model. This model is of interest to extract modeling and clinical knowledge characterizing the mechanical behavior of such a joint.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2019;141(8):084502-084502-9. doi:10.1115/1.4043290.

Finite element and machine learning modeling are two predictive paradigms that have rarely been bridged. In this study, we develop a parametric model to generate arterial geometries and accumulate a database of 12,172 2D finite element simulations modeling the hyperelastic behavior and resulting stress distribution. The arterial wall composition mimics vessels in atherosclerosis–a complex cardiovascular disease and one of the leading causes of death globally. We formulate the training data to predict the maximum von Mises stress, which could indicate risk of plaque rupture. Trained deep learning models are able to accurately predict the max von Mises stress within 9.86% error on a held-out test set. The deep neural networks outperform alternative prediction models and performance scales with amount of training data. Lastly, we examine the importance of contributing features on stress value and location prediction to gain intuitions on the underlying process. Moreover, deep neural networks can capture the functional mapping described by the finite element method, which has far-reaching implications for real-time and multiscale prediction tasks in biomechanics.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2019;141(8):084503-084503-4. doi:10.1115/1.4043522.

The electrical response of the skin to mechanical stretches is reported here. The electrical potential difference across the epidermis, i.e., transepidermal potential (TEP) of porcine skin samples subjected to cyclic stretching, was measured in real time to observe electrochemical change in epidermal tissue. In addition to a conventional method of TEP measurement for the whole of skin sample, a probe-type system with a fine-needle salt bridge was used for direct measurement of TEP at a targeted local point of the skin. TEP decreased with the increased mechanical stretches, and the change of TEP was found to be mostly occurred in the epidermis but not dermis nor hypodermis by comparing the results of conventional and the probe-type methods. The observed change of TEP value was quick, reversible, and strain-dependent. Considering from such characteristic behaviors, one of the possible mechanisms of the modulation of TEP would be influence of the streaming potential caused by the fluid flow during the physical deformation of the epidermis.

Topics: Skin , Probes , needles
Commentary by Dr. Valentin Fuster