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Accepted Manuscripts

BASIC VIEW  |  EXPANDED VIEW
research-article  
Swithin Razu and Trent M. Guess
J Biomech Eng   doi: 10.1115/1.4038507
This study leveraged data from the "Sixth Grand Challenge Competition to Predict in Vivo Knee Loads" to create a full-body musculoskeletal model that incorporates subject specific geometries of the right leg in order to concurrently predict knee contact forces, ligament forces, muscle forces, and ground contact forces. The objectives of this paper are twofold: First, to describe an electromyography (EMG)-driven modeling methodology to predict knee contact forces, and second to validate model predictions by evaluating the model predictions against known values for a patient with an instrumented total knee replacement (TKR) for three distinctly different gait styles (normal, smooth, and bouncy gait). A novel EMG-driven feedforward with feedback trim motor control strategy was used to concurrently estimate muscle forces and knee contact forces from standard motion capture data collected on the individual subject. The predicted medial, lateral, and total tibiofemoral forces represented the overall measured magnitude and temporal patterns with good root mean squared errors (RMSEs) and Pearson's correlation (?2). The model accuracy was high: medial, lateral, and total tibiofemoral contact force RMSEs = 0.15, 0.14, 0.21 body weight (BW), and (0.92< ?2<0.96) for normal gait; RMSEs = 0.18 BW, 0.21 BW, 0.29 BW, and (0.81< ?2<0.93) for smooth gait; and RMSEs = 0.21 BW, 0.22 BW, 0.33 BW, and (0.86< ?2<0.95) for bouncy gait, respectively.
TOPICS: Dynamics (Mechanics), Simulation, Electromyography, Knee, Muscle, Musculoskeletal system, Knee joint prostheses, Weight (Mass), Errors, Feedback, Feedforward control, Stress, Motor controls, Modeling
Technical Brief  
Jo P Pauls, Llion Roberts, Tom Burgess, John / F. Fraser, Shaun / D. Gregory and Geoff Tansley
J Biomech Eng   doi: 10.1115/1.4038429
Rotary blood pumps (RBPs) used for mechanical circulatory support of heart failure patients cannot passively change pump flow sufficiently in response to frequent variations in preload induced by active postural changes. A physiological control system that mimics the response of the healthy heart is needed to adjust pump flow according to patient demand. Thus, baseline data is required on how the healthy heart (i.e. heart rate (HR) and cardiac output (CO)) and circulatory system (i.e. systemic vascular resistance (SVR)) respond. This study investigated the response times of the healthy heart during active postural changes (supine-standing-supine) in 50 healthy subjects (27 male / 23 female). Early response times (te) and settling times (ts) were calculated for HR, CO and SVR from data continuously collected with impedance cardiography. The initial circulatory response of HR, CO and SVR resulted in te of 8.8 - 11.7 s when standing up and te of 4.7 - 5.8 s when lying back down. HR, CO and SVR settled in ts of 50.0 - 56.7 s and 46.3 - 66.5 s when standing up and lying down respectively. In conclusion, when compared to active stand up HR, CO and SVR responded significant faster initially when subjects were lying down (p<0.05); there were no significant differences in response times between male and female subjects. This data will be used during evaluation of physiological control systems for RBPs which may improve patient outcomes for end-stage heart failure patients.
TOPICS: Cardiovascular system, Pumps, Physiology, Heart failure, Flow (Dynamics), Control systems, Blood, Performance
research-article  
Fuyou Liang, Debao Guan and Jordi Alastruey
J Biomech Eng   doi: 10.1115/1.4038430
Hypertension is a well-documented predictive factor for cardiovascular events. Clinical studies have extensively demonstrated the differential hemodynamic consequences of various anti-hypertensive drugs, but failed to clearly elucidate the underlying mechanisms due to the difficulty in performing a quantitative deterministic analysis based on clinical data that carry confounding information stemming from inter-patient differences and the nonlinearity of cardiovascular hemodynamics. In the present study, a multi-scale model of the cardiovascular system was developed to quantitatively investigate the relationships between hemodynamic variables and cardiovascular properties under hypertensive conditions, aiming to establish a theoretical basis for assisting in the interpretation of clinical observations or optimization of therapy. Results demonstrated that heart period, central arterial stiffness and arteriolar radius were the major determinant factors for blood pressures and flow pulsatility indices both in large arteries and in the microcirculation. These factors differed in the degree and the way in which they affect hemodynamic variables due to their differential effects on wave reflections in the vascular system. In particular, it was found that the hemodynamic effects of varying arteriolar radius were considerably influenced by the state of central arterial stiffness, and vice versa, which implied the potential of optimizing anti-hypertensive treatment by selecting proper drugs based on patient-specific cardiovascular conditions. When analyzed in relation to clinical observations, the simulated results provided mechanistic explanations for the beneficial pressure-lowering effects of vasodilators as compared to ß-blockers, and highlighted the significance of monitoring and normalizing arterial stiffness in the treatment of hypertension.
TOPICS: Hemodynamics, Cardiovascular system, Stiffness, Drugs, Patient treatment, Pressure, Flow (Dynamics), Reflection, Waves, Blood, Optimization
research-article  
Catalin Picu, Sai Deogekar and Mohammad Islam
J Biomech Eng   doi: 10.1115/1.4038428
Connective tissue mechanics is highly non-linear, exhibits a strong Poisson effect and is associated with significant collagen fiber re-arrangement. Although the general features of the stress-strain behavior in tension and compression and under uniaxial, biaxial and shear loading have been discussed extensively, especially from the macroscopic perspective, the Poisson effect and the kinematics of filaments have received less attention. In general, the relationship between the microscopic fiber network mechanics and the macroscopic experimental observations remains poorly defined. The objective of the present work is to provide additional insight into this relationship. To this end, results from models of random collagen networks are compared with experimental data on reconstructed collagen gels, mouse skin dermis and the human amnion. Attention is devoted to the mechanism leading to the large Poisson effect observed in experiments. The effect of fiber tortuosity on network mechanics is also discussed. A comparison of biaxial and uniaxial loading response is performed. Such model validation is essential since these can be used to evaluate parameters important in tissue mechanics which are not accessible experimentally.
TOPICS: Kinematics, Fibers, Simulation, Biological tissues, Engineering simulation, Compression, Model validation, Skin, Tension, Stress, Shear (Mechanics)
research-article  
Peshala / P Thibotuwawa Gamage, Fardin Khalili, MD / Khurshidul Azad and Hansen / A. Mansy
J Biomech Eng   doi: 10.1115/1.4038431
Inspiratory flow in a multi-generation pig lung airways was numerically studied at a steady inlet flow rate of 3.2×10-4 m3/s corresponding to a Reynolds number of 1150 in the trachea. The model was validated by comparing velocity distributions with previous measurements and simulations in simplified airway geometries. Simulation results provided detailed maps of the axial and secondary flow patterns at different cross sections of the airway tree. The vortex core regions in the airways were visualized using absolute helicity values and suggested the presence of secondary flow vortices where two counter rotating vortices were observed at the main bifurcation and in many other bifurcations. Both laminar and turbulent flow were considered. Results showed that axial and secondary flows were comparable in the laminar and turbulent cases. Turbulent kinetic energy vanished in the more distal airways, which indicates that the flow in these airways approaches laminar flow conditions. The simulation results suggested viscous pressure drop values comparable to earlier studies. The monopodial asymmetric nature of airway branching in pigs resulted in airflow patterns that are different from the less asymmetric human airways. The major daughters of the pig airways tended to have high airflow ratios, which may lead to different particle distribution and sound generation patterns. These differences need to be taken into consideration when interpreting the results of animal studies involving pigs before generalizing these results to humans.
TOPICS: Flow (Dynamics), Modeling, Lung, Vortices, Turbulence, Air flow, Bifurcation, Simulation results, Trachea, Pressure drop, Laminar flow, Reynolds number, Simulation, Cross section (Physics), Engineering simulation, Kinetic energy, Particulate matter
research-article  
Lindsay L Loundagin, Tannin Schmidt and W. Brent Edwards
J Biomech Eng   doi: 10.1115/1.4038288
Stress fractures are common overuse injuries amongst runners associated with the mechanical fatigue of bone. Several in vivo biomechanical studies have investigated specific characteristics of the vertical ground reaction force (vGRF) in running and have observed an association between increased loading rate during impact and individuals with a history of stress fracture. The purpose of this study was to examine the fatigue behavior of cortical bone using vGRF-like loading profiles, including those that had been decomposed into their respective impact and active phase components. Thirty-eight cortical bone samples were extracted from bovine tibiae and femora. Hydrated samples were fatigue tested at room temperature in compression under load control using either a raw (n=10), active (n=10), low impact (n=10), or high impact (n=8) vGRF profile. The number of cycles to failure was quantified and the test was terminated if the sample survived 105 cycles. Fatigue life was significantly greater for both impact groups compared to the active and raw groups (p<0.001), with all low impact and 6 of 8 high impact samples surviving 105 cycles. The mean (± SD) number of cycles to failure for the active and raw groups were 12133 ± 11704 and 16552 ± 29612, respectively. The results suggest that loading rates associated with the impact phase of a typical vGRF in running have little influence on the mechanical fatigue behavior of bone relative to loading magnitude, warranting further investigation of the mechanism by which increased loading rates are associated with stress fracture.
TOPICS: Fatigue, Bone, Stress, Cycles, Fracture (Process), Fracture (Materials), Failure, Fatigue life, Wounds, Biomechanics, Temperature, Compression
research-article  
Lee F. Gabler, Hamed Joodaki, Jeff R. Crandall and Matthew B. Panzer
J Biomech Eng   doi: 10.1115/1.4038357
Linking head impact kinematics to injury risk has been the focus of numerous brain injury criteria. Although many early forms were developed using mechanics principles, recent criteria have been developed using empirical methods based on subsets of head impact data. In this study, a single-degree-of-freedom (sDOF) mechanical analogue was developed to study the link between rotational head kinematics and brain deformation. Model efficacy was assessed by comparing its dynamic response to strain-based brain injury predictors from finite element (FE) human head models. A series of idealized rotational pulses covering a broad range of acceleration and velocity magnitudes (0.1-15krad/s2 and 1-100rad/s) with durations between (1-3000ms) were applied to the mechanical models about each axis of the head. Results show that brain deformation magnitude is governed by three categories of rotational head motion each distinguished by impact duration relative to the brain’s natural period: for short-duration pulses, maximum brain deformation depended primarily on angular velocity magnitude; for long-duration pulses, brain deformation depended primarily on angular acceleration magnitude; and for pulses relatively close to the natural period, brain deformation depended on both velocity and acceleration magnitudes. These results suggest that brain deformation mechanics can be adequately explained by simple mechanical systems, since FE model responses and experimental brain injury tolerances exhibited similar patterns to the sDOF model. Finally, the sDOF model was the best correlate to strain-based responses, and highlighted fundamental limitations with existing rotational brain injury metrics.
TOPICS: Traumatic brain injury, Deformation, Brain, Kinematics, Dynamic response, Finite element model, Wounds, Finite element analysis, Risk
research-article  
Laura Hutchinson, Joel B Schwartz, Amy M. Morton, Irene S. Davis, Kevin Deluzio and Michael J Rainbow
J Biomech Eng   doi: 10.1115/1.4038358
When optical motion capture is used for motion analysis, reflective markers or a digitizer are typically used to record the location of anatomical landmarks identified through palpation. The landmarks are then used to construct anatomical coordinate systems. Failure to consistently identify landmarks through palpation over repeat tests creates artifacts in the kinematic waveforms. The purpose of this work was to improve intra- and inter-rater reliability in determining anatomical landmarks and the associated anatomical coordinate systems using a Marker Alignment Device. The device aids the subject in recreating the same standing posture over multiple tests, and recreates the anatomical landmarks from previous static calibration trials. We tested three different raters who identified landmarks on eleven subjects. The subjects performed walking trials and their gait kinematics were analyzed with and without the device. Ankle kinematics were not improved by the device suggesting manual palpation over repeat visits is just as effective as the Marker Alignment Device. Intra-class correlation coefficients between gait kinematics registered to the reference static trial and registered to follow-up static trials with and without the device were improved between 1% and 33% when the device was used. Importantly, out of plane hip and knee kinematics showed the greatest improvements in repeatability. These results suggest that the device is well suited to reducing palpation artifact during repeat visits to the gait lab.
TOPICS: Kinematics, Reliability, Calibration, Errors, Failure, Knee
research-article  
Mimmi K. Liukkonen, Mika E. Mononen, Paavo Vartiainen, Päivi Kaukinen, Timo Bragge, Juha-Sampo Suomalainen, Markus K.H. Malo, Sari Venesmaa, Pirjo Käkelä, Jussi Pihlajamäki, Pasi A. Karjalainen, Jari P. Arokoski and Rami Korhonen
J Biomech Eng   doi: 10.1115/1.4038330
The objective of the study was to investigate the effect of bariatric surgery-induced weight loss on knee gait and cartilage degeneration in osteoarthritis by combining magnetic resonance imaging, gait analysis, finite element modeling and cartilage degeneration algorithm. Gait analyses were performed for obese subjects before and one-year after the bariatric surgery. Finite element models were created before and after weight loss for those subjects who had not severe tibio-femoral knee cartilage loss. Knee cartilage degenerations were predicted using an adaptive cartilage degeneration algorithm which is based on cumulative overloading of cartilage, leading to iteratively altered cartilage properties during osteoarthritis. The average weight loss was 25.7±11.0kg corresponding to a 9.2±3.9kg/m2 decrease in BMI. External knee rotation moment increased and minimum knee flexion angle decreased significantly (p<0.05) after weight loss. Moreover, weight loss decreased maximum cartilage degeneration by 5±23% and 13±11% on the medial and lateral tibial cartilage surfaces, respectively. Average degenerated volumes in the medial and lateral tibial cartilage decreased by 3±31% and 7±32%, respectively, after weight loss. However, also increased degeneration levels could be observed due to altered knee kinetics. The present results suggest that moderate weight loss changes knee kinetics and kinematics and can slow-down cartilage degeneration for certain patients and knee compartment. Simulation results also suggest that prediction of cartilage degeneration is subject-specific and depend highly on the altered gait loading, not just the patient's weight.
TOPICS: Weight (Mass), Surgery, Cartilage, Knee, Osteoarthritis, Gait analysis, Algorithms, Finite element analysis, Modeling, Kinematics, Rotation, Simulation results, Magnetic resonance imaging, Finite element model
research-article  
Karin Lavon, Rotem Halevi, Gil Marom, Sagit Ben Zekry, Ashraf Hamdan, Hans Joachim Schäfers, Ehud Raanani and Rami Haj-Ali
J Biomech Eng   doi: 10.1115/1.4038329
Bicuspid aortic valve (BAV) is the most common type of congenital heart disease, occurring in 0.5-2% of the population, where the valve has only two rather than the three normal cusps. Valvular pathologies, such as aortic regurgitation and aortic stenosis, are associated with BAVs, thereby increasing the need for a better understanding of BAV kinematics and geometrical characteristics. The aim of this study is to investigate the influence of the non-fused cusp (NFC) angle in BAV type-1 configuration on the valve's structural and hemodynamic performance. Towards that goal, a parametric fluid-structure interaction (FSI) modeling approach of BAVs is presented. Four FSI models were generated with varying NFC angles between 120° and 180°. The FSI simulations were based on fully-coupled structural and fluid dynamic solvers and corresponded to physiologic values, including the anisotropic hyper-elastic behavior of the tissue. The simulated angles led to different mechanical behavior, such as eccentric jet flow direction with a wider opening shape that was found for the smaller NFC angles, while a narrower opening orifice followed by increased jet flow velocity was observed for the larger NFC angles. Smaller NFC angles led to higher concentrated flow shear stress on the NFC during peak systole, while higher maximal principal stresses were found in the raphe region during diastole. The proposed biomechanical models could explain the early failure of BAVs with decreased NFC angles, and suggests that a larger NFC angle is preferable in suture annuloplasty BAV repair surgery.
TOPICS: Valves, Fluid structure interaction, Jets, Biological tissues, Engineering simulation, Mechanical behavior, Modeling, Surgery, Diseases, Failure, Hemodynamics, Shapes, Kinematics, Flow (Dynamics), Fluids, Maintenance, Simulation, Stress, Biomechanics, Anisotropy, Physiology, Shear stress
research-article  
David Fulker, Bogdan Ene-Iordache and Tracie J. Barber
J Biomech Eng   doi: 10.1115/1.4038289
Arteriovenous fistulae are the preferred choice of vascular access in hemodialysis patients, however complications such as stenosis can lead to access failure or recirculation, which reduces dialysis efficiency. This study utilized computational fluid dynamics on a patient specific radio-cephalic fistula under hemodialysis treatment to determine the dynamics of access recirculation and identify the presence of disturbed flow. Metrics of transverse wall shear stress and oscillatory shear index were used to characterize the disturbed flow acting on the blood vessel wall, whilst a power spectral density analysis was used to calculate the any turbulence within the access. Results showed that turbulence is generated at the anastomosis and continues through the swing segment. The arterial needle dampens the flow as blood is extracted to the dialyzer, whilst the venous needle reintroduces turbulence due to the presence of jet flows. Adverse shear stresses are present throughout the vascular access and coincide with these complex flow fields. The position of the needles had no effect in minimizing these forces. However, improved blood extraction may occur when the arterial needle is placed further from the anastomosis, minimizing the effects of residual turbulent structures generated at the anastomosis. Furthermore, the arterial and venous needle may be placed in close proximity to each other without increasing the risk of access recirculation, in a healthy mature fistula, due to the relatively stable blood flow in this region. This may negate the need for a long cannulation segment and aid clinicians in optimizing needle placement for hemodialysis.
TOPICS: Simulation, Resolution (Optics), Computational fluid dynamics, Hemodialysis, needles, Flow (Dynamics), Turbulence, Blood, Shear stress, Blood flow, Risk, Dynamics (Mechanics), Failure, Blood vessels, Shear (Mechanics), Spectral energy distribution
research-article  
Xiaoya Guo, Don P. Giddens, David Molony, Chun Yang, Habib Samady, Jie Zheng, Gary Mintz, Akiko Maehara, Liang Wang, Xuan Pei, Zhi-Yong Li and Dalin Tang
J Biomech Eng   doi: 10.1115/1.4038263
Accurate cap thickness and stress/strain quantifications are of fundamental importance for vulnerable plaque research. Virtual histology intravascular ultrasound (VH-IVUS) sets cap thickness to zero when cap is under resolution limit and IVUS does not see it. An innovative modeling approach combining IVUS and optical coherence tomography (OCT) is introduced for cap thickness quantification and more accurate cap stress/strain calculations. In vivo IVUS and OCT coronary plaque data were acquired with informed consent obtained. IVUS and OCT images were merged to form the IVUS+OCT data set, with biplane angiography providing 3D vessel curvature. For components where VH-IVUS set zero cap thickness (i.e., no cap), a cap was added with minimum cap thickness set as 50 and 180 micron to generate IVUS50 and IVUS180 data sets for model construction, respectively. 3D FSI models based on IVUS+OCT, IVUS50 and IVUS180 data sets were constructed to investigate cap thickness impact on stress/strain calculations. Compared to IVUS+OCT, IVUS50 underestimated mean cap thickness (27 slices) by 34.5%, overestimated mean cap stress by 45.8%, (96.4 vs. 66.1 kPa). IVUS50 maximum cap stress was 59.2% higher than that from IVUS+OCT model (564.2 vs. 354.5 kPa). Differences between IVUS and IVUS+OCT models for cap strain and flow shear stress were modest (cap strain <12%; FSS <6%). IVUS+OCT data and models could provide more accurate cap thickness and stress/strain calculations which will serve as basis for further plaque investigations.
TOPICS: Stress, Modeling, Fluid structure interaction, Shear stress, Vessels, Flow (Dynamics), Construction, Coherence (Optics), Resolution (Optics), Ultrasound
research-article  
Iyad A. Fayssal, Fadl Moukalled, Samir Alam and Hussain Isma’eel
J Biomech Eng   doi: 10.1115/1.4038250
This paper reports on a new boundary condition formulation to model the total coronary myocardial flow and impedance characteristics of the myocardial vascular bed for any specific patient when considered for non-invasive diagnosis of fractional flow reserve (FFR). The developed boundary condition model inherits an implicit representation of the downstream truncated vascular bed and is based on integrating patient-specific physiologic parameters that can be non-invasively extracted for each patient to account for blood flow demand to the myocardium at rest and hyperemic conditions. The model is coupled to a three-dimensional (3D) collocated pressure-based finite volume method and used to characterize the “functional behavior” of a patient diseased coronary artery segment without the need for predicting the details of blood flow dynamics in the entire arterial system. Predictions generated with this boundary condition provided a deeper understanding of the embedded challenges behind non-invasive image-based diagnostic techniques when applied to human diseased coronary arteries. The overall numerical method and formulated boundary condition model are validated via two computational-based procedures and benchmarked with available measured data. The newly developed boundary condition is used via a designed computational methodology to (a) confirm the need for integrating patient-specific physiologic parameters when modeling the downstream vascular impedance, (b) interpret the embodied inaccuracies of computed FFRCT outcomes reported in the literature, and (c) discuss the current limitations and future challenges in shifting to non-invasive assessment of FFR.
TOPICS: Boundary-value problems, Coronary arteries, Outflow, Blood flow, Physiology, Flow (Dynamics), Modeling, Numerical analysis, Performance, Finite volume methods, Dynamics (Mechanics), Pressure, Myocardium
research-article  
Mitja Trkov, Jingang Yi, Tao Liu and Kang Li
J Biomech Eng   doi: 10.1115/1.4038251
Shoe-floor interactions play a crucial role in determining the possibility of potential slip and fall during human walking. Biomechanical and tribological parameters influence the friction characteristics between the shoe sole and the floor and the existing work mainly focus on experimental studies. In this paper, we present modeling, analysis, and experiments to understand slip and force distributions between the shoe sole and floor surface during human walking. We present results for both soft and hard sole material. The computational approaches for slip and friction force distributions are presented using a spring-beam networks model. The model predictions match the experimentally observed sole deformations with large soft sole deformation at the beginning and the end stages of the stance, which indicates the increased risk for slip. The experiments confirm that the required coefficient of friction and the deformation measurements can be used to predict slip occurrence. Moreover, the deformation and force distribution results provide further understanding and knowledge of slip initiation and termination under various biomechanical conditions.
TOPICS: Deformation, Tribology, Friction, Biomechanics, Modeling, Modeling analysis, Springs, Risk
research-article  
Hosein Naseri, Håkan Johansson and Karin Brolin
J Biomech Eng   doi: 10.1115/1.4038200
Finite element human body models are nowdays commonly used to simulate pre- and in-crash occupant response in order to develop advanced safety systems. In this study a biofidelic model for adipose tissue is developed for this application. It is a nonlinear viscoelastic model based on the Reese et al. formulation. The model is formulated in a large strain framework and applied for finite element simulation of two types of experiments: rheological experiments and ramped-displacement experiments. The adipose tissue behavior in both experiments are represented well by this model. It indicates the capability of the model to be used in large deformation and wide range of strain rates for application in human body models.
TOPICS: Biological tissues, Finite element analysis, Displacement, Deformation, Safety, Simulation, Rheology
research-article  
Ivan A. Kuznetsov and Andrey Kuznetsov
J Biomech Eng   doi: 10.1115/1.4038201
The goal of this paper is to use mathematical modeling to investigate the fate of dense core vesicles (DCVs) captured in en passant boutons located in nerve terminals. One possibility is that all DCVs captured in boutons are destroyed, another possibility is that captured DCVs can escape and reenter the pool of transiting DCVs that move through the boutons, and a third possibility is that some DCVs are destroyed in boutons, while some reenter the transiting pool. We developed a model by applying the conservation of DCVs in various compartments composing the terminal, to predict different scenarios that emerge from the above assumptions about the fate of DCVs captured in boutons. The simulations demonstrate that, if no DCV destruction in boutons is assumed and all captured DCVs reenter the transiting pool, the DCV fluxes evolve to a uniform circulation in a type Ib terminal at steady-state and the DCV flux remains constant from bouton to bouton. Because at steady-state the amount of captured DCVs is equal to the amount of DCVs that reenter the transiting pool, no decay of DCV fluxes occurs. In a type III terminal at steady-state, the anterograde DCV fluxes decay from bouton to bouton, while retrograde fluxes increase. This is explained by a larger capture efficiency of anterogradely moving DCVs than of retrogradely moving DCVs in type III boutons, while the captured DCVs that reenter the transiting pool are assumed to be equally split between anterogradely and retrogradely moving components.
TOPICS: Modeling, Flux (Metallurgy), Steady state, Simulation, Engineering simulation
research-article  
Ibrahim Chamseddine and Michael Kokkolaras
J Biomech Eng   doi: 10.1115/1.4038202
Nanoparticle-based drug delivery is a promising method to increase the therapeutic index of anti-cancer agents with low median toxic dose. The delivery efficiency, corresponding to the fraction of the injected nanoparticles that adhere to the tumor site, depends on nanoparticle size $a$ and aspect ratio $AR$. Currently, values for these variables are chosen empirically, and may not yield optimal targeted drug delivery. This study applies rigorous optimization to the design of nanoparticles. A preliminary investigation revealed that delivery efficiency increases monotonically with $a$ and $AR$. However, maximizing $a$ and $AR$ results in non-uniform drug distribution, which impairs tumor regression. Therefore, a multi-objective optimization problem (MO) is formulated to quantify the trade-off between nanoparticles accumulation and distribution. The MO is solved using the derivative-free Mesh Adaptive Direct Search algorithm. Theoretically, the Pareto-optimal set consists of an infinite number of mathematically equivalent solutions to the MO problem. However, interesting design solutions can be identified subjectively, e.g., the ellipsoid with a major axis of 720 nm and an aspect ratio of 7.45, as the solution closest to the utopia point. The MO problem formulation is then extended to optimize nanoparticle biochemical properties, in particular ligand-receptor binding affinity and ligand density. Optimizing physical and chemical properties simultaneously results in optimal designs with reduced nanoparticle sizes, thus enhanced cellular uptake. The presented study provides an insight on nanoparticle structures that have potential for producing desirable drug delivery.
TOPICS: Nanoparticles, Optimization, Anticancer drugs, Drug delivery systems, Tumors, Design, Density, Chemical properties, Algorithms, Drugs, Pareto optimization, Tradeoffs
research-article  
James W. Reinhardt and Keith Gooch
J Biomech Eng   doi: 10.1115/1.4037947
We developed an agent-based model that incorporates repetitively applied traction force within a discrete fiber network to understand how microstructural properties of the network influence mechanical properties and traction force-induced remodeling. An important difference between our model and similar finite-element models is that by implementing more biologically-realistic dynamic traction, we can explore a greater range of matrix remodeling. Here, we validated our model by reproducing qualitative trends observed in three sets of experimental data reported by others: tensile and shear testing of cell-free collagen gels, collagen remodeling around a single isolated cell, and collagen remodeling between pairs of cells. In response to tensile and shear strain, simulated acellular networks exhibited biphasic stress-strain curves indicative of strain-stiffening. Our data support the notion that strain-stiffening might occur as individual fibrils successively align along the axis of strain and become engaged in tension. In simulations with a single, contractile cell, peak collagen displacement occurred closest to the cell and decreased with increasing distance. In simulations with two cells, compaction of collagen between cells appeared inversely related to the initial distance between cells. Further analysis revealed strain energy was relatively uniform around the outer surface of cells separated by 250 microns, but became increasingly non-uniform as the distance between cells decreased. This pattern was partly attributable to the pattern of collagen compaction. These findings are of interest because fibril alignment, density, and strain energy may each contribute to contact guidance during tissue morphogenesis.
TOPICS: Fibers, Network models, Traction, Simulation, Compacting, Shear (Mechanics), Engineering simulation, Testing, Displacement, Finite element model, Stress-strain curves, Mechanical properties, Biological tissues, Density, Tension
research-article  
Douglas Fankell, Richard A. Regueiro, Eric Kramer, Virginia L. Ferguson and Mark E. Rentschler
J Biomech Eng   doi: 10.1115/1.4037950
Understanding the impact of thermally and mechanically loading biological tissue to supraphysiological levels is becoming of increasing importance as complex multi-physical tissue-device interactions increase. The ability to conduct accurate, patient specific computer simulations would provide surgeons with valuable insight into the physical processes occurring within the tissue as it is heated or cooled. Several studies have modeled tissue as porous media, yet fully coupled thermo-poromechanics (TPM) models are limited. Therefore, this study introduces a small deformation theory of modeling the TPM occurring within biological tissue. Next, the model is used to simulate the mass, momentum and energy balance occurring within an artery wall when heated by a tissue fusion device and compared to experimental values. Though limited by its small strain assumption, the model predicted final tissue temperature and water content within one standard deviation of experimental data for seven of seven simulations. Additionally, the model showed the ability to predict the final displacement of the tissue to within 15% of experimental results. These results promote potential design of novel medical devices and more accurate simulations allowing for scientists and surgeons to quickly, yet accurately, assess the effects of surgical procedures as well as provide a first step towards a fully coupled large deformation TPM finite element model.
TOPICS: Deformation, Biological tissues, Finite element model, Engineering simulation, Simulation, Momentum, Design, Temperature, Porous materials, Computer simulation, Energy budget (Physics), Medical devices, Modeling, Surgery, Displacement, Water
Review Article  
Zachary Abraham, Emma Hawley, Daniel Hayosh, Victoria Webster-Wood and Ozan Akkus
J Biomech Eng   doi: 10.1115/1.4037886
Motor proteins play critical roles in the normal function of cells and proper development of organisms. Among motor proteins, failings in the normal function of two types of proteins, kinesin and dynein, have been shown to lead many pathologies, including neurodegenerative diseases and cancers. As such, it is critical for researchers to understand the underlying mechanics and behaviors of these proteins, not only to shed light on how failures may lead to disease, but also to guide research towards novel treatment and nanoengineering solutions. To this end, many experimental techniques have been developed to measure the force and motility capabilities of these proteins. This review will: a) discuss such techniques, specifically microscopy, atomic force microscopy, optical trapping, and magnetic tweezers, and, b) the resulting nanomechanical properties of motor protein functions such as stalling force, velocity and dependence on ATP concentrations will be comparatively discussed. Additionally, this review will highlight the clinical importance of these proteins. Furthermore, as the understanding of the structure and function of motor proteins improves, novel applications are emerging in the field. Specifically, researchers have begun to modify the structure of existing proteins, thereby engineering novel elements to alter and improve native motor protein function, or even allow the motor proteins to perform entirely new tasks as parts of nanomachines. Kinesin and dynein are vital elements for the proper function of cells. While many exciting experiments have shed light on their function, mechanics, and applications, additional research is needed to completely understand their behavior.
TOPICS: Atomic force microscopy, Engines, Motors, Molecular machines, Microscopy, Cancer, Diseases, Failure, Proteins, Nanoengineering

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