0

### Special Section: Spotlight on the Future–Imaging and Biomechanical Engineering

J Biomech Eng. 2019;141(6):060901-060901-11. doi:10.1115/1.4040910.

Regional tissue mechanics play a fundamental role in the patient-specific function and remodeling of the cardiovascular system. Nevertheless, regional in vivo assessments of aortic kinematics remain lacking due to the challenge of imaging the thin aortic wall. Herein, we present a novel application of displacement encoding with stimulated echoes (DENSE) magnetic resonance imaging (MRI) to quantify the regional displacement and circumferential Green strain of the thoracic and abdominal aorta. Two-dimensional (2D) spiral cine DENSE and steady-state free procession (SSFP) cine images were acquired at 3T at either the infrarenal abdominal aorta (IAA), descending thoracic aorta (DTA), or distal aortic arch (DAA) in a pilot study of six healthy volunteers (22–59 y.o., 4 females). DENSE data were processed with multiple custom noise reduction techniques including time-smoothing, displacement vector smoothing, sectorized spatial smoothing, and reference point averaging to calculate circumferential Green strain across 16 equispaced sectors around the aorta. Each volunteer was scanned twice to evaluate interstudy repeatability. Circumferential Green strain was heterogeneously distributed in all volunteers and locations. The mean spatial heterogeneity index (standard deviation of all sector values divided by the mean strain) was 0.37 in the IAA, 0.28 in the DTA, and 0.59 in the DAA. Mean (homogenized) peak strain by DENSE for each cross section was consistent with the homogenized linearized strain estimated from SSFP cine. The mean difference in peak strain across all sectors following repeat imaging was −0.1±2.3%, with a mean absolute difference of 1.7%. Aortic cine DENSE MRI is a viable noninvasive technique for quantifying heterogeneous regional aortic wall strain and has significant potential to improve patient-specific clinical assessments of numerous aortopathies, as well as to provide the lacking spatiotemporal data required to refine patient-specific computational models of aortic growth and remodeling.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2019;141(6):060902-060902-16. doi:10.1115/1.4040603.

An analytical theory for the unconfined creep behavior of a cylindrical inclusion (simulating a soft tissue tumor) embedded in a cylindrical background sample (simulating normal tissue) is presented and analyzed in this paper. Both the inclusion and the background are considered as fluid-filled, porous materials, each of them being characterized by a set of mechanical properties. Specifically, in this paper, the inclusion is considered to be less permeable than the background. The cylindrical sample is compressed using a constant pressure within two frictionless plates and is allowed to expand in an unconfined way along the radial direction. Analytical expressions for the effective Poisson's ratio (EPR) and fluid pressure inside and outside the inclusion are derived and analyzed. The theoretical results are validated using finite element models (FEMs). Statistical analysis shows excellent agreement between the results obtained from the developed model and the results from FEM. Thus, the developed theoretical model can be used in medical imaging modalities such as ultrasound poroelastography to extract the mechanical parameters of tissues and/or to better understand the impact of different mechanical parameters on the estimated displacements, strains, stresses, and fluid pressure inside a tumor and in the surrounding tissue.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2019;141(6):060903-060903-12. doi:10.1115/1.4040604.

An analytical theory for the unconfined creep behavior of a cylindrical inclusion (simulating a soft tissue tumor) embedded in a cylindrical background sample (simulating normal tissue) is presented and analyzed in this paper. Both the inclusion and the background are considered as fluid-filled, porous materials, each of them being characterized by a set of mechanical parameters. Specifically, in this derivation, the inclusion is assumed to have significantly higher interstitial permeability than the background. The formulations of the effective Poisson's ratio (EPR) and fluid pressure in the inclusion and in the background are derived for the case of a sample subjected to a creep compression. The developed analytical expressions are validated using finite element models (FEM). Statistical comparison between the results obtained from the developed model and the results from FEM demonstrates accuracy of the proposed theoretical model higher than 99.4%. The model presented in this paper complements the one reported in the companion paper (Part I), which refers to the case of an inclusion having less interstitial permeability than the background.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2019;141(6):060904-060904-9. doi:10.1115/1.4041042.

The present study assessed the acute effects of isoproterenol on left ventricular (LV) mechanics in healthy rats with the hypothesis that $β$-adrenergic stimulation influences the mechanics of different myocardial regions of the LV wall in different ways. To accomplish this, magnetic resonance images were obtained in the LV of healthy rats with or without isoproterenol infusion. The LV contours were divided into basal, midventricular, and apical regions. Additionally, the midventricular myocardium was divided into three transmural layers with each layer partitioned into four segments (i.e., septal, inferior, lateral, and anterior). Peak systolic strains and torsion were quantified for each region. Isoproterenol significantly increased peak systolic radial strain and circumferential-longitudinal (CL) shear strain, as well as ventricular torsion, throughout the basal, midventricle, and apical regions. In the midventricle, isoproterenol significantly increased peak systolic radial strain, and induced significant increases in peak systolic circumferential strain and longitudinal strain in the septum. Isoproterenol consistently increased peak systolic CL shear strain in all midventricular segments. Ventricular torsion was significantly increased in nearly all segments except the inferior subendocardium. The effects of isoproterenol on LV systolic mechanics (i.e., three-dimensional (3D) strains and torsion) in healthy rats depend on the region. This region dependency is also strain component-specific. These results provide insight into the regional response of LV mechanics to $β$-adrenergic stimulation in rats and could act as a baseline for future studies on subclinical abnormalities associated with the inotropic response in heart disease.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2019;141(6):060905-060905-9. doi:10.1115/1.4040946.

Accurate individualized muscle architecture data are crucial for generating subject-specific musculoskeletal models to investigate movement and dynamic muscle function. Diffusion tensor imaging (DTI) magnetic resonance (MR) imaging has emerged as a promising method of gathering muscle architecture data in vivo; however, its accuracy in estimating parameters such as muscle fiber lengths for creating subject-specific musculoskeletal models has not been tested. Here, we provide a validation of the method of using anatomical magnetic resonance imaging (MRI) and DTI to gather muscle architecture data in vivo by directly comparing those data obtained from MR scans of three human cadaveric lower limbs to those from dissections. DTI was used to measure fiber lengths and pennation angles, while the anatomical images were used to estimate muscle mass, which were used to calculate physiological cross-sectional area (PCSA). The same data were then obtained through dissections, where it was found that on average muscle masses and fiber lengths matched well between the two methods (4% and 1% differences, respectively), while PCSA values had slightly larger differences (6%). Overall, these results suggest that DTI is a promising technique to gather in vivo muscle architecture data, but further refinement and complementary imaging techniques may be needed to realize these goals.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2019;141(6):060906-060906-9. doi:10.1115/1.4040773.

Image-based modeling is an active and growing area of biomedical research that utilizes medical imaging to create patient-specific simulations of physiological function. Under this paradigm, anatomical structures are segmented from a volumetric image, creating a geometric model that serves as a computational domain for physics-based modeling. A common application is the segmentation of cardiovascular structures to numerically model blood flow or tissue mechanics. The segmentation of medical image data typically results in a discrete boundary representation (surface mesh) of the segmented structure. However, it is often desirable to have an analytic representation of the model, which facilitates systematic manipulation. For example, the model then becomes easier to union with a medical device, or the geometry can be virtually altered to test or optimize a surgery. Furthermore, to employ increasingly popular isogeometric analysis (IGA) methods, the parameterization must be analysis suitable. Converting a discrete surface model to an analysis-suitable model remains a challenge, especially for complex branched structures commonly encountered in cardiovascular modeling. To address this challenge, we present a framework to convert discrete surface models of vascular geometries derived from medical image data into analysis-suitable nonuniform rational B-splines (NURBS) representation. This is achieved by decomposing the vascular geometry into a polycube structure that can be used to form a globally valid parameterization. We provide several practical examples and demonstrate the accuracy of the methods by quantifying the fidelity of the parameterization with respect to the input geometry.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2019;141(6):060907-060907-8. doi:10.1115/1.4043075.

Current in vivo abdominal aortic aneurysm (AAA) imaging approaches tend to focus on maximum diameter but do not measure three-dimensional (3D) vascular deformation or strain. Complex vessel geometries, heterogeneous wall compositions, and surrounding structures can all influence aortic strain. Improved understanding of complex aortic kinematics has the potential to increase our ability to predict aneurysm expansion and eventual rupture. Here, we describe a method that combines four-dimensional (4D) ultrasound and direct deformation estimation to compute in vivo 3D Green-Lagrange strain in murine angiotensin II-induced suprarenal dissecting aortic aneurysms, a commonly used small animal model. We compared heterogeneous patterns of the maximum, first-component 3D Green-Lagrange strain with vessel composition from mice with varying AAA morphologies. Intramural thrombus and focal breakage in the medial elastin significantly reduced aortic strain. Interestingly, a dissection that was not detected with high-frequency ultrasound also experienced reduced strain, suggesting medial elastin breakage that was later confirmed via histology. These results suggest that in vivo measurements of 3D strain can provide improved insight into aneurysm disease progression. While further work is needed with both preclinical animal models and human imaging studies, this initial murine study indicates that vessel strain should be considered when developing an improved metric for predicting aneurysm growth and rupture.

Commentary by Dr. Valentin Fuster

### Research Papers

J Biomech Eng. 2019;141(6):061001-061001-9. doi:10.1115/1.4043289.

Computational fluid dynamics (CFD) is a powerful method to investigate aneurysms. The primary focus of most investigations has been to compute various hemodynamic parameters to assess the risk posed by an aneurysm. Despite the occurrence of transitional flow in aneurysms, turbulence has not received much attention. In this article, we investigate turbulence in the context of abdominal aortic aneurysms (AAA). Since the clinical practice is to diagnose an AAA on the basis of its size, hypothetical axisymmetric geometries of various sizes are constructed. In general, just after the peak systole, a vortex ring is shed from the expansion region of an AAA. As the ring advects downstream, an azimuthal instability sets in and grows in amplitude thereby destabilizing the ring. The eventual breakdown of the vortex ring into smaller vortices leads to turbulent fluctuations. A residence time study is also done to identify blood recirculation zones, as a recirculation region can lead to degradation of the arterial wall. In some of the geometries simulated, the enhanced local mixing due to turbulence does not allow a recirculation zone to form, whereas in other geometries, turbulence had no effect on them. The location and consequence of a recirculation zone suggest that it could develop into an intraluminal thrombus (ILT). Finally, the possible impact of turbulence on the oscillatory shear index (OSI), a hemodynamic parameter, is explored. To conclude, this study highlights how a small change in the geometric aspects of an AAA can lead to a vastly different flow field.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2019;141(6):061002-061002-9. doi:10.1115/1.4043355.

Oxidation of aorta by hydroxyl radicals produces structural changes in arterial proteins like elastin and collagen. This in turn results in change in the mechanical response of aorta. In this paper, a thermodynamically consistent constitutive model is developed within the framework of mixture theory, to describe the changes in aorta and isolated elastin with oxidation. The model is then studied under uniaxial extension using experimental data from literature.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2019;141(6):061003-061003-14. doi:10.1115/1.4042902.

Coronary artery bypass grafts used to treat coronary artery disease (CAD) often fail due to compliance mismatch. In this study, we have developed an experimental/computational approach to fabricate an acellular biomimetic hybrid tissue engineered vascular graft (TEVG) composed of alternating layers of electrospun porcine gelatin/polycaprolactone (PCL) and human tropoelastin/PCL blends with the goal of compliance-matching to rat abdominal aorta, while maintaining specific geometrical constraints. Polymeric blends at three different gelatin:PCL (G:PCL) and tropoelastin:PCL (T:PCL) ratios (80:20, 50:50, and 20:80) were mechanically characterized. The stress–strain data were used to develop predictive models, which were used as part of an optimization scheme that was implemented to determine the ratios of G:PCL and T:PCL and the thickness of the individual layers within a TEVG that would compliance match a target compliance value. The hypocompliant, isocompliant, and hypercompliant grafts had target compliance values of 0.000256, 0.000568, and 0.000880 mmHg−1, respectively. Experimental validation of the optimization demonstrated that the hypercompliant and isocompliant grafts were not statistically significant from their respective target compliance values (p-value = 0.37 and 0.89, respectively). The experimental compliance values of the hypocompliant graft were statistically significant than their target compliance value (p-value = 0.047). We have successfully demonstrated a design optimization scheme that can be used to fabricate multilayered and biomimetic vascular grafts with targeted geometry and compliance.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2019;141(6):061004-061004-12. doi:10.1115/1.4043209.
OPEN ACCESS

Commercially available heart valves have many limitations, such as a lack of remodeling, risk of calcification, and thromboembolic problems. Many state-of-the-art tissue-engineered heart valves (TEHV) rely on recellularization to allow remodeling and transition to mechanical behavior of native tissues. Current in vitro testing is insufficient in characterizing a soon-to-be living valve due to this change in mechanical response; thus, it is imperative to understand the performance of an in situ valve. However, due to the complex in vivo environment, this is difficult to accomplish. Finite element (FE) analysis has become a standard tool for modeling mechanical behavior of heart valves; yet, research to date has mostly focused on commercial valves. The purpose of this study has been to evaluate the mechanical behavior of a TEHV material before and after 6 months of implantation in a rat subdermis model. This model allows the recellularization and remodeling potential of the material to be assessed via a simple and inexpensive means prior to more complex ovine orthotropic studies. Biaxial testing was utilized to evaluate the mechanical properties, and subsequently, constitutive model parameters were fit to the data to allow mechanical performance to be evaluated via FE analysis of a full cardiac cycle. Maximum principal stresses and strains from the leaflets and commissures were then analyzed. The results of this study demonstrate that the explanted tissues had reduced mechanical strength compared to the implants but were similar to the native tissues. For the FE models, this trend was continued with similar mechanical behavior in explant and native tissue groups and less compliant behavior in implant tissues. Histology demonstrated recellularization and remodeling although remodeled collagen had no clear directionality. In conclusion, we observed successful recellularization and remodeling of the tissue giving confidence to our TEHV material; however, the mechanical response indicates the additional remodeling would likely occur in the aortic/pulmonary position.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2019;141(6):061005-061005-9. doi:10.1115/1.4043356.

The aim of this study was to generate a subject-specific musculoskeletal muscle model, based on isometric and isovelocity measurements of the whole lower extremity. A two-step optimization procedure is presented for optimizing the muscle-tendon parameters (MTPs) for isometric and isovelocity joint torque profiles. A significant improvement in the prediction of joint torque profiles for both the solely isometric and a combined isometric and dynamic method of optimization when compared to the standard scaling method of the AnyBody Modeling System (AMS) was observed. Depending on the specific purpose of the model, it may be worth considering whether the isometric-only would be sufficient, or the additional dynamic data are required for the combined approach.

Commentary by Dr. Valentin Fuster