Colleen Witzenburg

Mechanical Changes in the Rat Right Ventricle with Decellularization

The stiffness, anisotropy, and heterogeneity of freshly dissected (control) and perfusion-decellularized rat right ventricles were compared using an anisotropic inverse mechanics method. Cruciform tissue samples were speckled and then tested under a series of different biaxial loading configurations with simultaneous force measurement on all four arms and displacement mapping via image correlation. Based on the displacement and force data, the sample was segmented into piecewise homogeneous partitions. Tissue stiffness and anisotropy were characterized for each partition using a large-deformation extension of the general linear elastic model. The perfusion-decellularized tissue had significantly higher stiffness than the control, suggesting that the cellular contribution to stiffness, at least under the conditions used, was relatively small. Neither anisotropy nor heterogeneity (measured by the partition standard deviation of the modulus and anisotropy) varied significantly between control and decellularized samples. We thus conclude that although decellularization produces quantitative differences in modulus, decellularized tissue can provide a useful model of the native tissue extracellular matrix. Further, the large-deformation inverse method presented herein can be used to characterize complex soft tissue behaviors.

Prefailure and Failure Mechanics of the Porcine Ascending Thoracic Aorta: Experiments and a Multiscale Model

Ascending thoracic aortic aneurysms (ATAA) have a high propensity for dissection, which occurs when the hemodynamic load exceeds the mechanical strength of the aortic media. Despite our recognition of this essential fact, the complex architecture of the media has made a predictive model of medial failure-even in the relatively simple case of the healthy vessel-difficult to achieve. As a first step towards a general model of ATAA failure, we characterized the mechanical behavior of healthy ascending thoracic aorta (ATA) media using uniaxial stretch-to-failure in both circumferential (n = 11) and axial (n = 11) orientations and equibiaxial extensions (n = 9). Both experiments demonstrated anisotropy, with higher tensile strength in the circumferential direction (2510 ± 439.3 kPa) compared to the axial direction (750 ± 102.6 kPa) for the uniaxial tests, and a ratio of 1.44 between the peak circumferential and axial loads in equibiaxial extension. Uniaxial tests for both orientations showed macroscopic tissue failure at a stretch of 1.9. A multiscale computational model, consisting of a realistically aligned interconnected fiber network in parallel with a neo-Hookean solid, was used to describe the data; failure was modeled at the fiber level, with an individual fiber failing when stretched beyond a critical threshold. The best-fit model results were within the 95% confidence intervals for uniaxial and biaxial experiments, including both prefailure and failure, and were consistent with properties of the components of the ATA media.

Failure of the porcine ascending aorta: Multidirectional experiments and a unifying microstructural model

The ascending thoracic aorta is poorly understood mechanically, especially its risk of dissection. To make better predictions of dissection risk, more information about the multidimensional failure behavior of the tissue is needed, and this information must be incorporated into an appropriate theoretical/computational model. Toward the creation of such a model, uniaxial, equibiaxial, peel, and shear lap tests were performed on healthy porcine ascending aorta samples. Uniaxial and equibiaxial tests showed anisotropy with greater stiffness and strength in the circumferential direction. Shear lap tests showed catastrophic failure at shear stresses (150-200 kPa) much lower than uniaxial tests (750-2500 kPa), consistent with the low peel tension (∼60 mN/mm). A novel multiscale computational model, including both prefailure and failure mechanics of the aorta, was developed. The microstructural part of the model included contributions from a collagen-reinforced elastin sheet and interlamellar connections representing fibrillin and smooth muscle. Components were represented as nonlinear fibers that failed at a critical stretch. Multiscale simulations of the different experiments were performed, and the model, appropriately specified, agreed well with all experimental data, representing a uniquely complete structure-based description of aorta mechanics. In addition, our experiments and model demonstrate the very low strength of the aorta in radial shear, suggesting an important possible mechanism for aortic dissection.

A Comparison of Phenomenologic Growth Laws for Myocardial Hypertrophy

The heart grows in response to changes in hemodynamic loading during normal development and in response to valve disease, hypertension, and other pathologies. In general, a left ventricle subjected to increased afterload (pressure overloading) exhibits concentric growth characterized by thickening of individual myocytes and the heart wall, while one experiencing increased preload (volume overloading) exhibits eccentric growth characterized by lengthening of myocytes and dilation of the cavity. Predictive models of cardiac growth could be important tools in evaluating treatments, guiding clinical decision making, and designing novel therapies for a range of diseases. Thus, in the past 20 years there has been considerable effort to simulate growth within the left ventricle. While a number of published equations or systems of equations (often termed “growth laws”) can capture some aspects of experimentally observed growth patterns, no direct comparisons of the various published models have been performed. Here we examine eight of these laws and compare them in a simple test-bed in which we imposed stretches measured during in vivo pressure and volume overload. Laws were compared based on their ability to predict experimentally measured patterns of growth in the myocardial fiber and radial directions as well as the ratio of fiber-to-radial growth. Three of the eight laws were able to reproduce most key aspects of growth following both pressure and volume overload. Although these three growth laws utilized different approaches to predict hypertrophy, they all employed multiple inputs that were weakly correlated during in vivo overload and therefore provided independent information about mechanics.

Automatic Segmentation of Mechanically Inhomogeneous Tissues Based on Deformation Gradient Jump

Variations in properties, active behavior, injury, scarring, and/or disease can all cause a tissues mechanical behavior to be heterogeneous. Advances in imaging technology allow for accurate full-field displacement tracking of both in vitro and in vivo deformation from an applied load. While detailed strain fields provide some insight into tissue behavior, material properties are usually determined by fitting stress-strain behavior with a constitutive equation. However, the determination of the mechanical behavior of heterogeneous soft tissue requires a spatially varying constitutive equation (i.e., one in which the material parameters vary with position). We present an approach that computationally dissects the sample domain into many homogeneous subdomains, wherein subdomain boundaries are formed by applying a betweenness based graphical analysis to the deformation gradient field to identify locations with large discontinuities. This novel partitioning technique successfully determined the shape, size and location of regions with locally similar material properties for: (1) a series of simulated soft tissue samples prescribed with both abrupt and gradual changes in anisotropy strength, prescribed fiber alignment, stiffness, and nonlinearity, (2) tissue analogs (PDMS and collagen gels) which were tested biaxially and speckle tracked (3) and soft tissues which exhibited a natural variation in properties (cadaveric supraspinatus tendon), a pathologic variation in properties (thoracic aorta containing transmural plaque), and active behavior (contracting cardiac sheet). The routine enables the dissection of samples computationally rather than physically, allowing for the study of small tissues specimens with unknown and irregular inhomogeneity.

Sex Differences in the Mechanical Behavior of the Decellularized Rat Left Ventricle

There are fundamental differences in the size and performance of male and female hearts. Even after adjustments for height and body surface area, the left ventricle of a healthy male is larger in both volume and mass [1]. There are differences in contractile performance between papillary muscle from male and female rats with male rats showing slower responses in both isometric and isotonic tests [2]. It is less clear, however, whether the underlying structure or mechanical properties vary between sexes as well. Of particular interest to us is the extracellular matrix (ECM) of the ventricular wall, which provides structural stability to the heart. This matrix can be isolated by perfusion decellularization [3].Copyright

Biomechanics of Myocardial Ischemia and Infarction

Each year, over seven million people suffer a myocardial infarction (heart attack). For those who survive the initial event, the mechanical properties of the scar tissue that gradually replaces the damaged muscle are a critical determinant of many life-threatening sequelae, such as infarct rupture and the development of heart failure. Thus, understanding the mechanics of healing infarct scar, its interaction with the rest of the heart, and the resulting changes in heart function are critical to devising effective therapies. Computational models play an essential role in understanding these potentially complex interactions. The first section of this chapter reviews the structure and mechanical properties of the normal heart and the methods used to study those properties. The second section discusses the structure and mechanical properties of healing post-infarction scar. The remaining sections review landmark analytical and computational models that provided insight into the functional consequences of myocardial infarction and potential therapies. Finally, we briefly consider emerging models of wound healing in the infarct region and growth and remodeling in the surviving myocardium that are beginning to predict the long-term effects of infarction and post-infarction therapies. In the future, multi-scale models that capture such remodeling in addition to the beat-to-beat mechanics of the heart hold great promise for designing novel therapies, not only for myocardial infarction but also for a wide range of cardiac pathologies.

A nonlinear anisotropic inverse method for computational dissection of inhomogeneous planar tissues

Abstract Quantification of the mechanical behavior of soft tissues is challenging due to their anisotropic, heterogeneous, and nonlinear nature. We present a method for the ‘computational dissection’ of a tissue, by which we mean the use of computational tools both to identify and to analyze regions within a tissue sample that have different mechanical properties. The approach employs an inverse technique applied to a series of planar biaxial experimental protocols. The aggregated data from multiple protocols provide the basis for (1) segmentation of the tissue into regions of similar properties, (2) linear analysis for the small-strain behavior, assuming uniform, linear, anisotropic behavior within each region, (3) subsequent nonlinear analysis following each individual experimental protocol path and using local linear properties, and (4) construction of a strain energy data set W(E) at every point in the material by integrating the differential stress–strain functions along each strain path. The approach has been applied to simulated data and captures not only the general nonlinear behavior but also the regional differences introduced into the simulated tissue sample.

Dissection of porcine ascending aortic media: Mechanical characterization and multiscale model

Ascending thoracic aortic aneurysm (aTAA) is a pathological condition with a high risk of dissection and rupture. Clinically, management of aTAA balances the risk of rupture with that of surgery-related complications. The risk of aneurysm rupture is known to correlate with aneurysm diameter.1,2 Aneurysms greater than 6 cm in diameter have a significantly higher risk of rupture.1 Current guidelines for intervention suggest surgical intervention for aTAA diameters greater than 5.5cm for patients without connective tissue disorders.1Copyright

Ascending thoracic aorta exhibits anisotropic failure behavior in shear lap testing

Aneurysm dissection and rupture, resulting in imminent death, is the primary risk associated with thoracic aortic aneurysms (TAA). Nearly 60% of TAA involves the ascending aorta [1]. Dissection and rupture occur when the remodeled tissue is no longer able to withstand the stresses generated by the arterial pressure. As the ascending TAA grows, however, changes in its mechanical behavior, particularly wall strength, are unknown.Copyright