Morphometric Reconstruction of Coronary Vasculature Incorporating Uniformity of Flow Dispersion

Experimental limitations in measurements of coronary flow in the beating heart have led to the development of in silico models of reconstructed coronary trees. Previous coronary reconstructions relied primarily on anatomical data, including statistical morphometry (e.g., diameters, length, connectivity, longitudinal position). Such reconstructions are non-unique, however, often leading to unrealistic predicted flow features. Thus, it is necessary to impose physiological flow constraints to ensure realistic tree reconstruction. Since a vessel flow depends on its diameter to fourth power, diameters are the logical candidates to guide vascular reconstructions to achieve realistic flows. Here, a diameter assignment method was developed where each vessel diameter was determined depending on its downstream tree size, aimed to reduce flow dispersion to within measured range. Since the coronary micro-vessels are responsible for a major portion of the flow resistance, the auto regulated coronary flow was analyzed in a morphometry-based reconstructed 400 vessel arterial microvascular sub-tree spanning vessel orders 1–6. Diameters in this subtree were re-assigned based on the flow criteria. The results revealed that diameter re-assignment, while adhering to measured morphometry, significantly reduced the flow dispersion to realistic levels while adhering to measured morphometry. The resulting network flow has longitudinal pressure distribution, flow fractal nature, and near-neighboring flow autocorrelation, which agree with measured coronary flow characteristics. Collectively, these results suggest that a realistic coronary tree reconstruction should impose not only morphometric data but also flow considerations. The work is of broad significance in providing a novel computational framework in the field of coronary microcirculation. It is essential for the study of coronary circulation by model simulation, based on a realistic network structure

Inverse finite element methods for extracting elastic-poroviscoelastic properties of cartilage and other soft tissues from indentation

Mechanical properties are essential for understanding diseases that afflict various soft tissues, such as osteoarthritic cartilage and hypertension which alters cardiovascular arteries. Although the linear elastic modulus is routinely measured for hard materials, standard methods are not available for extracting the nonlinear elastic, linear elastic and time-dependent properties of soft tissues. Consequently, the focus of this work is to develop indentation methods for soft biological tissues; since analytical solutions are not available for the general context, finite element simulations are used.First, parametric studies of finite indentation of hyperelastic layers are performed to examine if indentation has the potential to identify nonlinear elastic behavior. To answer this, spherical, flat-ended conical and cylindrical tips are examined and the influence of thickness is exploited. Also the influence of the specimen/substrate boundary condition (slip or non-slip) is clarified.Second, a new inverse method---the hyperelastic extraction algorithm (HPE)---was developed to extract two nonlinear elastic parameters from the indentation force-depth data, which is the basic measurement in an indentation test. The accuracy of the extracted parameters and the influence of noise in measurements on this accuracy were obtained. This showed that the standard Berkovitch tip could only extract one parameter with sufficient accuracy, since the indentation force-depth curve has limited sensitivity to both nonlinear elastic parameters.Third, indentation methods for testing tissues from small animals were explored. New methods for flat-ended conical tips are derived. These account for practical test issues like the difficulty in locating the surface or soft specimens. Also, finite element simulations are explored to elucidate the influence of specimen curvature on the indentation force-depth curve.Fourth, the influence of inhomogeneity and material anisotropy on the extracted average linear elastic modulus was studied. The focus here is on murine tibial cartilage, since recent experiments have shown that the modulus measured by a 15 mum tip is considerably larger than that obtained from a 90 mum tip. It is shown that a depth-dependent modulus could give rise to such a size effect.Lastly, parametric studies were performed within the small strain setting to understand the influence of permeability and viscoelastic properties on the indentation stress-relaxation response. The focus here is on cartilage, and specific test protocols (single-step vs. multi-step stress relaxation) are explored. An inverse algorithm was developed to extract the poroviscoelastic parameters. A sensitivity study using this algorithm shows that the instantaneous elastic modulus (which is a measure of the viscous relaxation) can be extracted with very good accuracy, but the permeability and long-time relaxation constant cannot be extracted with good accuracy. The thesis concludes with implications of these studies. The potential and limitations of indentation tests for studying cartilage and other soft tissues is discussed

Role of Coronary Myogenic Response in Pressure-Flow Autoregulation in Swine: A Meta-Analysis With Coronary Flow Modeling

Myogenic responses (pressure-dependent contractions) of coronary arterioles play a role in autoregulation (relatively constant flow vs. pressure). Publications on myogenic reactivity in swine coronaries vary in caliber, analysis, and degree of responsiveness. Further, data on myogenic responses and autoregulation in swine have not been completely compiled, compared, and modeled. Thus, it has been difficult to understand these physiological phenomena. Our purpose was to: (a) analyze myogenic data with standard criteria; (b) assign results to diameter categories defined by morphometry; and (c) use our novel multiscale flow model to determine the extent to which ex vivo myogenic reactivity can explain autoregulation in vivo. When myogenic responses from the literature are an input for our model, the predicted coronary autoregulation approaches in vivo observations. More complete and appropriate data are now available to investigate the regulation of coronary blood flow in swine, a highly relevant model for human physiology and disease