Insights Into Regional Adaptations in the Growing Pulmonary Artery Using a Meso-Scale Structural Model: Effects of Ascending Aorta Impingement

Congenital abnormalities of pulmonary artery often necessitate surgical repair or the use of autologous tissue and synthetic biomaterials as vascular grafts [1–3]. The patency of synthetic conduit replacements remains limited, often requiring further surgical re-interventions due to lack of adaptation to the normal growth of the child and/or functional failure of the graft [4]. The autologous conduit replacements are limited in supply and may not adjust to different flow environment of the graft site. Above all, an optimal vascular replacement should be able to accommodate somatic growth and closely mimic the structure, function, and physiologic function of the native vessel. In recent years, there has been a growing interest in the development of a living, autologous tissue graft that could address the critical need for growing substitutes for the repair of congenital cardiac defects [5–8], especially the pulmonary valve and artery (PA). The engineering foundation of such novel approaches must thus rest on an understanding of changes in the structure-function relationship that occur during postnatal maturation. Moreover, the distensibility of great arteries are important determinants of ventricular afterload and eventual dysfunction in the pulmonary hypertension, as well as many congenital defects [9]. Yet, relatively little known of the postnatal somatic growth characteristics of the PA. In general, the altered mechanical properties of the great arteries are primarily associated with remodeling of the collagen and elastin fiber networks. For example, biochemical studies in animals have shown a significant upsurge in the collagen and elastin synthesis and mass, as well as reorganization in hypertensive pulmonary arteries [10,11]. The perinatal period is associated with significant elastin and collagen accumulation in the pulmonary trunk and aorta in preparation for a marked postnatal increase in arterial pressure [12,13]. It is well known that newborn animals develop more severe pulmonary hypertension than adults with dramatic vascular changes [14], possibly due to the elastin and collagen synthesis being particularly sensitive to modulation by hypoxia during this time of rapid growth. Lammers et al. [15] have delineated the prominent role of elastin in the alteration of pulmonary artery mechanics in hypertensive calves. Moreover, structural and degradative alterations of medial elastin is found to be a major contributing factor in physiological phenomena such as aging, and the initiation and development of cardiovascular disease, such as aortic aneurysms [16,17]. We have recently demonstrated complex patterns of spatial growth in the growing ovine PA [18,19]. Our results indicated that the spatial and temporal surface growth deformation patterns of both arteries were heterogeneous, including an increase in taper in both arteries and increase in cross-sectional ellipticity of the PA. Interestingly, contact between the PA and AA resulted in increasing spatial heterogeneity in postnatal growth, with the PA demonstrating the greatest changes. Results of this study clearly underscored the fact that functional growth of the PA during postnatal maturation involves complex geometric adaptations. In a parallel study, we quantified the structural and biomechanical properties over the same age period [20]. Here, the PA wall demonstrated significant mechanical anisotropy, except in the posterior region where it was nearly isotropic, and overall modest changes in regional mechanical properties with growth. Perhaps our most interesting finding was that we found that the PA wall thickness was maintained over the entire growth period in spite of the substantial increase in vessel diameter. This suggests that the PA grows by in-plane tissue accumulation only, resulting in a 40% average increase in hoop stress over the growth period. Therefore, unlike the arterial wall remodeling due to hypertension [10,11,21], there is not strictly-held homeostatic maintenance of wall stress during the postnatal growth period. This rather surprising result opens the door for many questions, such as whether are there alterations in the effective moduli of the collagen and elastin networks during the growth period. To begin to address these questions, one can utilize constitutive models which incorporate several important aspects of the underlying microstructure. Structurally based models can help elucidate the mechanisms governing the structure-function relationship of biological tissues and elucidate what happens during the remodeling period. Such approaches have been utilized for arterial tissue remodeling [22,23], as well as the PA [24–26]. However, the models developed so far have not addressed the mechanical behavior of normal growing vessels from the early juvenile to the adult states, either as a contiguous growth model or as a set of quasi-static steps. Moreover, the reliability of such models considerably depends on the accurate quantification of organization and load-bearing behavior of fibrous components of the tissue. In the case of the PA, these are collagen, elastin, and to a lesser extent, smooth muscle as the mechanically significant structural components. Thus, the elastin and collagen structure-function relationship of the normal PA and in connection to growth changes need to be utilized in such models. In the present study, we utilized the extensive experimental measurements of the growing PA to develop a structural model for the PA in the juvenile and adult states. Novel to this approach was the explicit treatment of the elastin phase as a population of fibers as opposed to single material phase as in other studies of the PA. The developed constitutive model also took into account the contributions of the ground matrix, consisting of smooth muscle cells and other noncellular materials. When applied to the available data, we demonstrate that we were able to delineate the structure-function relationship of PA wall in the postnatal growth period in the juvenile and adult states.