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Computational models of arterial growth and remodeling promise to increase our understanding of basic biological processes, such as development, tissue maintenance, and aging, the biomechanics of functional adaptation, the progression and treatment of disease, responses to injuries, and even the design of improved replacement vessels and implanted medical devices. Ensuring reliability of and confidence in such models requires appropriate attention to verification and validation, including parameter sensitivity studies. In this paper, we classi different types of parameters within a constrained mature model of arterial growth and remodeling; we then evaluate the sensitivity of model predictions to parameter values that are not known directly from experiments ,for cases of modest sustained alterations in blood flow and pressure as well as increased axial extension. Particular attention is directed toward complementary roles of smooth muscle vasoactivity and matrix turnover, with an emphasis on mechanosensitive changes in the rates of turnover of intramural fibrillar collagen and smooth muscle in maturity. It is shown that vasoactive changes influence the rapid change in caliber that is needed to maintain wall shear stress near its homeostatic level and the longer term changes in wall thickness that are needed to maintain circumferential wall stress near its homeostatic target. Moreover, it is shown that competing effects of intramural and wall shear stress-regulated rates of turnover can develop complex coupled responses. Finally, results demonstrate that the sensitivity to parameter values depends upon the type of perturbation from normalcy, with changes in axial stretch being most sensitive consistent with empirical reports. [DOI: 10.1115/1.3192144] Keywords: vasoactivity, stress, collagen turnover, verification, experimental design

Hyperglycemia can alter the mechanical properties of tissues through the formation of advanced glycation endproducts in matrix proteins that have long half-lives. We used a custom experimental system and subdomain finite element method to quantify alterations in the regional multiaxial mechanical properties of porcine lens capsules that were cultured for 8 or 14 weeks in high glucose versus control media. Findings revealed that high glucose significantly stiffened the capsules in both the circumferential and the meridional directions, but it did not affect the known regional variations in anisotropy. Such information could be important in the design of both improved clinical procedures and intraocular implants for diabetic patients [DOI: 10.1115/1.2401192] Keywords: hyperglycemia, diabetes, biomechanics, cataracts, type IV collagen

The lens capsule of the eye plays fundamental biomechanical roles in both normal physiological processes and clinical interventions. There has been modest attention given to the mechanical properties of this important membrane, however, and prior studies have focused on 1-D analyses of the data. We present results that suggest that the porcine anterior lens capsule has a complex, regionally dependent, nonlinear, anisotropic behavior. Specifically, using a subdomain inverse finite element method to analyze data collected via a new biplane video-based test system, we found that the lens capsule is nearly isotropic (in-plane) near the pole but progressively stiffer in the circumferential compared to the meridional direction as one approaches the equator. Because the porcine capsule is a good model of the young human capsule, there is strong motivation to determine if similar regional variations exist in the human lens capsule for knowledge of such complexities may allow us to improve the design of surgical procedures and implants. [DOI: 10.1115/1.2401188] Keywords: cataracts, accommodation, biomechanics, stress, stiffness

The mechanisms by which intracranial aneurysms develop, enlarge, and rupture are unknown, and it remains difficult to collect the longitudinal patient-based information needed to improve our understanding. We submit, therefore, that mathematical models hold promise by allowing us to propose and test competing hypotheses on potential mechanisms of aneurysmal enlargement and to compare predicted outcomes with limited clinical information--in this way, we may begin to narrow the possible mechanisms and thereby focus experimental studies. In this paper, we present a constrained mixture model of evolving thin-walled, fusiform aneurysms and compare multiple competing hypotheses with regard to the production, removal, and alignment of the collagen that provides the structural integrity of the wall. The results show that this type of approach has the capability to infer potential means by which lesions enlarge and whether such changes are likely to produce a stable or unstable process. Such information can better direct the requisite histopathological examinations, particularly on the need to quantify collagen orientations as a function of lesion geometry. [DOI: 10.1115/1.2132374] Keywords: collagen turnover, wall stress, aneurysms, biomechanics

Supra-physiological temperatures are increasingly being used to treat many different soft tissue diseases and injuries. To identify improved clinical treatments, however, there is a need for better information on the effect of the mechanics on the thermal damage process as well as the effect of the incurred damage on the subsequent mechanical properties. In this paper, we report the first biaxial data on the stress relaxation behavior of a collagenous tissue before and after thermal damage. Based on a two-dimensional finite strain viscoelastic model, which incorporates an exponential elastic response, it is shown that the thermal damage can significantly decrease the characteristic time for stress relaxation and the stress residual. [DOI: 10.1115/1.1934222] Keywords: Biothermomechanics, Denaturation, Thermal Damage, Pseudoelasticity

ABSTRACT--Many arterial diseases manifest at bifurcations, as for example, atherosclerosis and aneurysms. Findings over the last three decades reveal the important role of mechanics in the genesis and treatment of [...]

Much of our understanding of vascular mechanotransduction has come from studies using either cell culture or in vivo animal models, but the recent success of organ culture systems offers an exciting alternative. In studying cell-mediated vascular adaptations to altered loading, organ culture allows one to impose well-controlled mechanical loads and to perform multiaxial mechanical tests on the same vessel throughout the culture period, and thereby to observe cell-mediated vascular adaptations independent of neural and hormonal effects. Here, we present a computer-controlled perfused organ culture and biomechanical testing device designed for small caliber (50-5000 micron) blood vessels. This device can control precisely the pulsatile pressure, luminal flow, and axial load (or stretch) and perform intermittent biaxial (pressure-diameter and axial load-length) and functional tests to quantify adaptations in mechanical behavior and cellular function, respectively. Device capabilities are demonstrated by culturing mouse carotid arteries for 4 days. Keywords: Ex Vivo Perfusion, Organ Culture, Remodeling, Mechanical Properties, Vascular Smooth Muscle, Endothelium

Most soft tissues that are treated clinically via heating experience multiaxial states of stress and strain in vivo and are subject to complex constraints during treatment. Remarkably, however, there are no prior data on changes in the multiaxial mechanical behavior of a collagenous tissue subjected to isometric constraints during heating. This paper presents the first biaxial stress-stretch data on a collagenous membrane (epicardium) before and after heating while subjected to various biaxial isometric constraints. It was found that isometric heating does not allow the increase in stiffness at low strains that occurs following isotonic heating. Moreover, increasing the degree of stretch prior to heating increased the thermal stability of the tissue consistent with the concept that mechanical loading primarily affects the activation entropy, not the activation energy.

Evidence from diverse investigations suggests that arterial growth and remodeling correlates well with changes in mechanical stresses from their homeostatic values. Ultimately, therefore, there is a need for a comprehensive theory that accounts for changes in the 3-D distribution of stress within the arterial wall, including residual stress, and its relation to the mechanisms of mechanotransduction. Here, however, we consider a simpler theory that allows competing hypotheses to be tested easily, that can provide guidance in the development of a 3-D theory, and that may be useful in modeling solid-fluid interactions and interpreting clinical data. Specifically, we present a 2-D constrained mixture model for the adaptation of a cylindrical artery in response to a sustained alteration in flow. Using a rule-of-mixtures model for the stress response and first order kinetics for the production and removal of the three primary load-bearing constituents within the wall, we illustrate capabilities of the model by comparing responses given complete versus negligible turnover of elastin. Findings suggest that biological constraints may result in suboptimal adaptations, consistent with reported observations. To build upon this finding, however, there is a need for significantly more data to guide the hypothesis testing as well as the formulation of specific constitutive relations within the model.

Recent isothermal biaxial isotonic tests suggest that increasing the temperature hastens the rate of denaturation of epicardium whereas increasing the mechanical load during heating delays this process, findings that are consistent with prior uniaxial tests on tendons. Yet, contrary to uniaxial reports, a clear time-temperature-load equivalency was not found in this multiaxial setting. There is, therefore, a need to delineate multiaxial thermomechanical behavior in greater detail and ultimately, to correlate changes therein with the underlying microstructure. Toward this end, we describe a new experimental approach for quantifying heating-induced changes in the multiaxial mechanical response of thin sheet-like specimens. Illustrative results are presented for bovine epicardium subjected to nine different thermomechanical loading protocols. Among other results, it is shown that thermal damage tends to increase the stiffness at low strains and that overall changes in extensibility correlate well with the degree of thermal damage independent of the specific thermomechanical protocol. Multiaxial changes in behavior are nevertheless complex, and there is a need for significantly more testing before constitutive relations can be formulated. [DOI: 10.1115/1.1567754] Keywords: Thermal Damage, Collagen Denaturation, Stress-Strain, Pseudoelasticity