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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

It is widely accepted that numerous cell types respond to mechanical stimuli, yet there is no general agreement as to whether particular cells respond directly to stress, strain, strain-rate, strain-energy, or other mechanical quantities. By recalling the definitions of the mathematical (not physical) concepts of stress and strain, it is suggested herein that cells cannot respond directly to these continuum metrics or to quantities derived from them -- mechanistic models will need to be based on more fundamental quantities, as, for example, inter-atomic forces or conformational changes of the appropriate molecules. Nonetheless, the concepts of stress and strain should continue to play an important role in mechanobiology, both in the identification of empirical correlations and in the development of phenomenological constitutive models, each of which can contribute to our basic understanding as well as help in the design of future experiments and some clinical interventions. It is important to remember, therefore, that empirical correlations and most constitutive relations in continuum mechanics do not seek to model the actual physics -- rather, their utility is in their predictive capability, which is often achieved via different relations in terms of different metrics for the same material under different conditions. Hence, with regard to quantifying cellular responses to mechanical stimuli, we must delineate between the identification of fundamental mechanisms and the formulation of phenomenological correlations, the latter of which only requires convenient metrics that need not be unique or physical. [DOI: 10.1115/1.1406131]

Understanding how transmural distributions of stress relate to the mechanisms of vascular growth, remodeling, and disease necessitates computations that are based on a constitutive relation for the arterial wall. Although a number of candidate relations are in the literature, they have not been compared in detail. In this note, three commonly used descriptors of the passive behavior of common carotid arteries are compared using simple 'thought experiments.' It is shown that two of the three relations are inherently limited in the degree of anisotropy they allow, that each predicts a different anisotropy, and that one yields physically unrealistic predictions given many of the published values of the material parameters. based on this comparison, it appears that the relation proposed by Chuong and Fung is the best available, though there may be a need to search for an alternate form, particularly for muscular arteries. The methods presented herein are offered as a guide to help the experimentalist identify alternate forms of pseudostrain-energy functions for arteries.

We present data from isothermal, isotonic-shrinkage tests wherein bovine chordae tendineae were subjected to well-defined constant temperatures (from 65 to 90 [degrees] C), durations of heating (from 180 to 3600 s), and isotonic uniaxial stresses during heating (from 100 to 650 kPa). Tissue response during heating and 'recover' at 37 [degrees] C following heating was evaluated in terms of the axial shrinkage, a gross indicator of underlying heat-induced denaturation. There were three key findings. First, scaling the heating time via temperature and load-dependent characteristic times for the denaturation process collapsed all shrinkage data to a single curve, and thereby revealed a time-temperature-load equivalency. Second, the characteristic times exhibited an Arrhenius-type behavior with temperature wherein the slopes were nearly independent of applied load - this suggested that applied loads during heating affect the activation entropy, not energy. Third, all specimens exhibited a time-dependent, partial recovery when returned to 37 [degrees] C following heating, but the degree of recovery decreased with increases in the load imposed during heating. These new findings on heat-induced changes in tissue behavior will aid in the design of improved clinical heating protocols and provide guidance for the requisite constitutive formulations.

We performed in vitro pressure-diameter and axial force-length experiments on nondiseased, passive bovine coronary arteries subjected to bath temperatures from 21 to 80 [degrees] C for 90 s to 4 hr. Over the strain ranges studied, we found that: (a) vessel behavior remained the same over 20 min of testing at 21 to 55 [degrees] C, (b) vessels stiffened multiaxially after 5 min of exposure to 60 [degrees] C and continued to stiffen over 20 min of testing, (c) dramatic multiaxial vessel stiffening and shrinkage occurred after 90 s of exposure to 70 and 80 [degrees]C, and (d) heat-induced changes at 70 [degrees]C depended on the intraluminal pressure during heating. Thus, passive bovine coronary arteries exhibit a complex thermomechanical behavior that depends on the temperature, duration of thermal exposure, and the mechanical loads applied during heating.

A theoretical approach for evaluating the constitutive relation involved in the nonlinear and anisotropic biomechanical behavior of an epicardium membrane is presented. The approach, which uses an in-plane stress resultant tensor to express the membrane's governing differential equations, is capable of identifying the response function characteristics of the heart's right and leftheart ventricles directly from experimental data.