Biomedical subjects

Jay D Humphrey

Publications and source records attributed to Jay D Humphrey.

12 recordsLinked to original sources

PubMed2007

Effects of biaxial stretch on arteriolar function in vitro.

Mounting evidence suggests that the normal biomechanical state of arteries may include a nearly equibiaxial intramural stress and that arteries tend to undergo rapid and dramatic remodeling when perturbed from this normal state. Technical developments since the early 1980s have enabled in vitro (acute) and ex vivo (chronic culture) study of isolated, perfused microvessels, and it is clear that these vessels share many functional similarities with arteries. To date, however, there has been no systematic study of the effects of in-plane biaxial loading on the biomechanical behavior of arterioles. Here we describe a modification to a prior in vitro arterial test system that allowed us to investigate the role of altered axial stretch on the passive, myogenic, and norepinephrine-stimulated biaxial behavior of isolated rat cremaster arterioles. We show that axial stretches from 85% to 110% of values often used in the laboratory and consistent with those normally experienced in situ induce modest changes in the measured mean circumferential and axial stress-stretch behavior and in measures of distensibility and myogenic index. Nevertheless, altered axial stretch has a dramatic effect on the biaxial state of stress, and nearly equibiaxial stresses occur at axial stretches larger than those typically used in isolated arteriole studies. This finding is consistent with estimates of material and functional behavior in arterioles and suggests that long-term ex vivo studies, wherein vessel growth and remodeling are critical, should be performed at higher axial lengths than have been used during most prior in vitro tests.

Animals↗

PubMed2006

Biaxial biomechanical adaptations of mouse carotid arteries cultured at altered axial extension.

Many have studied the roles of altered blood flow and pressure on adaptive responses of blood vessels, but few have studied the role of altered axial loads. We exposed common carotid arteries from wild-type mice to low, medium, or high axial extensions while maintaining the same pressure and luminal flow rate for two days in culture, and studied adaptations in vessel geometry, in vitro loads, and stresses while collecting biaxial biomechanical (pressure-diameter and axial force-length) data on Day 0 (initial control conditions), Day 1, and Day 2. In addition, we compared vasoreactive responses to phenylephrine, carbamylcholine chloride, and sodium nitroprusside at the end of the 2-day culture period. We found significant differences in the structural (e.g., pressure-axial force and axial force-length) responses between groups as well as within each group over time. These adaptations seem to be aimed at restoring the mechanical state from a perturbed condition (e.g., low or high axial extension) toward a normal 'homeostatic' condition. Although structural responses (e.g., pressure-axial force and axial force-length) differed between groups on Day 2, the material behavior (e.g., circumferential and axial stress-stretch responses) did not differ significantly between groups.

Animals↗

PubMed2006

Influence of glycerol on the mechanical reversibility and thermal damage susceptibility of collagenous tissues.

Clinical procedures wherein supraphysiologic temperatures must be achieved in deep layers of tissue via light are often compromised by optical scattering and absorption. Optical clearing of tissue superficial to the target improves the efficacy of such procedures. Glycerol is an attractive chemical agent for achieving dramatic reductions in tissue turbidity, but its net effects on healthy tissue are not fully understood. In this paper, we investigate possible alterations of biaxial mechanical properties in a model collagenous tissue, bovine epicardium, induced by glycerol. Furthermore, we examine the effects of glycerol on the biaxial thermomechanical properties of epicardium constrained at near-physiologic length. It is seen that mechanical changes induced by glycerol are fully reversed upon rehydration in normal saline. Moreover, glycerol protects cleared tissue by increasing its thermal stability and minimizing thermal alterations of mechanical properties.

Animals↗

PubMed2005

A 2D constrained mixture model for arterial adaptations to large changes in flow, pressure and axial stretch.

Soft tissue growth and remodelling (G&R) are achieved through highly complex, temporally regulated mechanisms that lead to the adaptation of structurally significant cells and extracellular matrix proteins. Herein we present a constrained mixture model to describe vascular adaptations in response to large perturbations in luminal flow rate, transmural pressure and axial extension. In the associated simulations, G&R occur in evolving loaded (i.e. current) configurations. Although several hypotheses are employed with regard to vasoregulatory mechanisms and rates of growth and turnover of individual constituents, the main hypothesis is that each structural constituent is produced within a range of homeostatic stresses (or stretches). As a result, although material that was produced in one configuration may have the same mechanical behaviour as that produced in another configuration, these materials will possess different natural configurations and contribute a different structural response to the mixture. Our simulations illustrate how, by simply evolving the reference states of individual constituents, blood vessels can adapt their structure and function to restore wall stresses.

Arteries↗

PubMed2005

Stress distribution in a circular membrane with a central fixation.

Clinical interventions can change the mechanical environment of the tissues targeted for therapy. In order to design better procedures, it is important to understand cellular responses to altered mechanical stress. Rigid fixation is one example of a constraint imposed on living tissues as a result of implanted devices. This results in disturbed stress and strain fields, with potentially strong gradients. Herein, we numerically solve the governing nonlinear ordinary differential equation for the stress distribution in a finitely deformed anisotropic circular membrane with a concentric fixation by applying a zero-displacement condition at the inner circumference. Results show that rigid fixations yield distributions of stress and strain that are markedly different from tissue defects with traction-free boundaries. Moreover the material anisotropy plays a significant role in the manner the stress redistributes regardless of the size of fixation. The present study will contribute to the design of experiments to determine cellular reactions involved in the failure of interventional treatments.

Animals↗

PubMed2004

Upregulation of vascular arginase in hypertension decreases nitric oxide-mediated dilation of coronary arterioles.

One characteristic of hypertension is a decreased endothelium-dependent nitric oxide (NO)-mediated vasodilation; however, the underlying mechanism is complex. In endothelial cells (ECs), L-arginine is the substrate for both NO synthase (NOS) and arginase. Because arginase has recently been shown to modulate NO-mediated dilation of coronary arterioles by reducing l-arginine availability, we hypothesized that upregulation of vascular arginase in hypertension contributes to decreased NO-mediated vasodilation. To test this hypothesis, hypertension (mean arterial blood pressure >150 mm Hg) was maintained for 8 weeks in pigs by aortic coarctation. Coronary arterioles from normotensive (NT) and hypertensive (HT) pigs were isolated and pressurized for in vitro study. NT vessels dilated dose-dependently to adenosine (partially mediated by endothelial release of NO) and sodium nitroprusside (endothelium-independent vasodilator). Conversely, HT vessels exhibited reduced dilation to adenosine but dilated normally to sodium nitroprusside. Adenosine-stimulated NO release was increased approximately 3-fold in NT vessels but was reduced in HT vessels. Moreover, arginase activity was 2-fold higher in HT vessels. Inhibition of arginase activity by N(omega)-hydroxy-nor-l-arginine or incubation with l-arginine partially restored NO release and dilation to adenosine in HT vessels. Immunohistochemistry showed that arginase expression was increased but NOS expression was decreased in arteriolar ECs of HT vessels. These results suggest that NO-mediated dilation of coronary arterioles is inhibited in hypertension by an increase in arginase activity in EC, which limits l-arginine availability to NOS for NO production. The inability of arginase blockade or l-arginine supplementation to completely restore vasodilation may be related to downregulation of endothelial NOS expression.

Animals↗

PubMed2004

Building a functional artery: issues from the perspective of mechanics.

Despite the many successes of arterial tissue engineering, clinically viable implants may be a decade or more away. Fortunately, there is much more that we can learn from native vessels with regard to designing for optimal structure, function, and properties. Herein, we examine recent observations in vascular biology from the perspective of nonlinear mechanics. Moreover, we use a constrained mixture model to study potential contributions of individual wall constituents. In both cases, the unique biological and mechanical roles of elastin come to the forefront, especially its role in generating and modulating residual stress within the wall, which appears to be key to multiple growth and remodeling responses.

Animals↗

PubMed2004

Kinetics of thermal damage to a collagenous membrane under biaxial isotonic loading.

Prior isothermal uniaxial isotonic tests on tendons reveal that higher temperatures hasten the rate of thermal denaturation whereas larger mechanical loads delay it; moreover, these findings suggest a time-temperature-load equivalency whereby similar levels of denaturation, as reflected by tissue shrinkage, can be attained via many combinations of heating time, temperature level, and mechanical loading. Yet, most tissues and organs experience multiaxial loads in vivo, and their microstructure differs significantly from that of tendons, thus, we must also evaluate the effects of multiaxial stresses on the kinetics of denaturation in other tissues. In this paper, we describe a new experimental approach for performing isothermal biaxial isotonic tests on thin sheet-like specimens and we report effects of various thermomechanical loads on the rate and amount of multiaxial shrinkage of bovine epicardium. Consistent with uniaxial studies, epicardial shrinkage generally increased sigmoidally with heating time, and a characteristic heating time revealed increases in the rate of shrinkage with higher temperature and decreases with larger biaxial loads. Although this characteristic time exhibited an Arrhenius-type character, time-temperature-load equivalency was not obtained when scaling time with this metric. General multiaxial thermomechanics is thus too complex to explain via a simple extension of uniaxial findings on tendons and there is a pressing need for more data and an appropriate theoretical framework.

Animals↗

PubMed2003

A potential role of smooth muscle tone in early hypertension: a theoretical study.

A conspicuous long-term consequence of hypertension is a thickening of the arterial wall, which many suggest returns the circumferential wall stress toward its normal value. This thickening results from an increase in smooth muscle and extracellular matrix, with the associated growth and remodeling processes depending on a host of regulatory signals that likely include the altered mechanical environment. Although the precise mechanotransduction pathways remain unknown, we propose that vasoconstriction may be an early response of the arterial wall to a step-change in pressure. In particular, computations suggest that such a response can decrease the magnitude and transmural gradients of the pressure-induced wall stresses and return the mean wall shear stress toward its homeostatic value. Such an initial 'compensatory vasoconstriction' could also help set into motion subsequent growth and remodeling responses due to growth regulatory characteristics of the vasoactive molecules (e.g., nitric oxide, endothelin-1, angiotensin-II). Although the consequences of growth and remodeling have been the focus of prior biomechanical and histological studies, early responses dictate subsequent developments and therefore deserve increased attention in vascular biomechanics and mechanobiology.

Animals↗

PubMed2003

A sub-domain inverse finite element characterization of hyperelastic membranes including soft tissues.

Quantification of the mechanical behavior of hyperelastic membranes in their service configuration, particularly biological tissues, is often challenging because of the complicated geometry, material heterogeneity, and nonlinear behavior under finite strains. Parameter estimation thus requires sophisticated techniques like the inverse finite element method. These techniques can also become difficult to apply, however, if the domain and boundary conditions are complex (e.g. a non-axisymmetric aneurysm). Quantification can alternatively be achieved by applying the inverse finite element method over sub-domains rather than the entire domain. The advantage of this technique, which is consistent with standard experimental practice, is that one can assume homogeneity of the material behavior as well as of the local stress and strain fields. In this paper, we develop a sub-domain inverse finite element method for characterizing the material properties of inflated hyperelastic membranes, including soft tissues. We illustrate the performance of this method for three different classes of materials: neo-Hookean, Mooney Rivlin, and Fung-exponential.

Computer Simulation↗

PubMed2002

Biomechanics.

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Biomechanical Phenomena↗

PubMedDate not supplied

A novel aortic coarctation model for studying hypertension in the pig.

We have developed a reproducible renovascular model of hypertension via a controllable, suprarenal aortic coarctation in the pig. This model has many potential applications, including investigation of the effects of acute hypertension in the conscious animal; identification of cardiac and vascular adaptations to chronic hypertension and their reversal; determining the effect of pharmacologic agents or other interventions on hypertension; and furthering our understanding of the implications of chronic hypertension on neurologic function. A totally implantable system was devised by attaching a reinforced silicone vascular occluder to a vascular access port. The occluder was placed around the suprarenal aorta proximal to the diaphragm. Ten pigs were made hypertensive by sequentially inflating the occluder. In six pigs, telemetric monitoring of blood pressure was used to determine when the pigs had reached target pressures (mean arterial blood pressure >150 mm Hg). Four pigs did not have telemetry units placed and blood pressure and heart rate were monitored for 4 weeks by periodically restraining the pigs in a sling. Two pigs reversed their occlusion due to presumed technical errors; the remaining pigs were studied for 4 (n = 5) or 8 (n = 3) weeks and then euthanized. Advantages of this model of aortic coarctation are that the occlusions are performed in awake animals and excessive occlusion of the aorta resulting in neurologic dysfunction or other distress to the animal can be easily corrected by simply withdrawing a small amount of the fluid used for inflation of the occluder. Additionally, removal of the constriction does not require a second surgical procedure.

Aldosterone↗