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Editorial

J Biomech Eng. 2009;131(10):100201-100201-1. doi:10.1115/1.3254319.
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We are pleased to publish the second in a series of special issues published in the Journal of Biomechanical Engineering that focus in high-impact areas. The current issue grew out of a Symposium on the Mechanics of Growth and Remodeling in Native and Engineered Tissues, which took place at the 2008 Summer Bioengineering Conference, Marco Island, FL, June 25–29, 2008.

Commentary by Dr. Valentin Fuster

Research Papers

J Biomech Eng. 2009;131(10):101001-101001-12. doi:10.1115/1.3192138.

A framework is formulated within the theory of mixtures for continuum modeling of biological tissue growth that explicitly addresses cell division, using a homogenized representation of cells and their extracellular matrix (ECM). The model relies on the description of the cell as containing a solution of water and osmolytes, and having a porous solid matrix. The division of a cell into two nearly identical daughter cells is modeled as the doubling of the cell solid matrix and osmolyte content, producing an increase in water uptake via osmotic effects. This framework is also generalized to account for the growth of ECM-bound molecular species that impart a fixed charge density (FCD) to the tissue, such as proteoglycans. This FCD similarly induces osmotic effects, resulting in extracellular water uptake and osmotic pressurization of the ECM interstitial fluid, with concomitant swelling of its solid matrix. Applications of this growth model are illustrated in several examples.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2009;131(10):101002-101002-11. doi:10.1115/1.3192139.

A constituent based nonlinear viscoelastic (VE) model was modified from a previous study (Vena, , 2006, “A Constituent-Based Model for the Nonlinear Viscoelastic Behavior of Ligaments  ,” J. Biomech. Eng., 128, pp. 449–457) to incorporate a glycosaminoglycan (GAG)-collagen (COL) stress balance using compressible elastic stress constitutive equations specific to articular cartilage (AC). For uniaxial loading of a mixture of quasilinear VE constituents, time constant and relaxation ratio equations are derived to highlight how a mixture of constituents with distinct quasilinear VE properties is one mechanism that produces a nonlinear VE tissue. Uniaxial tension experiments were performed with newborn bovine AC specimens before and after 55% and 85% GAG depletion treatment with guanidine. Experimental tissue VE parameters were calculated directly from stress relaxation data, while intrinsic COL VE parameters were calculated by curve fitting the data with the nonlinear VE model with intrinsic GAG viscoelasticity neglected. Select tissue and intrinsic COL VE parameters were significantly different from control and experimental groups and correlated with GAG content, suggesting that GAG-COL interactions exist to modulate tissue and COL mechanical properties. Comparison of the results from this and other studies that subjected more mature AC tissue to GAG depletion treatment suggests that the GAGs interact with the COL network in a manner that may be beneficial for rapid volumetric expansion during developmental growth while protecting cells from excessive matrix strains. Furthermore, the underlying GAG-COL interactions appear to diminish as the tissue matures, indicating a distinctive remodeling response during developmental growth.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2009;131(10):101003-101003-14. doi:10.1115/1.3192141.

The physiological mechanisms that give rise to the inception and development of a cerebral aneurysm are accepted to involve the interplay between the local mechanical forces acting on the arterial wall and the biological processes occurring at the cellular level. In fact, the wall shear stresses (WSSs) that act on the endothelial cells are thought to play a pivotal role. A computational framework is proposed to explore the link between the evolution of a cerebral aneurysm and the influence of hemodynamic stimuli that act on the endothelial cells. An aneurysm evolution model, which utilizes a realistic microstructural model of the arterial wall, is combined with detailed 3D hemodynamic solutions. The evolution of the blood flow within the developing aneurysm determines the distributions of the WSS and the spatial WSS gradient (WSSG) that act on the endothelial cell layer of the tissue. Two illustrative examples are considered: Degradation of the elastinous constituents is driven by deviations of WSS or the WSSG from normotensive values. This model provides the basis to further explore the etiology of aneurysmal disease.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2009;131(10):101004-101004-8. doi:10.1115/1.3192142.

A novel structure-based mathematical model of arterial remodeling in response to a sustained increase in pressure is proposed. The model includes two major aspects of remodeling in a healthy matured vessel. First, the deviation of the wall stress and flow-induced shear stress from their normal physiological values drives the changes in the arterial geometry. Second, the new mass that is produced during remodeling results from an increase in the mass of smooth muscle cells and collagen fibers. The model additionally accounts for the effect of the average pulsatile strain on the recruitment of collagen fibers in load bearing. The model was used to simulate remodeling of a human thoracic aorta, and the results are in good agreement with previously published model predictions and experimental data. The model predicts that the total arterial volume rapidly increases during the early stages of remodeling and remains virtually constant thereafter, despite the continuing stress-driven geometrical remodeling. Moreover, the effects of a perfect or incomplete restoration of the arterial compliance on the remodeling outputs were analyzed. For instance, the model predicts that the pattern of the time course of the opening angle depends on the extent to which the average pulsatile strain is restored at the end of the remodeling process. Future experimental studies on the time course of compliance, opening angle, and mass fractions of collagen, elastin, and smooth muscle cells can validate and improve the introduced hypotheses of the model.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2009;131(10):101005-101005-11. doi:10.1115/1.3192143.
Abstract
Commentary by Dr. Valentin Fuster
J Biomech Eng. 2009;131(10):101006-101006-11. doi:10.1115/1.3192144.

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 classify different types of parameters within a constrained mixture 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.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2009;131(10):101007-101007-7. doi:10.1115/1.3200908.

Permeability of the mineralized bone tissue is a critical element in understanding fluid flow occurring in the lacunar-canalicular porosity (PLC) compartment of bone and its role in bone nutrition and mechanotransduction. However, the estimation of bone permeability at the tissue level is affected by the influence of the vascular porosity in macroscopic samples containing several osteons. In this communication, both analytical and experimental approaches are proposed to estimate the lacunar-canalicular permeability in a single osteon. Data from an experimental stress-relaxation test in a single osteon are used to derive the PLC permeability by curve fitting to theoretical results from a compressible transverse isotropic poroelastic model of a porous annular disk under a ramp loading history (2007, “Compressible and Incompressible Constituents in Anisotropic Poroelasticity: The Problem of Unconfined Compression of a Disk,” J. Mech. Phys. Solids, 55, pp. 161–193; 2008, “The Unconfined Compression of a Poroelastic Annular Cylindrical Disk,” Mech. Mater., 40(6), pp. 507–523). The PLC tissue intrinsic permeability in the radial direction of the osteon was found to be dependent on the strain rate used and within the range of O(1024)O(1025). The reported values of PLC permeability are in reasonable agreement with previously reported values derived using finite element analysis (FEA) and nanoindentation approaches.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2009;131(10):101008-101008-3. doi:10.1115/1.3200909.

Remodeling of tissue in response to physical stress is a very complex process. The changes in the stimulus (cause) and response (effect) must be measured and the results must be organized into mathematical forms that are suitable for predictions and applications. An experiment where the stimulus (pressure, flow, shear stress, etc.) can be changed approximately as a step function (a step plus a perturbation) and the response (structure, material properties, function, etc.), which can be measured over time, can be simulated by indicial response functions (IRFs). The IRF is a mathematical expression of the ratio of the change in a particular feature of the system in response to a unit step change in stimulus. The IRF approach provides a quantitative description of the remodeling process, simplifies the interpretation of data, and greatly increases the potential of using the experimental data for prediction of the outcome for future experiments. The objective of this review is to provide an overview of the IRF approach including some exemplary systems. The goal is to illustrate how the indicial expressions make it possible to integrate biological complexity by convolution. The time courses of stimuli represent half of the convolution while the time course of changes in response represents the second half of the convolution. The IRF approach provides an understanding of the physiological problems with mathematical accuracy and may be conducive to new findings.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2009;131(10):101009-101009-8. doi:10.1115/1.3200910.

Arterial axial strains, present in the in vivo environment, often become reduced due to either bypass grafting or the normal aging process. Since the prevalence of hypertension increases with aging, arteries are often exposed to both decreased axial stretch and increased transmural pressure. The combined effects of these mechanical stimuli on the mechanical properties of vessels have not previously been determined. Porcine carotid arteries were cultured for 9 days at normal and reduced axial stretch ratios in the presence of normotensive and hypertensive transmural pressures using ex vivo perfusion techniques. Measurements of the amount of axial stress were obtained through longitudinal tension tests while inflation-deflation test results were used to determine circumferential stresses and incremental moduli. Macroscopic changes in artery geometry and zero-stress state opening angles were measured. Arteries cultured ex vivo remodeled in response to the mechanical environment, resulting in changes in arterial dimensions of up to 25% and changes in zero-stress opening angles of up to 55°. While pressure primarily affected circumferential remodeling and axial stretch primarily affected axial remodeling, there were clear examples of interactions between these mechanical stimuli. Culture with hypertensive pressure, especially when coupled with reduced axial loading, resulted in a rightward shift in the pressure-diameter relationship relative to arteries cultured with normotensive pressure. The observed differences in the pressure-diameter curves for cultured arteries were due to changes in artery geometry and, in some cases, changes in the arteries’ intrinsic mechanical properties. Relative to freshly isolated arteries, arteries cultured under mechanical conditions similar to in vivo conditions were stiffer, suggesting that aspects of the ex vivo culture other than the mechanical environment also influenced changes in the arteries’ mechanical properties. These results confirm the well-known importance of transmural pressure with regard to arterial wall mechanics while highlighting additional roles for axial stretch in determining mechanical behavior.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2009;131(10):101010-101010-7. doi:10.1115/1.3200911.

A model for saccular cerebral aneurysm growth, proposed by Kroon and Holzapfel (2007, “A Model for Saccular Cerebral Aneurysm Growth in a Human Middle Cerebral Artery,” J. Theor. Biol., 247, pp. 775–787; 2008, “Modeling of Saccular Aneurysm Growth in a Human Middle Cerebral Artery,” ASME J. Biomech. Eng., 130, p. 051012), is further investigated. A human middle cerebral artery is modeled as a two-layer cylinder where the layers correspond to the media and the adventitia. The immediate loss of media in the location of the aneurysm is taken to be responsible for the initiation of the aneurysm growth. The aneurysm is regarded as a development of the adventitia, which is composed of several distinct layers of collagen fibers perfectly aligned in specified directions. The collagen fibers are the only load-bearing constituent in the aneurysm wall; their production and degradation depend on the stretch of the wall and are responsible for the aneurysm growth. The anisotropy of the surrounding media was modeled using the strain-energy function proposed by Holzapfel (2000, “A New Constitutive Framework for Arterial Wall Mechanics and a Comparative Study of Material Models,” J. Elast., 61, pp. 1–48), which is valid for an elastic material with two families of fibers. It was shown that the inclusion of fibers in the media reduced the maximum principal Cauchy stress and the maximum shear stress in the aneurysm wall. The thickness increase in the aneurysm wall due to material growth was also decreased. Varying the fiber angle in the media from a circumferential direction to a deviation of 10 deg from the circumferential direction did, however, only show a little effect. Altering the axial in situ stretch of the artery had a much larger effect in terms of the steady-state shape of the aneurysm and the resulting stresses in the aneurysm wall. The peak values of the maximum principal stress and the thickness increase both became significantly higher for larger axial stretches.

Topics: Fibers , Stress , Aneurysms
Commentary by Dr. Valentin Fuster
J Biomech Eng. 2009;131(10):101011-101011-6. doi:10.1115/1.3202785.

The effect of pulse pressure on arterial wall remodeling has not been clearly defined. The objective of this study was to evaluate matrix remodeling in arteries under nonpulsatile and hyperpulsatile pressure as compared with arteries under normal pulsatile pressure. Porcine carotid arteries were cultured for 3 and 7 days under normal, nonpulsatile, and hyperpulsatile pressures with the same mean pressure and flow rate using an ex vivo organ culture model. Fenestrae in the internal elastic lamina, collagen, fibronectin, and gap junction protein connexin 43 were examined in these arteries using confocal microscopy, immunoblotting, and immunohistochemistry. Our results showed that after 7 days, the mean fenestrae size and the area fraction of fenestrae decreased significantly in nonpulsatile arteries (51% and 45%, respectively) and hyperpulsatile arteries (45% and 54%, respectively) when compared with normal pulsatile arteries. Fibronectin decreased (29.9%) in nonpulsatile arteries after 3 days but showed no change after 7 days, while collagen I levels increased significantly (106%) in hyperpulsatile arteries after 7 days. The expression of connexin 43 increased by 35.3% in hyperpulsatile arteries after 7 days but showed no difference in nonpulsatile arteries. In conclusion, our results demonstrated, for the first time, that an increase or a decrease in pulse pressure from its normal physiologic level stimulates structural changes in the arterial wall matrix. However, hyperpulsatile pressure has a more pronounced effect than the diminished pulse pressure. This effect helps to explain the correlation between increasing wall stiffness and increasing pulse pressure in vivo.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2009;131(10):101012-101012-10. doi:10.1115/1.3192140.

Aligned nanofibrous scaffolds hold tremendous potential for the engineering of dense connective tissues. These biomimetic micropatterns direct organized cell-mediated matrix deposition and can be tuned to possess nonlinear and anisotropic mechanical properties. For these scaffolds to function in vivo, however, they must either recapitulate the full dynamic mechanical range of the native tissue upon implantation or must foster cell infiltration and matrix deposition so as to enable construct maturation to meet these criteria. In our recent studies, we noted that cell infiltration into dense aligned structures is limited but could be expedited via the inclusion of a distinct rapidly eroding sacrificial component. In the present study, we sought to further the fabrication of dynamic nanofibrous constructs by combining multiple-fiber populations, each with distinct mechanical characteristics, into a single composite nanofibrous scaffold. Toward this goal, we developed a novel method for the generation of aligned electrospun composites containing rapidly eroding (PEO), moderately degradable (PLGA and PCL/PLGA), and slowly degrading (PCL) fiber populations. We evaluated the mechanical properties of these composites upon formation and with degradation in a physiologic environment. Furthermore, we employed a hyperelastic constrained-mixture model to capture the nonlinear and time-dependent properties of these scaffolds when formed as single-fiber populations or in multipolymer composites. After validating this model, we demonstrated that by carefully selecting fiber populations with differing mechanical properties and altering the relative fraction of each, a wide range of mechanical properties (and degradation characteristics) can be achieved. This advance allows for the rational design of nanofibrous scaffolds to match native tissue properties and will significantly enhance our ability to fabricate replacements for load-bearing tissues of the musculoskeletal system.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2009;131(10):101013-101013-8. doi:10.1115/1.3202559.

Early stage cerebral aneurysms are characterized by the disruption of the internal elastic lamina. The cause of this breakdown is still not understood, but it has been conjectured to be due to fatigue failure and/or by a breakdown in homeostatic mechanisms in the wall arising from some aspect of the local hemodynamics and wall tension. We propose to model this disruption using a structural damage model. It is built on a previously introduced nonlinear, inelastic multi-mechanism model for cerebral arteries (2005, “An Inelastic Multi-Mechanism Constitutive Equation for Cerebral Arterial Tissue,” Biomech. Model. Mechanobiol., 4(4), pp. 235–248), as well as a recent generalization to include the wall anisotropy (2009, “A Structural Multi-Mechanism Constitutive Equation for Cerebral Arterial Tissue,” Int. J. Solids Struct., 46(14–15), pp. 2920–2928). The current model includes subfailure damage of the elastin, represented by changes in the tissue mechanical properties and unloaded reference length. A structural model is used to characterize the gradual degradation, failure of elastin, and recruitment of anisotropic collagen fibers. The collagen fibers are arranged in two helically oriented families with dispersion in their orientation. Available inelastic experimental data for cerebral arteries are used to evaluate the constitutive model. It is then implemented in a commercial finite element analysis package and validated using analytical solutions with representative values for cerebral arterial tissue.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2009;131(10):101014-101014-7. doi:10.1115/1.4000064.

The fibroblast-populated collagen lattice is an attractive model tissue for in vitro studies of cell behavior and as the basis for bioartificial tissues. In spite of its simplicity—containing only collagen and cells—the system is surprisingly difficult to describe mechanically because of the ability of the cells to remodel the matrix, including compaction at short times and synthesis and/or degradation (and cell proliferation) at longer times. The objectives of this work were to measure the equilibrium modulus of fibroblast-populated gels with different collagen and cell concentrations, and to use that characterization as the basis for a theoretical model that could be used to predict gel mechanics based on conditions. Although many observations were as expected (e.g., the gel compacts more when there are more cells in it, and the gel is stiffer when there is more collagen in it), an unexpected result arose: the final modulus of the gel was not dependent solely on the final composition. Even if it compacted more than a gel that was originally at a high collagen concentration, a gel that started at a low collagen concentration remained less stiff than the higher-concentration gel. In light of these results and experimental studies by others, we propose a model in which the gel compaction is not homogeneous but consists instead of extreme densification near the cells in an otherwise unchanged matrix. By treating the dense regions as spherical inclusions, we used classical composite material theory to develop an expression for the modulus of a compacted gel based on the initial collagen density and the final inclusion (i.e., cell) density. The new model fit the data for moderately compacted gels well but broke down, as expected, for larger volume fractions at which the underlying model assumptions did not apply.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2009;131(10):101015-101015-11. doi:10.1115/1.3207013.

Good predictions of the local mechanical environment of the tissue with known geometry and applied loads are fundamental to quantifying the biological response of tissues to mechanical stimuli. Whereas mean stresses in cylindrical sections of blood vessels may be calculated directly from measured loads and vessel geometry (e.g., Laplace’s law), predicting how these stresses are distributed across the wall requires knowledge of the constitutive behavior of the tissue. Previously, we reported biaxial biomechanical data for mouse carotid arteries before and after exposure to altered axial extension in organ culture. Here we considered phenomenological and microstructurally motivated constitutive models and identified material parameters for each via nonlinear regression. Specifically, we considered the model of Chuong and Fung, a four fiber-family model, and several new variants of a rule-of-mixtures model; in the latter, we modeled the artery as a mixture of collagen, elastin, muscle, and water. We found that the four fiber-family model fitted data significantly better than the model of Chuong and Fung. When identifying parameters for the rule-of-mixtures models, we imposed penalties that required each constituent to be structurally significant; e.g., elastin contributing significantly to the overall response over low loads and collagen dominating the response over high loads. Such constraints ascribe additional microstructural “meaning” to the constitutive model. Although imposing such penalties necessarily reduces the goodness of fit of model predictions to experimental data compared to regression without such penalties, the modest reduction in the goodness of fit observed in our results was off-set by the improved structural interpretation such models provide. Such microstructurally motivated models will be useful in characterizing vascular growth and remodeling in terms of the evolution of microstructural metrics that may be quantified experimentally.

Topics: Fibers , Stress , Vessels , Muscle
Commentary by Dr. Valentin Fuster
J Biomech Eng. 2009;131(10):101016-101016-12. doi:10.1115/1.4000124.

Mechanical stimulation has been shown to dramatically improve mechanical and functional properties of gel-derived tissue engineered blood vessels (TEBVs). Adjusting factors such as cell source, type of extracellular matrix, cross-linking, magnitude, frequency, and time course of mechanical stimuli (among many other factors) make interpretation of experimental results challenging. Interpretation of data from such multifactor experiments requires modeling. We present a modeling framework and simulations for mechanically mediated growth, remodeling, plasticity, and damage of gel-derived TEBVs that merge ideas from classical plasticity, volumetric growth, and continuum damage mechanics. Our results are compared with published data and suggest that this model framework can predict the evolution of geometry and material behavior under common experimental loading scenarios.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2009;131(10):101017-101017-9. doi:10.1115/1.4000151.

The incidence of ligament injury has recently been estimated at 400,000/year. The preferred treatment is reconstruction using an allograft, but outcomes are limited by donor availability, biomechanical incompatibility, and immune rejection. The creation of an engineered ligament in vitro solely from patient bone marrow stromal cells (has the potential to greatly enhance outcomes in knee reconstructions. Our laboratory has developed a scaffoldless method to engineer three-dimensional (3D) ligament and bone constructs from rat bone marrow stem cells in vitro. Coculture of these two engineered constructs results in a 3D bone-ligament-bone (BLB) construct with viable entheses, which was successfully used for medial collateral ligament (MCL) replacement in a rat model. 1 month and 2 month implantations were applied to the engineered BLBs. Implantation of 3D BLBs in a MCL replacement application demonstrated that our in vitro engineered tissues grew and remodeled quickly in vivo to an advanced phenotype and partially restored function of the knee. The explanted 3D BLB ligament region stained positively for type I collagen and elastin and was well vascularized after 1 and 2 months in vivo. Tangent moduli of the ligament portion of the 3D BLB 1 month explants increased by a factor of 2.4 over in vitro controls, to a value equivalent to those observed in 14-day-old neonatal rat MCLs. The 3D BLB 1 month explants also exhibited a functionally graded response that closely matched native MCL inhomogeneity, indicating the constructs functionally adapted in vivo.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2009;131(10):101018-101018-11. doi:10.1115/1.4000182.

The urinary bladder wall (UBW), which is composed of smooth muscle, collagen, and elastin, undergoes profound remodeling in response to changes in mechanical loading resulting from various pathologies. In our laboratory, we have observed the production of fibrillar elastin in the extracellular matrix (ECM), which makes the UBW a particularly attractive tissue to investigate smooth muscle tissue remodeling. In the present study, we explored the mechanical role that de novo elastin fibers play in altering UBW ECM mechanical behavior using a structural constitutive modeling approach. The mechanical behavior of the collagen fiber component of the UBW ECM was determined from the biaxial stress-stretch response of normal UBW ECM, based on bimodal fiber recruitment that was motivated by the UBW’s unique collagen fiber structure. The resulting fiber ensemble model was then combined with an experimentally derived fiber angular distribution to predict the biaxial mechanical behavior of normal and the elastin-rich UBW ECM to elucidate the underlying mechanisms of elastin production. Results indicated that UBW ECM exhibited a distinct structure with highly coiled collagen fiber bundles and visible elastic fibers in the pathological situation. Elastin-rich UBW ECM had a distinct mechanical behavior with higher compliance, attributable to the indirect effect of elastin fibers contracting the collagen fiber network, resulting in a retracted unloaded reference state of the tissue. In conclusion, our results suggest that the urinary bladder responds to prolonged periods of high strain by increasing its effective compliance through the interaction between collagen and de novo synthesized elastic fibers.

Commentary by Dr. Valentin Fuster

Technical Briefs

J Biomech Eng. 2009;131(10):104501-104501-3. doi:10.1115/1.3207014.

Organ culture systems are used to study remodeling of arteries and to fabricate tissue engineered vascular grafts. Investigations to date focused on changes in geometry and mechanical response of arteries or constructs associated with controlled sustained alterations in the global load parameters such as the arterial pressure, flow, or axial stretch. A new experimental paradigm is proposed, which is based on the simultaneous independent control of local mechanical parameters such as mean strain or stress in the arterial wall and flow-induced shear at the intima. An organ culture system and methodology were developed, which controls pressure, flow, and axial length of a specimen in order to maintain the local mechanical parameters at prescribed values. The operation of the system is illustrated by maintenance of elevated axial medial stress in porcine carotid artery, while keeping the mean circumferential stress and flow-induced shear stress at baseline values. Previously unknown aspects of remodeling that might be revealed by the novel approach are discussed.

Commentary by Dr. Valentin Fuster

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