Mechanosensing through talin 1 contributes to tissue mechanical homeostasis.

It is widely believed that tissue mechanical properties, determined mainly by the extracellular matrix (ECM), are actively maintained. However, despite its broad importance to biology and medicine, tissue mechanical homeostasis is poorly understood. To explore this hypothesis, we developed mutations in the mechanosensitive protein talin1 that alter cellular sensing of ECM stiffness. Mutation of a novel mechanosensitive site between talin1 rod domain helix bundles 1 and 2 (R1 and R2) shifted cellular stiffness sensing curves, enabling cells to spread and exert tension on compliant substrates. Opening of the R1-R2 interface promotes binding of the ARP2/3 complex subunit ARPC5L, which mediates the altered stiffness sensing. Ascending aortas from mice bearing these mutations show increased compliance, less fibrillar collagen, and rupture at lower pressure. Together, these results demonstrate that cellular stiffness sensing regulates ECM mechanical properties. These data thus directly support the mechanical homeostasis hypothesis and identify a novel mechanosensitive interaction within talin that contributes to this mechanism.

Effects of Age, Sex, and Extracellular Matrix Integrity on Aortic Dilatation and Rupture in a Mouse Model of Marfan Syndrome.

BACKGROUND: Transmural failure of the aorta is responsible for substantial morbidity and mortality; it occurs when mechanical stress exceeds strength. The aortic root and ascending aorta are susceptible to dissection and rupture in Marfan syndrome, a connective tissue disorder characterized by a progressive reduction in elastic fiber integrity. Whereas competent elastic fibers endow the aorta with compliance and resilience, cross-linked collagen fibers confer stiffness and strength. We hypothesized that postnatal reductions in matrix cross-linking increase aortopathy when turnover rates are high. METHODS: We combined ex vivo biaxial mechanical testing with multimodality histological examinations to quantify expected age- and sex-dependent structural vulnerability of the ascending aorta in Fbn1C1041G/+ Marfan versus wild-type mice without and with 4-week exposures to ß-aminopropionitrile, an inhibitor of lysyl oxidase-mediated cross-linking of newly synthesized elastic and collagen fibers. RESULTS: We found a strong ß-aminopropionitrile-associated sexual dimorphism in aortic dilatation in Marfan mice and aortic rupture in wild-type mice, with dilatation correlating with compromised elastic fiber integrity and rupture correlating with compromised collagen fibril organization. A lower incidence of rupture of ß-aminopropionitrile-exposed Marfan aortas associated with increased lysyl oxidase, suggesting a compensatory remodeling of collagen that slows disease progression in the otherwise compromised Fbn1C1041G/+ aorta. CONCLUSIONS: Collagen fiber structure and function in the Marfan aorta are augmented, in part, by increased lysyl oxidase in female and especially male mice, which improves structural integrity, particularly via fibrils in the adventitia. Preserving or promoting collagen cross-linking may represent a therapeutic target for an otherwise vulnerable aorta.

Stability Analysis of Arteries Under Torsion.

Vascular tortuosity may impede blood flow, occlude the lumen, and ultimately lead to ischemia or even infarction. Mechanical loads like blood pressure, axial force, and also torsion are key factors participating in this complex mechanobiological process. The available studies on arterial torsion instability followed computational or experimental approaches, yet single available theoretical study had modeled the artery as isotropic linear elastic. This paper aim is to validate a theoretical model of arterial torsion instability against experimental data. The artery is modeled as a single-layered, nonlinear, hyperelastic, anisotropic solid, with parameters calibrated from experiment. Linear bifurcation analysis is then performed to predict experimentally measured stability margins. Uncertainties in geometrical parameters and in measured mechanical response were considered. Also, the type of rate (incremental) boundary conditions (RBCs) impact on the results was examined (e.g., dead load, fluid pressure). The predicted critical torque and twist angle followed the experimentally measured trends. The closest prediction errors in the critical torque and twist rate were 22% and 67%, respectively. Using the different RBCs incurred differences of up to 50% difference within the model predictions. The present results suggest that the model may require further improvements. However, it offers an approach that can be used to predict allowable twist levels in surgical procedures (like anastomosis and grafting) and in the design of stents for arteries subjected to high torsion levels (like the femoropopliteal arteries). It may also be instructive in understanding biomechanical processes like arterial tortuosity, kinking, and coiling.

Instability of Incompatible Bilayered Soft Tissues and the Role of Interface Conditions.

Mechanical stability analysis is instructive in explaining biological processes like morphogenesis, organogenesis, and pathogenesis of soft tissues. Consideration of the layered, residually stressed structure of tissues, requires accounting for the joint effects of interface conditions and layer incompatibility. This paper is concerned with the influence of imposed rate (incremental) interface conditions (RICs) on critical loads in soft tissues, within the context of linear bifurcation analysis. Aiming at simplicity, we analyze a model of bilayered isotropic hyperelastic (neo-Hookean) spherical shells with residual stresses generated by "shrink-fitting" two perfectly bonded layers with radial interfacial incompatibility. This setting allows a comparison between available, seemingly equivalent, interface conditions commonly used in the literature of layered media stability. We analytically determine the circumstances under which the interface conditions are equivalent or not, and numerically demonstrate significant differences between interface conditions with increasing level of layer incompatibility. Differences of more than tenfold in buckling and 30% in inflation instability critical loads are recorded using the different RICs. Contrasting instability characteristics are also revealed using the different RICs in the presence of incompatibility: inflation instability can occur before pressure maximum, and spontaneous instability may be excluded for thin shells. These findings are relevant to the growing body of stability studies of layered and residually stressed tissues. The impact of interface conditions on critical thresholds is significant in studies that use concepts of instability to draw conclusions about the normal development and the pathologies of tissues like arteries, esophagus, airways, and the brain.

On Rate Boundary Conditions for Soft Tissue Bifurcation Analysis.

Mechanical instability of soft tissues can either risk their normal function or alternatively trigger patterning mechanisms during growth and morphogenesis processes. Unlike standard stability analysis of linear elastic bodies, for soft tissues undergoing large deformations it is imperative to account for the nonlinearities induced by the coupling between load and surface changes at onset of instability. The related issue of boundary conditions, in context of soft tissues, has hardly been addressed in the literature, with most of available research employing dead-load conditions. This paper is concerned with the influence of imposed homogeneous rate (incremental) surface data on critical loads and associated modes in soft tissues, within the context of linear bifurcation analysis. Material behavior is modeled by compressible isotropic hyperelastic strain energy functions (SEFs), with experimentally validated material parameters for the Fung-Demiray SEF, over a range of constitutive response (including brain and liver tissues). For simplicity, we examine benchmark problems of basic spherical patterns: full sphere, spherical cavity, and thick spherical shell. Limiting the analysis to primary hydrostatic states we arrive at universal closed-form solutions, thus providing insight on the role of imposed boundary data. Influence of selected rate boundary conditions (RBCs) like dead-load and fluid-pressure (FP), coupled with constitutive parameters, on the existence and levels of bifurcation loads is compared and discussed. It is argued that the selection of the appropriate type of homogeneous RBC can have a critical effect on the level of bifurcation loads and even exclude the emergence of bifurcation instabilities.

Sensitivity of Arterial Hyperelastic Models to Uncertainties in Stress-Free Measurements.

Despite major advances made in modeling vascular tissue biomechanics, the predictive power of constitutive models is still limited by uncertainty of the input data. Specifically, key measurements, like the geometry of the stress-free (SF) state, involve a definite, sometimes non-negligible, degree of uncertainty. Here, we introduce a new approach for sensitivity analysis of vascular hyperelastic constitutive models to uncertainty in SF measurements. We have considered two vascular hyperelastic models: the phenomenological Fung model and the structure-motivated Holzapfel-Gasser-Ogden (HGO) model. Our results indicate up to 160% errors in the identified constitutive parameters for a 5% measurement uncertainty in the SF data. Relative margins of errors of up to 30% in the luminal pressure, 36% in the axial force, and over 200% in the stress predictions were recorded for 10% uncertainties. These findings are relevant to the large body of studies involving experimentally based modeling and analysis of vascular tissues. The impact of uncertainties on calibrated constitutive parameters is significant in context of studies that use constitutive parameters to draw conclusions about the underlying microstructure of vascular tissues, their growth and remodeling processes, and aging and disease states. The propagation of uncertainties into the predictions of biophysical parameters, e.g., force, luminal pressure, and wall stresses, is of practical importance in the design and execution of clinical devices and interventions. Furthermore, insights provided by the present findings may lead to more robust parameters identification techniques, and serve as selection criteria in the trade-off between model complexity and sensitivity.