Atherosclerotic Calcifications Have a Local Effect on the Peel Behavior of Human Aortic Media.

Aortic dissections, characterized by the propagation of a tear through the layers of the vessel wall, are critical, life-threatening events. Aortic calcifications are a common comorbidity in both acute and chronic dissections, yet their impact on dissection mechanics remains unclear. Using micro-computed tomography (CT) imaging, peel testing, and finite element modeling, this study examines the interplay between atherosclerotic calcifications and dissection mechanics. Samples cut from cadaveric human thoracic aortas were micro-CT imaged and subsequently peel-tested to map peel tension curves to the location of aortic calcifications. Empirical mode decomposition separated peel tension curves into high and low-frequency components, with high-frequency effects corresponding to interlamellar bonding mechanics and low-frequency effects to peel tension fluctuations. Finally, we used an idealized finite element model to examine how stiff calcifications affect aortic failure mechanics. Results showed that atherosclerosis influences dissection behavior on multiple length scales. Experimentally, atherosclerotic samples exhibited higher peel tensions and greater variance in the axial direction. The variation was driven by increased amplitudes of low-frequency tension fluctuations in diseased samples, indicating that more catastrophic propagations occur near calcifications. The simulations corroborated this finding, suggesting that the low-frequency changes resulted from the presence of a stiff calcification in the vessel wall. There were also modifications to the high-frequency peel mechanics, a response likely attributable to alterations in the microstructure and interlamellar bonding within the media. Considered collectively, these findings demonstrate that dissection mechanics are modified in aortic media nearby and adjacent to aortic calcifications.

Vibrotactile perception in Dupuytren disease.

PURPOSE: Dupuytren disease (DD) has been associated with enlarged Pacinian corpuscles (PCs) and with PCs having a greater number of lamellae. Based on these associations, we hypothesized that subjects with DD would have altered sensitivity to high-frequency vibrations and that the changes would be more prominent at 250 Hz, where healthy subjects demonstrate the highest sensitivity. METHODS: A novel device was created to deliver vibrations of specific frequencies and amplitudes to the fingers and palm. Using a Psi-marginal adaptive algorithm, vibrotactile perception thresholds (VPTs) were determined in 36 subjects with DD and 74 subjects without DD. Experiments were performed at 250 Hz and 500 Hz at the fingertip and palm. The VPTs were statistically analyzed with respect to disease status, age, gender, location tested, and frequency tested. RESULTS: We found that VPT increases with age, which agrees with findings by others. Women showed greater sensitivity (i.e. lower VPT) than men. Men exhibited lower sensitivity in DD versus healthy subjects, but the results were not statistically significant. In subjects with DD presenting unilaterally, the unaffected hand was more sensitive than the affected hand, in particular for a 250 Hz stimulus applied to the finger. CONCLUSIONS: The data on vibration sensitivity obtained from a large group of subjects with and without DD present interesting trends that may serve as a useful reference to future DD researchers. Understanding additional symptoms of DD may facilitate development of novel diagnostic or prognostic protocols.

Modeling distributed forces within cell adhesions of varying size on continuous substrates.

Cell migration and traction are essential to many biological phenomena, and one of their key features is sensitivity to substrate stiffness, which biophysical models, such as the motor-clutch model and the cell migration simulator can predict and explain. However, these models have not accounted for the finite size of adhesions, the spatial distribution of forces within adhesions. Here, we derive an expression that relates varying adhesion radius ( R) and spatial distribution of force within an adhesion (described by s) to the effective substrate stiffness ( κsub ), as a function of the Young's modulus of the substrate ( E Y ), which yields the relation, κsub=RsEY , for two-dimensional cell cultures. Experimentally, we found that a cone-shaped force distribution ( s = 1.05) can describe the observed displacements of hydrogels deformed by adherent U251 glioma cells. Also, we found that the experimentally observed adhesion radius increases linearly with the cell protrusion force, consistent with the predictions of the motor-clutch model with spatially distributed clutches. We also found that, theoretically, the influence of one protrusion on another through a continuous elastic environment is negligible. Overall, we conclude cells can potentially control their own interpretation of the mechanics of the environment by controlling adhesion size and spatial distribution of forces within an adhesion.

Dicer1 Deficiency in the Idiopathic Pulmonary Fibrosis Fibroblastic Focus Promotes Fibrosis by Suppressing MicroRNA Biogenesis.

RATIONALE: The lung extracellular matrix (ECM) in idiopathic pulmonary fibrosis (IPF) mediates progression of fibrosis by decreasing fibroblast expression of miR-29 (microRNA-29), a master negative regulator of ECM production. The molecular mechanism is undefined. IPF-ECM is stiffer than normal. Stiffness drives fibroblast ECM production in a YAP (yes-associated protein)-dependent manner, and YAP is a known regulator of miR-29. Therefore, we tested the hypothesis that negative regulation of miR-29 by IPF-ECM was mediated by mechanotransduction of stiffness. OBJECTIVES: To determine how IPF-ECM negatively regulates miR-29. METHODS: We decellularized lung ECM using detergents and prepared polyacrylamide hydrogels of defined stiffness by varying acrylamide concentrations. Mechanistic studies were guided by immunohistochemistry of IPF lung and used cell culture, RNA-binding protein assays, and xenograft models. MEASUREMENTS AND MAIN RESULTS: Contrary to our hypothesis, we excluded fibroblast mechanotransduction of ECM stiffness as the primary mechanism deregulating miR-29. Instead, systematic examination of miR-29 biogenesis revealed a microRNA processing defect that impeded processing of miR-29 into its mature bioactive forms. Immunohistochemical analysis of the microRNA processing machinery in IPF lung specimens revealed decreased Dicer1 expression in the procollagen-rich myofibroblastic core of fibroblastic foci compared with the focus perimeter and adjacent alveolar walls. Mechanistically, IPF-ECM increased association of the Dicer1 transcript with RNA binding protein AUF1 (AU-binding factor 1), and Dicer1 knockdown conferred primary human lung fibroblasts with cell-autonomous fibrogenicity in zebrafish and mouse lung xenograft models. CONCLUSIONS: Our data identify suppression of fibroblast Dicer1 expression in the myofibroblast-rich IPF fibroblastic focus core as a central step in the mechanism by which the ECM sustains fibrosis progression in IPF.

Computational simulation of altitude change-induced intraocular pressure alteration in patients with intravitreal gas bubbles.

PURPOSE: To study the impact of altitude on the intraocular pressure (IOP) in an eye with an intravitreal gas bubble. METHODS: A mathematical model was developed to simulate intravitreal gas bubble expansion caused by change in altitude. Mechanical deformation of the eye was simulated using a finite-element model. Intraocular pressure-driven changes in aqueous humor flow were also considered. Two cases were studied: 1) ascent from sea level to 3,000 ft followed by immediate return to sea level and 2) ascent to 3,000 ft followed by prolonged exposure to 3,000 ft. The effect of IOP-lowering medications was studied by changing the model parameters. RESULTS: The IOP increase was directly related to the initial bubble size when ascent to 3,000 ft was simulated. When prolonged exposure to high altitude was modeled, loss of aqueous humor led to a less elevated value of IOP. In a typical simulated case, when the outflow facility was increased, the predicted IOP rise was reduced by 28%. CONCLUSION: Theoretical modeling of an eye with an intravitreal gas bubble can help an ophthalmologist evaluate the impact of altitude-induced IOP changes. Our model suggests that IOP-lowering drugs could help manage altitude-induced IOP changes in the presence of intravitreal gas bubbles.

Generalized anisotropic inverse mechanics for soft tissues.

Elastography, which is the imaging of soft tissues on the basis of elastic modulus (or, more generally, stiffness) has become increasingly popular in the last decades and holds promise for application in many medical areas. Most of the attention has focused on inhomogeneous materials that are locally isotropic, the intent being to detect a (stiff) tumor within a (compliant) tissue. Many tissues of mechanical interest, however, are anisotropic, so a method capable of determining material anisotropy would be attractive. We present here an approach to determine the mechanical anisotropy of inhomogeneous, anisotropic tissues, by directly solving the finite element representation of the Cauchy stress balance in the tissue. The method divides the sample domain into subdomains assumed to have uniform properties and solves for the material constants in each subdomain. Two-dimensional simulated experiments on linear anisotropic inhomogeneous systems demonstrate the ability of the method, and simulated experiments on a nonlinear model demonstrate the ability of the method to capture anisotropy qualitatively even though only a linear model is used in the inverse problem. As with any inverse problem, ill-posedness is a serious concern, and multiple tests may need to be done on the same sample to determine the properties with confidence.

A cryoinjury model using engineered tissue equivalents for cryosurgical applications.

Cryosurgery is emerging as a promising treatment modality for various cancers, but there are still challenges to be addressed to improve its efficacy. Two primary challenges are determining thermal injury thresholds for various types of cell/tissue, and understanding of the mechanisms of freezing induced cell/tissue injury within a cryolesion. To address these challenges, various model systems ranging from cell suspensions to three-dimensional in vivo tissues have been developed and used. However, these models are either oversimplifications of in vivo tissues or difficult to control and extract precise experimental conditions from. Therefore, a more readily controllable model system with tissue-like characteristics is needed. In this study, a cryoinjury model was developed using tissue engineering technology, and the capabilities of the model were demonstrated. Engineered tissue equivalents (TEs) were constructed by seeding and culturing cells in a type I collagen matrix. Two different cell lines were used in this study, AT-1 rat prostate tumor cells and LNCaP human prostate cancer cells. The constructed TEs underwent a freeze/thaw cycle imitating in vivo cryosurgery. Thermal conditions within TEs during freeze/thaw cycles were characterized, and the responses of TEs to these thermal conditions including freezing induced cellular injury and extracellular matrix damage were investigated at three different time points. The results illustrate the feasibility to establish thermal thresholds of cryoinjury for different cell/tissue types using the presently developed model, and its potential capabilities to study cell death mechanisms, cell proliferation or migration, and extracellular matrix structural damage after a freeze/thaw cycle.