Deteriorated Vascular Homeostasis in Hypertension: Experimental Evidence from Aorta, Brain, and Pancreatic Vasculature.

Hypertension, as a primary risk factor for many fatal disorders, is prevalent in the elderly. There is wide literature on hypertension dealing with its biological and/or biochemical aspects; however, limited research is available on the multifactorial nature of hypertension from a mechanobiological standpoint. This study intended to study in parallel histopathological alterations and deviated protein expressions with the mechanical behavior of the hypertensive tissues. The Goldblatt (2K1C) method was chosen for induction of renovascular hypertension in rabbits. The microstructural and immunohistological characteristics of the aortic, pancreatic, and brain vasculature were investigated. The mechanical properties of the aortic tissue were also evaluated using biaxial tensile tests. Our findings indicated severe hypertrophy of the hypertensive vessels and declined content of intact smooth muscle cells. Most of the collagen I content of the wall was compromised and less functional type III collagen was highly expressed. Reversed collagen I to collagen III ratio was the main contributor to the hypertrophic and less stiff hypertensive vessel walls. The multifactorial nature of hypertension is illustrated, and smooth muscle cell detachment is identified as the sign of described degenerative cascades all along the arterial tree.

Probing the possibility of lesion formation/progression in vicinity of a primary atherosclerotic plaque: A fluid-solid interaction study and angiographic evidences.

It is shown that certain locations in the arterial tree, such as coronary and cerebral arteries, are more prevalent to plaque formation. Endothelial activation and consequent plaque development are attributed to local hemodynamic parameters such as wall shear stress (WSS), oscillatory shear index (OSI), relative residence time (RRT), and stress phase angle. After a certain level of plaque progression, these hemodynamic parameters are disturbed before and after the plaque. In the current study, it is hypothesized that the vicinity of a primary lesion is susceptible for further degeneration and second plaque formation. A fluid-solid interaction (FSI) model of the coronary artery with different levels of asymmetric constriction, is simulated and the trend of hemodynamic parameters were studied in both of the plaque side (PS) and the opposite wall (facing the plaque [PF]). Also, a novel factor is introduced that can identify the high-risk regions associated with WSS oscillations to negative values. Our results indicate that when more than half of the artery is constricted, the downstream of the plaque is highly exposed to endothelial pathogenesis the PS, such that negative WSS, and as well, critical values of OSI and RRT, that is, -1.2 Pa, 0.42 and 6.5 s, respectively arise in this region. PS endothelial cells in this region exposed to the highest risk of atherosclerosis based on the proposed index (3 out of 3). As well, three cases of angiographic images are provided that confirms existence of secondary lesion close to the primary one as predicted by our computational simulations.

The effects of mutation on the drug binding affinity of Neuraminidase: case study of Capsaicin using steered molecular dynamics simulation.

The influenza virus is an important respiratory pathogen that causes many incidences of diseases and even death each year. One of the primary factors of this virus is the Neuraminidase surface protein, which causes the virus to leave the host cell and spread to new target cells. The main antiviral medication for influenza is designed as a protein inhibitor ligand that prevents further spread of the disease, and eventually relieves the emerged symptoms. The effectiveness of such inhibitory drugs is highly associated with their binding affinity. In this paper, the binding affinity of an herbal ligand of Capsaicin bound to Neuraminidase of the influenza virus is investigated using steered molecular dynamics (SMD) simulation. Since mutations of the virus directly impact the binding affinity of the inhibitory drugs, different mutations were generated by using Mutagenesis module. The rapid spread of infection during the avian influenza A/H5N1 epidemic has raised concerns about far more dangerous consequences if the virus becomes resistant to current drugs. Currently, oseltamivir (Tamiflu), zanamivir (Relenza), pramivir (Rapivab), and laninamivir (Inavir) are increasingly used to treat the flu. However, with the rapid evolution of the virus, some drug-resistant strains are emerging. Therefore, it is very important to seek alternative therapies and identify the roots of drug resistance. Obtained results demonstrated a reduced binding affinity for the applied mutations. This reduction in binding affinity will cause the virus mutation to become resistant to the drug, which will spread the disease and make it more difficult to treat. From a molecular prospect, this decrease in binding affinity is due to the loss of a number of effective bonds between the ligand and the receptor, which occurs with mutations of the wild-type (WT) species. The results of the present study can be used in the rational design of novel drugs that are compatible with specific mutations.

Mechanobiology of the arterial tissue from the aortic root to the diaphragm.

Arterial tissue microstructure and its mechanical properties directly correlate with cardiovascular diseases such as atherosclerosis and aneurysm. Experienced hemodynamic loads are the primary factor of arterial tissue remodeling. By virtue of altering hemodynamic loads along the arterial tree, respective structure-function relations will be region-dependent. Since, there is limited experimental evidence on these structure-function homeostases, the current study, aims to report microstructural and mechanical alterations along the aorta from the aortic root up to the diaphragm, where intense hemodynamic alterations take place. The ascending, arch, and descending parts of the same cadaveric aortas were investigated by histomechanical examinations. Anatomical landmarks were labeled on the specimens, and then biaxial tensile tests were conducted on samples from each region. Furthermore, area fractions of elastin and collagen were measured on stained sections of the tissue. Also, a fragmentation index of elastin tissue is proposed for quantitative measurement of ECM integrity, which correlates with the nature of experienced hemodynamic loads. For the ascending aorta and the aortic arch, different values for mechanical properties and fragmentation index are observed even in a specific cross-section of the artery. It is primarily due to the complex loading regimes and curved geometry. Conversely, microstructural and mechanical features along the descending aorta exhibited minimal variations, and hence, smooth blood flow and pressure waves are expected in this region, which is well-documented in the literature. Both of the microstructural and mechanical features of the aorta vary along the arterial tree depending on the hemodynamic and geometric complexities they incur and may shed light on the initiation of cardiovascular diseases.

Total ankle replacement along with subtalar joint arthrodesis: In-vitro and in-silico biomechanical investigations.

Total ankle replacement (TAR) and subtalar joint (STJ) fusion, are popular treatments for ankle osteoarthritis (OA). Short endurance limits the former, and movement disability comes with the latter. It is hypothesized here that fusion of the STJ can improve the longevity of the TAR prosthesis. In this study, a fresh human cadaver's ankle joint underwent TAR surgery, and strain patterns in the vicinity of prosthesis were recorded after the application of axial compressive load on tibia, resembling stance phase of the gait. Then, STJ of the same sample fused (FTAR), and a similar test procedure was pursued. The obtained strains in the FTAR were smaller than those of the TAR (p < .01). Finite element models of the tested samples were also made, and validated by experimental strains. The validated FE models were then employed to find stress distribution on the tibial plateau and prosthesis compartments. FTAR demonstrated more regular stress profiles in bone-prosthesis interface. Also, maximum von Mises stress in the talar component of the FTAR is approximately half of that in the TAR (8 and 15 MPa, respectively). Based on the results of this study, having a more symmetric load distribution on the prosthesis after STJ fusion, longevity of the TAR may likely increase.

Contribution of atherosclerotic plaque location and severity to the near-wall hemodynamics of the carotid bifurcation: an experimental study and FSI modeling.

Atherosclerosis is initiated by endothelial injury that is related to abnormal values of hemodynamic parameters such as wall shear stress (WSS), oscillatory shear index (OSI) and stress phase angle (SPA), which are more common in arterial bifurcations due to the complex structure. An experimental model of human carotid bifurcation with accurate geometrical and mechanical features was set up, and using realistic pulsatile flow rates, the inlet and outlet pressure pulses were measured for normal and stenosed models with 40% and 80% severities at common carotid (CCA), internal carotid (ICA) and external carotid (ECA) arteries. Based on the obtained experimental data, fluid-structure models were developed to obtain WSS, OSI, and SPA and evaluate pathological consequences at different locations. Mild severity had minor impact, however, inducing severe 80% stenosis in each branch led to considerable localized changes of hemodynamic parameters both in the stenosis site and other locations. This included sharp increases in WSS values accompanied by very low values close to zero before and after the peaks. Severe stenosis not only caused significant changes in the local artery, but also in other branches. OSI and SPA were less sensitive to stenosis, although high peaks were observed on bifurcation site for the stenosis at ECA. The interconnection of arteries at carotid bifurcation results in altered pressure/flow patterns in all branches when a stenosis is applied in any site. Such effect confirms pathological findings that atherosclerotic plaques are observed simultaneously in different carotid branches, although with different degrees of plaque growth and severity.

Microstructural modeling of Achilles Tendon biomechanics focusing on bone insertion site.

The interface between the Achilles Tendon (AT) and calcaneus comprises soft and hard connective tissues. Such interfaces are vulnerable to mechanical damage. Tendon to Bone Insertion Region (TBIR) has unique microstructural characteristics for reinforcement. This region constitutes almost 10% of the AT's distal end. The rest of the tendon (tendon proper) has longitudinal fiber orientation with no mineral content. Although, the TBIR lacks longitudinally organized fibers and at the same time, incorporates mineral molecules. In this study, a 3D computational model of the TBIR proposed to underline several reinforcement mechanisms. The obtained results showed that off-axis alignment of fibers, when coupled with the mineral deposition, shifts the stress concentration region to the tendon proper. In the case of altering each parameter individually, probable failure observed in the bone interface, which causes complications in surgical procedure or during healing. A gradual increase of mineral compensates for the stiffness mismatch between the AT and calcaneus. The proposed computational framework illustrated the complementary roles of fiber orientation and mineral molecules: nearly transverse orientation of fibers alleviated the stress concentration locally, while mineral deposition directly enhanced the TBIR stiffness.

Characterization of mechanical properties of lamellar structure of the aortic wall: Effect of aging.

Arterial wall tissues are sensitive to their mechanical surroundings and remodel their structure and mechanical properties when subjected to mechanical stimuli such as increased arterial pressure. Such remodeling is evident in hypertension and aging. Aging is characterized by stiffening of the artery wall which is assigned to disturbed elastin function and increased collagen content. To better understand and provide new insight on microstructural changes induced by aging, the lamellar model of the aortic media was utilized to characterize and compare wall structure and mechanical behavior of the young and old human thoracic aortic samples. Such model regards arterial media as two sets of alternating concentric layers, namely sheets of elastin and interlamellar layers. Histological and biaxial tests were performed and microstructural features and stress-strain curves of media were evaluated in young and old age groups. Then using optimization algorithms and hyperelastic constitutive equations the stress-strain curves of layers were evaluated for both age groups. Results indicated slight elevation in the volume fraction of interlamellar layer among old subjects most probably due to age related collagen deposition. Aging indicated substantial stiffening of interlamellar layers accompanied by noticeable softening of elastic lamellae. The general significant stiffening of old samples were attributed to both increase of volume fraction of interlamellar layers and earlier recruitment of collagen fibers during load bearing due to functional loss of elastin within wall lamellae. Mechanical characterization of lamellar structure of wall media is beneficial in study of arterial remodeling in response to alternated mechanical environment in aging and clinical conditions through coupling of wall microstructure and mechanical behavior.

Analysis of arterial wall remodeling in hypertension based on lamellar modeling.

Arterial wall remodels its geometry and mechanical properties in response to hypertension to maintain functionality. The elevated pressure is sensed through cellular mechanotransduction pathways, and extra extracellular matrix is synthesized, leading to thickening and stiffening. The present study enquires the response of aortic lamellar structure to hypertensive blood pressure regarding unchanged circumferential stress "profile" across the media as remodeling criterion. We tested the hypothesis that alterations in the thickness of structural layers contributes to maintain stress profile with least deviation from normotensive conditions. To test this notion, finite element analysis was recruited to evaluate stress profile, considering wall residual stress, and lamellar structure was adjusted through an optimization algorithm. Our results indicated 47% increased thickness of the aortic media that originates from nonhomogenous thickening of the microstructural units. The thickening and stiffening responses of the wall tissue were coupled, and the optimized pattern of hypertension-induced remodeling was established.

Evaluation of Biaxial Mechanical Properties of Aortic Media Based on the Lamellar Microstructure.

Evaluation of the mechanical properties of arterial wall components is necessary for establishing a precise mechanical model applicable in various physiological and pathological conditions, such as remodeling. In this contribution, a new approach for the evaluation of the mechanical properties of aortic media accounting for the lamellar structure is proposed. We assumed aortic media to be composed of two sets of concentric layers, namely sheets of elastin (Layer I) and interstitial layers composed of mostly collagen bundles, fine elastic fibers and smooth muscle cells (Layer II). Biaxial mechanical tests were carried out on human thoracic aortic samples, and histological staining was performed to distinguish wall lamellae for determining the dimensions of the layers. A neo-Hookean strain energy function (SEF) for Layer I and a four-parameter exponential SEF for Layer II were allocated. Nonlinear regression was used to find the material parameters of the proposed microstructural model based on experimental data. The non-linear behavior of media layers confirmed the higher contribution of elastic tissue in lower strains and the gradual engagement of collagen fibers. The resulting model determines the nonlinear anisotropic behavior of aortic media through the lamellar microstructure and can be assistive in the study of wall remodeling due to alterations in lamellar structure during pathological conditions and aging.