bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of periodic alterations in shear on vascular macromolecular uptake
Authors: Friedman Morton H. , Henderson Joel M. , Aukerman Jean A. , Clingan Paul A.
Published: November 2024

Experiments were carried out in swine to test the hypothesis that changes in the fluid dynamic environment of the arterial wall, with time constants of several minutes to perhaps a few hours, prompt adaptive responses that transiently increase endothelial permeability. After parenteral Evans Blue Dye (EBD) administration, the hemodynamics of the external iliac arteries of the experimental animals were altered using a reversible arteriovenous femoral shunt. For 3 h, the shunt was opened and closed with a period (τ) between 1–180 min. Subsequently, the animal was euthanized and the iliac vessels were photographed en face to obtain the distribution of EBD‐bound albumin uptake by the tissue during its exposure to the dye. Albumin uptake increases with τ in a fashion that can be explained by an a priori model of the adaptive permeability response, with a time constant of about an hour.
Correlated expression of adhesive properties for both white and red blood cells during inflammation
Authors: Rogowski Ori , Zeltser David , Rotstein Rivka , Shapira Itzhak , Avitzour Daniel , Fusman Renato , Mardi Tamar , Prochorov Vitaly , Arber Nadir , Berliner Shlomo
Published: November 2024

The state of leukocyte and erythrocyte adhesiveness/aggregation was determined in the peripheral blood of 382 patients with infection/inflammation as well as in 72 controls by using a simple slide test and image analysis. A highly significant correlation (r=0.4, n=455, p<0.001) was found between the state of leukocyte and erythrocyte adhesiveness/aggregation. The extent of both leukocyte and erythrocyte aggregation correlated with the concentration of fibrinogen. Significant aggregation of leukocytes with erythrocytes was noted as well. We conclude that both leukocyte and erythrocyte aggregation occur in the peripheral blood of patients with infection/inflammation. Such cell aggregation, which might have detrimental rheological consequences, can be detected by using our novel technique.
Predicted wall shear rate gradients in T‐type arteriolar bifurcations
Authors: Noren David , Palmer Harvey J. , Frame Mary D.
Published: November 2024

The purpose of this study was to examine the theoretical impact of the local bifurcation geometry on the shear rate gradient in a divergent arteriolar‐type bifurcation. Newtonian flow through an arteriolar bifurcation was modeled using 3‐dimensional computational fluid dynamics (CFD). Branching angles of 30○, 50○, 70○, 90○, 110○, 130○, and 150○ were studied at a Reynolds number (Re) of 0.01 in seven separate models. Both the flow split (30%) and the branch to main vessel diameter ratio (4/5) were held constant. Velocity profiles were predicted to deviate significantly from a parabolic form, both immediately before and after the branch. This deviation was shown to be a function of the local bifurcation geometry of each model, which consisted of a branching angle and associated feed‐branch intersection shape. Immediately before and after the branch, the shear rate along the lateral branching wall was predicted to exceed (5‐fold) that calculated for fully developed flow in the feed. In vivo data were from the anesthetized (pentobarbital, 70 mg/kg) hamster cremaster muscle preparation. Red blood cells were used as flow markers in arteriolar branch points (n=74) show that a significant gradient in shear rate occurs at the locations and branch shapes predicted by the computational model. Thus, for low Re divergent flow, the gradient in shear rate measured for non‐Newtonian conditions, is approximated by a finite element fluid dynamics model of Newtonian flow.
Aggregation of human RBC in binary dextran–PEG polymer mixtures
Authors: Neu B. , Armstrong J.K. , Fisher T.C. , Meiselman H.J.
Published: November 2024

The present study was prompted by prior reports suggesting that small polymers can affect RBC aggregation induced by large macromolecules. Human RBC were washed and re‐suspended in isotonic buffer solutions containing 72.5 kDa dextran (DEX 70, 2 g/dl) or 35.0 kDa poly(ethylene glycol) (PEG 35, 0.35 g/dl), then tested for aggregation in these solutions with and without various concentrations of smaller dextrans (10.5 and 18.1 kDa) or PEGs (3.35, 7.5 and 10.0 kDa). RBC aggregation was measured at stasis and at low shear using a photometric cone‐plate system (Myrenne Aggregometer) and RBC electrophoretic mobility (EPM) in the various polymer solutions via an automated system (E4, HaSoTec GmbH). Our results indicate: (1) a heterogeneous effect with greater reduction of aggregation for small PEGs added to DEX 70 or for small dextrans added to PEG 35 than for small polymers of the same species; (2) for cells in DEX 70, aggregation decreased with increasing molecular mass and concentration of the small dextrans or PEGs; (3) for cells in PEG 35, small dextrans decreased aggregation with increasing molecular mass and concentration, whereas small PEGs had minimal effects with a minor influence of concentration and an inverse association between molecular mass and inhibition of aggregation. RBC EPM results indicated the expected polymer depletion for cells in DEX 70 or PEG 35, and that small PEGs yielded greater EPM values than small dextrans for cells in PEG 35 whereas the opposite was true for cells in DEX 70. Interpretation of our results in terms of the depletion model for RBC aggregations appears appropriate, and our findings are consistent with the assumption that inhibition of aggregation occurs because of an increase of small molecules in the depletion region. Our results thus suggest the merit of further studies of red blood cell aggregation in binary polymer systems.
Flow around cells adhered to a microvessel wall II: Comparison to flow around adherent cells in channel flow
Authors: Sugihara‐Seki Masako
Published: November 2024

The flow around adherent cells in a parallel‐plate channel and that in a circular cylindrical tube are numerically analyzed, and their effects on the adherent cells are compared. The cells are modeled as rigid spherical particles and they are assumed to be attached to a wall of a 2D channel uniformly in a square array, or a wall of a circular tube regularly in a line along the tube axis. It is found that, when the size ratios of the particle‐to‐channel height and the particle‐to‐tube diameter are smaller than approximately 0.2, the distributions of the shear stress and the pressure exerted on the surface of an adherent particle as well as the drag force and torque acting on it compare favorably in the 2D channel flow and tube flow. As the size ratios increase from 0.2, the differences between the 2D channel and the tube increase drastically, especially when separation distances between neighboring particles are large.
Mechanisms for cell activation and its consequences for biorheology and microcirculation: Multi‐organ failure in shock
Authors: Schmid‐Schönbein Geert W. , Kistler Erik B. , Hugli Tony E.
Published: November 2024

Activation of cells in the vascular compartment causes profound alteration of cell rheological properties with impairment of the microcirculation and initiation of inflammatory reactions. Many cardiovascular diseases have been shown to be associated with cell activation and inflammation. While this situation offers the opportunity for new interventions against the deleterious effects of cell activation, there is the need for a better understanding of the mechanisms that lead to cell activation in the first place. We review here several mechanisms for cell activation in the circulation. We show that in shock, a condition associated with severe forms of cell activation, humoral cell activation factors can be detected in plasma. Further analysis indicates that the source of these humoral activators may be due to the action of pancreatic digestive enzymes in the intestine. Ischemia may serve to open the intestinal brush border and permit entry of pancreatic enzymes into the wall of the intestine to initiate self digestion. In this process low molecular weight but potent cell activators are produced which may escape via the intestinal circulation and the lymphatics into the general circulation. Inhibition of pancreatic enzymes in the lumen of the intestine leads to complete attenuation of humoral activator production as well as many of the deleterious sequelae that accompany shock, such as inflammation and multi‐organ failure. We outline a method to carry out biochemical isolation of the cell activators derived from pancreatic enzymes. This analysis shows that there are multiple species of cell activators above and beyond currently known species, many of which have molecular weights below 3000 Da. Identification of the mechanisms that lead to cell activation is an important part to understand the mechanisms that lead to alterations of rheological properties of blood cells in disease and dysfunction of the endothelium and parenchymal cells. Our current evidence suggests that pancreatic digestive enzymes and tissue enzymes may play a central role in humoral activator production.
Effect of the endothelial surface layer on transmission of fluid shear stress to endothelial cells
Authors: Secomb T.W. , Hsu R. , Pries A.R.
Published: November 2024

Responses of vascular endothelial cells to mechanical shear stresses resulting from blood flow are involved in regulation of blood flow, in structural adaptation of vessels, and in vascular disease. Interior surfaces of blood vessels are lined with a layer of bound or adsorbed macromolecules, known as the endothelial surface layer (ESL). In vivo investigations have shown that this layer has a width of order 1 μm, that it substantially impedes plasma flow, and that it excludes flowing red blood cells. Here, the effect of the ESL on transmission of shear stress to endothelial cells is examined using a theoretical model. The layer is assumed to consist of a matrix of molecular chains extending from the surface, held in tension by a slight increase in colloid osmotic pressure relative to that in free‐flowing plasma. It is shown that, under physiological conditions, shear stress is transmitted to the endothelial surface almost entirely by the matrix, and fluid shear stresses on endothelial cell membranes are very small. Rapid fluctuations in shear stress are strongly attenuated by the layer. The ESL may therefore play an important role in sensing of shear stress by endothelial cells.
Correlation of gene expression with physiological functions: Examples of pulmonary blood vessel rheology, hypoxic hypertension, and tissue remodeling
Authors: Huang Wei , Sher Yuh‐Pyng , Peck Konan , Fung Yuan Cheng
Published: November 2024

Microarray gene chip technology is a powerful invention looking for applications. A general principle is proposed here to direct the power of the technology toward physiology, medicine, and pharmacology. Our principle is to match quantitative measures of gene expression with the trend of mathematical parameters that describe biological functions. Mathematical parameterization is the heart. The procedure is illustrated by lung physiology, including the hypoxic hypertension, rheological properties of the tissues, and the remodeling of the pulmonary arterial wall under hypertensive stress. We show first how to reduce the experimental results on these physiological functions into mathematical formulas, and how the parameters of these formulas describe the functional trends precisely. Then under the assumption that the microarray reveals gene activities quantitatively, we match the trends of the gene activity with the trends of the functional parameters. Genes whose trends do match are interpreted as relevant to the functions. Those that do not match are considered irrelevant to the functions. The more functions we consider, the fewer will be the number of genes that are relevant to all functions. Thus we learn about the generality and specificity of the influence of genes on physiology.
Effects of morphological patterning on endothelial cell migration
Authors: Li Song , Bhatia Sangeeta , Hu Ying‐Li , Shiu Yan‐Ting , Li Yi‐Shuan , Usami Shunichi , Chien Shu
Published: November 2024

The migration of vascular endothelial cells (ECs) plays an important role in vascular remodeling. Here we studied the effects of cell morphology on the migration of bovine aortic ECs by culturing cells on micropatterned strips of collagen matrix (60‐, 30‐, and 15‐μm wide). The spreading areas of the cells on 15‐ and 30‐μm wide strips were 30% lower than those on 60‐ μm wide strips and unpatterned collagen. The cells on 15‐μm wide strips completely aligned in the direction of the strip, and had significantly lower shape index than those in all other groups. On strips of all widths, ECs tended to migrate in the direction of strips. ECs on 15‐μm wide strips had highest speed, particularly in the direction of the strip. Vinculin staining showed that the leading edge of ECs on 15‐μm wide strips had focal adhesions that were oriented with their lamellipodial protrusion and the direction of cell migration; this arrangement of the focal adhesions may promote EC migration. The present study provides direct evidence on the role of cell morphology in EC migration, and will help us to understand the mechanisms of EC migration during angiogenesis and wound healing.
Fluid shear stress suppresses interleukin 8 production by vascular endothelial cells
Authors: Kato Hisayoshi , Uchimura Isao , Nawa Chigure , Kawakami Akio , Numano Fujio
Published: November 2024

The effects of shear stress on interleukin 8 (IL‐8) production by human umbilical vein endothelial cells (HUVEC) were studied by subjecting the HUVEC to a steady flow laminar shear stress of up to 0.7 N/m2 in a parallel plate flow chamber. Shear stress decreased IL‐8 mRNA expression in a dose and time‐dependent fashion. High glucose concentrations increased IL‐8 mRNA levels in a MAPK‐p38‐dependent manner, which was suppressed by shear stress. Measurement of IL‐8 protein in HUVEC culture media by ELISA demonstrated that IL‐8 secretion was also increased by high glucose and suppressed by shear stress. These results suggest that the anti‐atherogenic effect of shear stress arises partly from the suppression of the production of IL‐8 which has been shown to trigger the adhesion of monocytes to a vascular endothelium and also acts as a mitogen and chemoattractant for vascular smooth muscle cells.
Large strain behaviour of brain tissue in shear: Some experimental data and differential constitutive model
Authors: Bilston Lynne E. , Liu Zizhen , Phan‐Thien Nhan
Published: November 2024

In this paper, some experimental measurements of the behaviour of bovine brain tissue under large shear strains in vitro are reported, and a constitutive model which is consistent with the data is developed. It was determined that brain tissue is not strain‐time separable, showing slower relaxation at higher strains, and that the stresses in shear are not linear with increasing shear strain. The new constitutive model is a differential model, including both an “elastic” term, of the Mooney type and a nonlinear viscoelastic term. The latter allows for the change in relaxation behaviour with strain, by modifying an upper convected multimode Maxwell model with a damping function. The model shows good agreement with the experimental shear results and could be used to describe other types of data.
Biorheological characteristics of skin after expansion
Authors: Zeng Yanjun , Huang Kun , Xu Chuanqing , Zhang Jing , Sun Guangci
Published: November 2024

This study investigated the changes in biorheological characteristics of skin after expansion. Expanders were implanted into the back of eight adult dogs, and after an eight‐week expansion the expanded and the non‐expanded control skins were transferred to an adjacent site. The expanded specimens and their controls were obtained at 3, 6, 12 and 24 weeks after transfer, and their biorheological characteristics and histological changes were studied. The characteristics of the stress–relaxation, the stress–strain relationship and tensile strength of the expanded and control specimens were measured. The tests demonstrated that during the initial stage after transfer, the biorheological properties of experimental specimens differed significantly from those of their controls. However, the differences between expanded and control specimens began to lessen gradually with increasing recovery time. When the recovery time reached 24 weeks or longer, the experimental skin exhibited the same mechanical properties as the control skin. Histological examination of expanded specimens showed thickened epidermis and thinned dermis. But there were no significant histological differences between expanded skins and their controls after 24 weeks.
The functional environment of chondrocytes within cartilage subjected to compressive loading: A theoretical and experimental approach
Authors: Wang Christopher C.‐B. , Guo X. Edward , Sun Dongning , Mow Van C. , Ateshian Gerard A. , Hung Clark T.
Published: November 2024

A non‐invasive methodology (based on video microscopy, optimized digital image correlation and thin plate spline smoothing technique) has been developed to determine the intrinsic tissue stiffness (Ha) and the intrinsic fixed charge density (c0 F) distribution for hydrated soft tissues such as articular cartilage. Using this technique, the depth‐dependent inhomogeneous parameters Ha(z) and c0 F(z) were determined for young bovine cartilage and incorporated into a triphasic mixture model. This model was then used to predict the mechanical and electrochemical events (stress, strain, fluid/osmotic pressure, and electrical potentials) inside the tissue specimen under a confined compression stress relaxation test. The integration of experimental measurements with theoretical analyses can help to understand the unique material behaviors of articular cartilage. Coupled with biological assays of cell‐scale biosynthesis, there is also a great potential in the future to study chondrocyte mechanotransduction in situ with a new level of specificity.
The influence of repair tissue maturation on the response to oscillatory compression in a cartilage defect repair model
Authors: Hunter Christopher J. , Levenston Marc E.
Published: November 2024

This study examined the effects of mechanical compression on engineered cartilage in a novel hybrid culture system. Cylindrical holes were cut in discs of bovine articular cartilage and filled with agarose gels containing chondrocytes. These constructs were compressed in radiolabeled medium under static or oscillatory unconfined compression. Oscillatory compression at 1 Hz significantly stimulated synthesis above static control levels. Control experiments indicate that oscillatory compression does not stimulate freshly cast gels (without annuli), but does so after several weeks. This may be because physiologic fluid flow levels do not occur until sufficient extracellular matrix has accumulated. Finite element models predict minimal fluid flow in the gel core, and minimal differences in flow patterns between free and constrained gels. However, the models predict fluid pressures in constrained gels to be substantially higher than those in free gels. Our results suggest that pressure variations may influence synthesis of engineered cartilage matrices, with implications for construct development and post‐implantation survival.
The role of fibril reinforcement in the mechanical behavior of cartilage
Authors: Li LePing , Buschmann M.D. , Shirazi‐Adl A.
Published: November 2024

Collagen fibril reinforcement was incorporated into a nonlinear poroelastic model for articular cartilage in unconfined compression. It was found that the radial fibrils play a predominant role in the transient mechanical behavior but a less important role in the equilibrium response of cartilage. The radial fibrils are in tension and can be highly stressed during compression, in contrast to low compressive stresses in all directions for the proteoglycan matrix after a small initial compression. The strain dependent fibril stiffening produces strong nonlinear transient response; the fibrils provide extra stiffness to balance a rising fluid pressure and to restrain stress increase in the proteoglycans. The fibril reinforcement, induced by the fluid pressure and flow, also accounts for a complex pattern of strain‐magnitude and strain‐rate dependence of cartilage stiffness.
The functional expression of connexin 43 in articular chondrocytes is increased by interleukin 1β: Evidence for a Ca2+‐dependent mechanism
Authors: Tonon Rossana , D'Andrea Paola
Published: November 2024

Cell‐to‐cell interactions and gap junctions‐dependent communication are crucially involved in chondrogenic differentiation, while in adult articular cartilage direct intercellular communication occurs mainly among chondrocytes facing the outer cartilage layer. Chondrocytes extracted from adult articular cartilage and grown in primary culture express connexin 43 and form functional gap junctions capable of sustaining the propagation of intercellular Ca2+ waves. Degradation of articular cartilage is a characteristic feature of arthritic diseases and is associated to increased levels of interleukin‐1 (IL‐1) in the synovial fluid. We have examined the effects of IL‐1 on gap junctional communication in cultured rabbit articular chondrocytes. Incubation with IL‐1 potentiated the transmission of intercellular Ca2+ waves and the intercellular transfer of Lucifer yellow. The stimulatory effect was accompanied by a dose‐dependent increase in the expression of connexin 43 and by an enhanced connexin 43 immunostaining at sites of cell‐to‐cell contact. IL‐1 stimulation induced a dose‐dependent increase of cytosolic Ca2+ and activates protein tyrosine phosphorylation. IL‐1‐dependent up‐regulation of connexin 43 could be prevented by intracellular Ca2+ chelation, but not by inhibitors of protein tyrosine kinases, suggesting a crucial role of cytosolic Ca2+ in regulating the expression of connexin 43. IL‐1 is one of the most potent cytokines that promotes cartilage catabolism: its modulation of intercellular communication represents a novel mechanism by which proinflammatory mediators regulate the activity of cartilage cells.
Growth factors in cartilage tissue engineering
Authors: van Osch Gerjo J.V.M. , Mandl Erik W. , Marijnissen Willem J.C.M. , van der Veen Simone W. , Verwoerd‐Verhoef Henriette L. , Verhaar Jan A.N.
Published: November 2024

Tissue engineering of cartilage consists of two steps. Firstly, the cells from a small biopsy of patient's own tissue have to be multiplied. During this multiplication process they lose their cartilage phenotype. In the second step, these cells have to be stimulated to re‐express their cartilage phenotype and produce cartilage matrix. Growth factors can be used to improve cell multiplication, redifferentiation and production of matrix. The choice of growth factors should be made for each phase of the tissue engineering process separately, taking into account cell phenotype and the presence of extracellular matrix. This paper demonstrates some examples of the use of growth factors to increase the amount, the quality and the assembly of the matrix components produced for cartilage tissue engineering. In addition it shows that the “culture history” (e.g., addition of growth factors during cell multiplication or preculture period in a 3‐dimensional environment) of the cells influences the effect of growth factor addition. The data demonstrate the potency as well as the limitations of the use of growth factors in cartilage tissue engineering.
In vitro study of intracellular IL‐1β production and β1 integrins expression in stimulated chondrocytes – Effect of rhein
Authors: Gigant‐Huselstein C. , Dumas D. , Payan E. , Muller S. , Bensoussan D. , Netter P. , Stoltz J.F.
Published: November 2024

The purpose of the present study was to investigate the intracellular IL‐1β production and β1 integrins (α4/β1 and α5/β1) expression on chondrocytes.

Chondroytes monolayer (human chondrosarcoma cell line HEM‐C55) were incubated for 12, 24 and 48 hours in the presence of Tumor Necrosis Factor‐α (TNF‐α, Sigma, France) or recombinant human IL‐1α (rh‐IL1α, Becton Dickinson, France). After direct immunolabelling, cells were either analyzed on FACScan flow cytometer (Becton Dickinson, France), or observed under an epi‐fluorescence inverted microscope equipped with the CellScan EPRTM optical scanning acquisition system (IPLab‐Scanalytics, USA). We found that the IL‐1β mean fluorescence intensity in flow cytometry and in 3D microscopy was increased in the presence of TNF‐α or rh‐IL‐1α, and α4/β1 or α5/β1 expression was higher on stimulated cells than on control cells.

On the other hand, we have evaluated the in vitro effects of rhein (10−5 M, Negma, France), an active metabolite of diacerein, on the intracellular IL‐1β and β1 integrins expressed by stimulated or no‐stimulated chondrocytes. The results indicated that rhein leads to a reduction of IL‐1β synthesis whereas a weak decrease of β1 integrins receptors expression is observed.

From this study, it seems that rhein partially reduce cytokine‐induced intracellular IL‐1β production, and it has a weak action on α4/β1 or α5/β1 receptors.
The biochemical content of articular cartilage: An original MRI approach
Authors: Loeuille Damien , Olivier Pierre , Watrin Astrid , Grossin Laurent , Gonord Patrick , Guillot Geneviève , Etienne Stéphanie , Blum Alain , Netter Patrick , Gillet Pierre
Published: November 2024

The MR aspect of articular cartilage, that reflects the interactions between protons and macromolecular constituents, is affected by the intrinsic tissue structure (water content, the content of matrix constituents, collagen network organization), imager characteristics, and acquisition parameters. On the T1‐weighted sequences, the bovine articular cartilage appears as an homogeneous tissue in high signal intensity, whatever the age of animals considered, whereas on the T2‐weighted sequences, the articular bovine cartilage presents variations of its imaging pattern (laminar appearance) well correlated to the variations of its histological and biochemical structure. The T2 relaxation time measurement (T2 mapping), which reflects quantitatively the signal intensity variations observed on T2 weighted sequences, is a way to evaluate more precisely the modifications of cartilage structure during the aging and maturation processes (rat's study). This technique so far confined to experimental micro‐imagers is now developed on clinical imagers. Consequently, it may permit to depict the early stages of osteoarthritic disease (OA) or to evaluate the chondroprotective effect of drugs.
Activation and extinction models for platelet adhesion
Authors: David T. , Walker P.G.
Published: November 2024

Adherent platelets are an important part of both thrombus formation and in certain stages of atherogenesis. Platelets can be activated by potent chemicals released from adherent platelets and adhere far more readily than unactivated ones. An analytical and numerical model is presented utilising high Peclet number for the activation and adhesion of platelets in shear flows. The model uses a similarity transformation, which characterises the relationship between convective, diffusive transport and the bulk platelet activating reaction mechanism. A first order surface reaction mechanism is used to model platelet adhesion at the wall (cell) surface. The reduced Damköhler number, ℳ, characterises the importance of the bulk reaction and includes both convective and diffusive terms. For a high rate of blood flow (ℳ→0) the activation of platelets can effectively be terminated. In contrast, for (ℳ→∞) an inner layer of activated platelets exists with an infinitesimally thin reaction sheet separating activated and non‐activated platelets. This characterisation by the Damköhler number highlights results found clinically, in that thrombus forms in areas of low shear (high ℳ) and in some cases an increased blood flow (low ℳ) can inhibit the activation of platelets completely. The model shows the critical balance that exists between convection, diffusion and reaction.
Endothelial control of vascular tone by nitric oxide and gap junctions: A haemodynamic perspective
Authors: Griffith Tudor M.
Published: November 2024

Local haemodynamic forces acting on the endothelium modulate vascular tone through mechanisms that normalize intimal shear stress. This flow‐dependent diameter response contributes to the optimization of circulatory function and is mediated via shear stress‐induced release of NO, vasodilator prostanoids and a putative endothelium‐derived hyperpolarizing factor or EDHF. There is growing evidence that NO/prostanoid independent relaxations involve direct heterocellular signalling between endothelial and smooth muscle cells via gap junctions.
Multiscale modelling as a tool to prescribe realistic boundary conditions for the study of surgical procedures
Authors: Laganà K. , Dubini G. , Migliavacca F. , Pietrabissa R. , Pennati G. , Veneziani A. , Quarteroni A.
Published: November 2024

This work was motivated by the problems of analysing detailed 3D models of vascular districts with complex anatomy. It suggests an approach to prescribing realistic boundary conditions to use in order to obtain information on local as well as global haemodynamics. A method was developed which simultaneously solves Navier–Stokes equations for local information and a non‐linear system of ordinary differential equations for global information. This is based on the principle that an anatomically detailed 3D model of a cardiovascular district can be achieved by using the finite element method. In turn the finite element method requires a specific boundary condition set. The approach outlined in this work is to include the system of ordinary differential equations in the boundary condition set. Such a multiscale approach was first applied to two controls: (i) a 3D model of a straight tube in a simple hydraulic network and (ii) a 3D model of a straight coronary vessel in a lumped‐parameter model of the cardiovascular system. The results obtained are very close to the solutions available for the pipe geometry. This paper also presents preliminary results from the application of the methodology to a particular haemodynamic problem: namely the fluid dynamics of a systemic‐to‐pulmonary shunt in paediatric cardiac surgery.
Combined CFD and MRI study of blood flow in a human ascending aorta model
Authors: Leuprecht Armin , Perktold Karl , Kozerke Sebastian , Boesiger Peter
Published: November 2024

Physiological correct modelling of blood flow through the human ascending aorta is done by combining computational fluid dynamics (CFD) and magnetic resonance imaging (MRI). This method provides a relatively new approach in the analysis and quantification of the haemodynamic variables. Velocity patterns and wall shear stress distributions occurring in the ascending aorta of an individual subject are examined. Geometrical data and inflow velocity profiles just downstream of the valve were acquired from MRI measurements. Based on the extraction of arterial cross‐sections a computer model of the time‐dependent geometrical vessel wall was generated. After surface creation the arterial lumen was filled with an appropriate 3D finite element mesh. The mathematical description of the blood flow uses the Navier–Stokes equations applying an Arbitrary Lagrangian–Eulerian modification with respect to the time‐varying geometry with externally imposed boundary motion. The numerical approach uses our recently developed finite element solver. The computational results agree very well with the measured data.
Breaking symmetry in non‐planar bifurcations: Distribution of flow and wall shear stress
Authors: Lu Yiling , Lu Xiyun , Zhuang Lixian , Wang Wen
Published: November 2024

Non‐planarity in blood vessels is known to influence arterial flows and wall shear stress. To gain insight, computational fluid dynamics (CFD) has been used to investigate effects of curvature and out‐of‐plane geometry on the distribution of fluid flows and wall shear stresses in a hypothetical non‐planar bifurcation. Three‐dimensional Navier–Stokes equations for a steady state Newtonian fluid were solved numerically using a finite element method. Non‐planarity in one of the two daughter vessels is found to deflect flow from the inner wall of the vessel to the outer wall and to cause changes in the distribution of wall shear stresses. Results from this study agree to experimental observations and CFD simulations in the literature, and support the view that non‐planarity in blood vessels is a factor with important haemodynamic significance and may play a key role in vascular biology and pathophysiology.
Laminar‐to‐turbulent transition in pulsatile flow through a stenosis
Authors: Mallinger Francois , Drikakis Dimitris
Published: November 2024

Laminar‐to‐turbulent transition in pulsatile flow through a stenosis is studied by means of three‐dimensional numerical simulations. The flow transition is associated with the occurrence of a flow instability initiating in the stenosis region. The instability is manifested by a three‐dimensional symmetry‐breaking and leads to asymmetric separation and intense swirling motion downstream of the stenosis. The above have profound effects on the wall shear stress (WSS). The simulations reveal that the asymmetric separation is extended several radii downstream of the stenosis with substantial WSS fluctuations, in both space and time, occurring in the poststenotic region.
Quantitative comparison of CFD predicted and MRI measured velocity fields in a carotid bifurcation phantom
Authors: Long Quan , Xu X. Yun , Köhler Uwe , Robertson Malcolm B. , Marshall Ian , Hoskins Peter
Published: November 2024

Steady flow of a blood mimicking fluid in a physiologically realistic model of the human carotid bifurcation was studied using both magnetic resonance imaging (MRI) and computational fluid dynamics (CFD) modelling techniques. Quantitative comparisons of the 3D velocity field in the bifurcation phantom were made between phase contrast MRI measurements and CFD predictions. The geometry for the CFD model was reconstructed from T1 weighted MR imaging of the test phantom. It was found that the predicted velocity fields were in fair agreement with MR measured velocities. In both the internal and external carotid arteries, the agreement between CFD predictions and MRI measurements was better along the inner–outer wall axis with a correlation factor C>0.897 (average 0.939) where the velocity profiles were skewed, than along the anterior–posterior axis (average correlation factor 0.876) where the velocity profiles were in M‐shape.
Variability of 3D arterial geometry and dynamics, and its pathologic implications
Authors: Friedman Morton H.
Published: November 2024

Geometric parameters and features vary within the vasculature. Furthermore, at any given anatomic site, there are substantial variations in geometry among individuals. These variations can contribute to a corresponding variability in the hemodynamic environment and, to the extent that hemodynamics affects the atherosclerotic process, the progress of vascular disease. Measurements of the geometry and wall morphometry of post‐mortem human coronary arteries demonstrate a relationship between these variables that supports the notion that geometric variations can contribute to a corresponding variability in the local rate of progression of arterial disease. The dynamic geometry of the coronary arteries also varies from site to site and among individuals, and this variability too may play a role in the epidemiology of coronary artery disease.
Combined MR imaging and numerical simulation of flow in realistic arterial bypass graft models
Authors: Papaharilaou Y. , Doorly D.J. , Sherwin S.J. , Peiro J. , Griffith C. , Cheshire N. , Zervas V. , Anderson J. , Sanghera B. , Watkins N. , Caro C.G.
Published: November 2024

We report methods for (a) transforming a three‐dimensional geometry acquired by magnetic resonance angiography (MRA) in vivo, or by imaging a model cast, into a computational surface representation, (b) use of this to construct a three dimensional numerical grid for computational fluid dynamic (CFD) studies, and (c) use of the surface representation to produce a stereo‐lithographic replica of the real detailed geometry, at a scale convenient for detailed magnetic resonance imaging (MRI) flow studies. This is applied to assess the local flow field in realistic geometry arterial bypass grafts. Results from a parallel numerical simulation and MRI measurement of flow in an aorto‐coronary bypass graft with various inlet flow conditions demonstrate the strong influence of the graft inlet waveform on the perianastomotic flow field. A sinusoidal and a multi harmonic coronary flow waveform both with a mean Reynolds number (Re) of 100 and a Womersley parameter of 2.7 were applied at the graft inlet. A weak axial flow separation region just distal to the toe was found in sinusoidal flow near end deceleration (Re = 25). At the same location and approximately the same point in the cycle (Re = 30) but in coronary flow, the axial flow separation was stronger and more spatially pronounced. No axial flow separation occurred in steady flow for Re = 100. Numerical predictions indicate a region in the vicinity of the suture line (where there is a local narrowing of the graft) with a wall shear magnitude in excess of five times that associated with fully developed flow at the graft inlet.
Haemodynamic flow: Symmetry and synthesis
Authors: Dewey C. Forbes
Published: November 2024

This paper is presented as a summary and synthesis of the presentations at the conference entitled “Breaking Symmetry in Haemodynamics”. As the accompanying papers will attest, there has been enormous progress in understanding the effects of fluid flow on the arterial endothelium and the consequential effects on the vessel wall. It is now clearly understood that the focal lesions found in atherosclerotic arteries are the product of asymmetrical flow and the resulting disturbed flow that occurs near arterial bifurcations and other selected points around the human vasculature. The flow in large vessels can now be determined accurately with MR and in vitro cast models. Although theory allows arterial flow to be characterized by asymmetry in time and space, our understanding of the processes that act to translate this asymmetry into pathology is becoming much more symmetric, or complete. The new frontiers of research in arterial flow are now translating to smaller scales, at the cellular level and below.
Interactions of mechanotransduction pathways
Authors: Labrador Vénus , Chen Kuang‐Den , Li Yi‐Shuan , Muller Sylvaine , Stoltz Jean‐François , Chien Shu
Published: November 2024

Integrins may serve as mechanosensors in endothelial cells (ECs): shear stress causes integrin–Shc association, assembly of the signaling complex and then leads to JNK activation. Flow also mediates selective and cell‐specific alterations in vascular cell G‐protein expression that correlate with changes in cell‐signalling, G‐protein functionality and modulate Ca2+ concentration. In this study, we explored the cross‐talks between EC membrane mechanosensors, such as integrins, ion channels, and G‐proteins in shear stress‐induced signal transduction by their specific inhibition. Confluent monolayer of bovine aortic endothelial cells (BAECs) were incubated with or without specific inhibitors prior to shearing experiments. Our results showed an attenuation of integrin–Shc association under shear stress with RGD, and with PTX, but not with BAPTA/AM. The inhibitions of shear‐activated JNK are similar for RGD and PTX. However, unlike for integrin association, the chelation of calcium reduced JNK activation. These results provide several lines of evidence of the interactions between different mechanosensors in ECs. First, integrin–Shc association required cell attachment and G‐protein activity, but not intracellular calcium. Second, shear‐induced JNK activation is regulated by multiple mechano‐sensing mechanisms such as integrin, G‐protein and calcium concentration.
Effects of laminar shear stress on IL‐8 mRNA expression in endothelial cells
Authors: Chen Huaiqing , Wu Lizhi , Liu Xiaoheng , Chen Youqin , Wang Boyao
Published: November 2024

In order to demonstrate that IL‐8 mRNA expression in endothelial cells is not only regulated by chemical factors, but also by mechanical factors, in this article, after pretreating cultured human umbilical vein endothelial cells (HUVECs) with shear stress for different time, we employed both RT‐PCR to assay IL‐8 mRNA expression and immunocytochemical staining to detect NF‐κB activation in HUVECs. We found that: (i) IL‐8 mRNA expressed little in HUVECs untreated or pretreated with low laminar shear stress for 0.5 hour; IL‐8 mRNA expression was increased when HUVECs were pretreated with low laminar shear stress for 1 hour, and increased further when pretreated for 2 hours; (ii) the immunoreactivity of NF‐κB p65 in the nuclei of HUVECs untreated or pretreated with low laminar shear stress for 0.5 hour was negative, while it became weak positive in the nuclei of HUVECs pretreated with shear stress for 1 hour and positive in the nuclei of HUVECs pretreated for 2 hours. The results imply that low laminar shear stress was capable of inducing IL‐8 gene expression and activating NF‐κB, which were both time‐dependent. The induction of IL‐8 gene expression by laminar shear stress is probably due to the activation of NF‐κB. We suggest that IL‐8 mRNA expression in endothelial cells induced by low shear stress may play a key role in the pathogenesis and development of both inflammation and arterioatherosclerosis.
Disparate aggrecan gene expression in chondrocytes subjected to hypotonic and hypertonic loading in 2D and 3D culture
Authors: Hung Clark T. , LeRoux Michelle A. , Palmer Glyn D. , Chao P.‐H. Grace , Lo Sansan , Valhmu Wilmot B.
Published: November 2024

The effects of hypotonic (180 mOsm) and hypertonic (580 mOsm) medium loading on chondrocyte aggrecan gene expression in 2D monolayer and 3D hydrogel culture (agarose or alginate) were studied. Aggrecan promoter activity was monitored using a luciferase reporter gene assay and transient transfection. Osmotic loading was observed to differentially affect promoter activity, with hypotonic loading generally producing at least a 40% elevation in promoter activity, except for the case of alginate where a 50% suppression was observed. Hypertonic loading produced at least a 35% decrease in activity for all cultures. Similar osmolality‐induced changes to aggrecan mRNA levels were observed in monolayer cells using qPCR. Deletion of exon 1 blocked the sensitivity of monolayer cells to hypertonic but not hypotonic medium changes. Confocal microscopy measurements suggested that the degree of hypotonic swelling in cells encapsulated in 3D matrix was restricted compared to monolayer cells whereas the degree of hypertonic shrinking was similar under both culture conditions.
Stress responses of mammalian cells to high hydrostatic pressure
Authors: Kaarniranta Kai , Elo Mika A. , Sironen Reijo K. , Karjalainen Hannu M. , Helminen Heikki J. , Lammi Mikko J.
Published: November 2024

High hydrostatic pressure causes stress response in many types of mammalian cells. We have previously shown that an accumulation of heat shock protein 70 (Hsp70) in a chondrocytic cell line occurred without an activation of the gene itself. Stabilization of the hsp70 mRNA was shown to be the reason for the Hsp70 stress response in the pressurized cells. Since accumulation of Hsp70 in pressurized cells indicated that high hydrostatic pressure induces a stress response without heat shock transcription factor activation, we decided to investigate the activation of two other stress‐associated transcription factors, activator protein‐1 (AP‐1) and nuclear factor‐κB (NF‐κB). Induction of Hsp70 in immortalized and primary chondrocytes, murine Neuro‐2a neuroblastoma and HeLa cervical carcinoma cell lines was investigated at both mRNA and protein levels. In immortalized chondrocytes and HeLa cells, hsp70 mRNA levels were clearly elevated after 6 hours of the onset of 30 MPa continuous hydrostatic pressure, while in primary chondrocytes and Neuro‐2a cells (the cells known to be stress‐sensitive) no induction was observed. Surprisingly, neither heat shock nor high hydrostatic pressure could induce the hsp70 mRNA in Neuro‐2a cells, although an activation of heat shock transcription factor could be observed in heat‐shocked cells. No activation of the AP‐1 and NF‐κB binding to their target DNA sequences could be shown in the immortalized chondrocytes.
The mechanosensitivity of cartilage oligomeric matrix protein (COMP)
Authors: Giannoni Paolo , Siegrist Mark , Hunziker Ernst B. , Wong Marcy
Published: November 2024

Physical forces are known to influence the synthesis, assembly and degradation of the cartilage extracellular matrix. The expression of cartilage oligomeric matrix protein (COMP) was found to be sensitive to long term cyclic compression. Explants of calf articular cartilage as well as cylindrical alginate/chondrocyte constructs were subjected to uniaxial unconfined dynamic compression for 18 hours after which total mRNA was extracted from samples. COMP expression was assessed by means of semi‐quantitative RT–PCR and Northern blot techniques. The COMP transcript was found to be significantly enriched upon compression in both experimental systems. Incubation with anti‐β1 integrin blocking antibodies abolished the mechanosensitivity of COMP expression. In addition, the presence of a fully developed pericellular matrix was shown to be a prerequisite for enhanced COMP expression with cyclic loading. Cell/matrix interactions are therefore one of the key events in mechanotransduction in chondrocytes.
Biomechanical properties of knee articular cartilage
Authors: Laasanen M.S. , Töyräs J. , Korhonen R.K. , Rieppo J. , Saarakkala S. , Nieminen M.T. , Hirvonen J. , Jurvelin J.S.
Published: November 2024

Structure and properties of knee articular cartilage are adapted to stresses exposed on it during physiological activities. In this study, we describe site‐ and depth‐dependence of the biomechanical properties of bovine knee articular cartilage. We also investigate the effects of tissue structure and composition on the biomechanical parameters as well as characterize experimentally and numerically the compression–tension nonlinearity of the cartilage matrix. In vitro mechano‐optical measurements of articular cartilage in unconfined compression geometry are conducted to obtain material parameters, such as thickness, Young's and aggregate modulus or Poisson's ratio of the tissue. The experimental results revealed significant site‐ and depth‐dependent variations in recorded parameters. After enzymatic modification of matrix collagen or proteoglycans our results show that collagen primarily controls the dynamic tissue response while proteoglycans affect more the static properties. Experimental measurements in compression and tension suggest a nonlinear compression–tension behavior of articular cartilage in the direction perpendicular to articular surface. Fibril reinforced poroelastic finite element model was used to capture the experimentally found compression–tension nonlinearity of articular cartilage.