Juan M. Jiménez

Hemodynamically driven stent strut design.

Stents are deployed to physically reopen stenotic regions of arteries and to restore blood flow. However, inflammation and localized stent thrombosis remain a risk for all current commercial stent designs. Computational fluid dynamics results predict that nonstreamlined stent struts deployed at the arterial surface in contact with flowing blood, regardless of the strut height, promote the creation of proximal and distal flow conditions that are characterized by flow recirculation, low flow (shear) rates, and prolonged particle residence time. Furthermore, low shear rates yield an environment less conducive for endothelialization, while local flow recirculation zones can serve as micro-reaction chambers where procoagulant and pro-inflammatory elements from the blood and vessel wall accumulate. By merging aerodynamic theory with local hemodynamic conditions we propose a streamlined stent strut design that promotes the development of a local flow field free of recirculation zones, which is predicted to inhibit thrombosis and is more conducive for endothelialization.

Lymph flow regulates collecting lymphatic vessel maturation in vivo

Fluid shear forces have established roles in blood vascular development and function, but whether such forces similarly influence the low-flow lymphatic system is unknown. It has been difficult to test the contribution of fluid forces in vivo because mechanical or genetic perturbations that alter flow often have direct effects on vessel growth. Here, we investigated the functional role of flow in lymphatic vessel development using mice deficient for the platelet-specific receptor C-type lectin-like receptor 2 (CLEC2) as blood backfills the lymphatic network and blocks lymph flow in these animals. CLEC2-deficient animals exhibited normal growth of the primary mesenteric lymphatic plexus but failed to form valves in these vessels or remodel them into a structured, hierarchical network. Smooth muscle cell coverage (SMC coverage) of CLEC2-deficient lymphatic vessels was both premature and excessive, a phenotype identical to that observed with loss of the lymphatic endothelial transcription factor FOXC2. In vitro evaluation of lymphatic endothelial cells (LECs) revealed that low, reversing shear stress is sufficient to induce expression of genes required for lymphatic valve development and identified GATA2 as an upstream transcriptional regulator of FOXC2 and the lymphatic valve genetic program. These studies reveal that lymph flow initiates and regulates many of the key steps in collecting lymphatic vessel maturation and development.

Macro- and microscale variables regulate stent haemodynamics, fibrin deposition and thrombomodulin expression.

Drug eluting stents are associated with late stent thrombosis (LST), delayed healing and prolonged exposure of stent struts to blood flow. Using macroscale disturbed and undisturbed fluid flow waveforms, we numerically and experimentally determined the effects of microscale model strut geometries upon the generation of prothrombotic conditions that are mediated by flow perturbations. Rectangular cross-sectional stent strut geometries of varying heights and corresponding streamlined versions were studied in the presence of disturbed and undisturbed bulk fluid flow. Numerical simulations and particle flow visualization experiments demonstrated that the interaction of bulk fluid flow and stent struts regulated the generation, size and dynamics of the peristrut flow recirculation zones. In the absence of endothelial cells, deposition of thrombin-generated fibrin occurred primarily in the recirculation zones. When endothelium was present, peristrut expression of anticoagulant thrombomodulin (TM) was dependent on strut height and geometry. Thinner and streamlined strut geometries reduced peristrut flow recirculation zones decreasing prothrombotic fibrin deposition and increasing endothelial anticoagulant TM expression. The studies define physical and functional consequences of macro- and microscale variables that relate to thrombogenicity associated with the most current stent designs, and particularly to LST.

The intermediate wake of a body of revolution at high Reynolds numbers

Results are presented on the flow field downstream of a body of revolution for Reynolds numbers based on a model length ranging from 1.1 × 10 6 to 67 × 10 6 . The maximum Reynolds number is more than an order of magnitude larger than that obtained in previous laboratory wake studies. Measurements are taken in the intermediate wake at locations 3, 6, 9, 12 and 15 diameters downstream from the stern in the midline plane. The model is based on an idealized submarine shape (DARPA SUBOFF), and it is mounted in a wind tunnel on a support shaped like a semi-infinite sail. The mean velocity distributions on the side opposite the support demonstrate self-similarity at all locations and Reynolds numbers, whereas the mean velocity distribution on the side of the support displays significant effects of the support wake. None of the Reynolds stress distributions of the flow attain self-similarity, and for all except the lowest Reynolds number, the support introduces a significant asymmetry into the wake which results in a decrease in the radial and streamwise turbulence intensities on the support side. The distributions continue to evolve with downstream position and Reynolds number, although a slow approach to the expected asymptotic behaviour is observed with increasing distance downstream.

Endothelial Epigenetics in Biomechanical Stress Disturbed Flow–Mediated Epigenomic Plasticity In Vivo and In Vitro

Arterial endothelial phenotype is regulated by local hemodynamic forces that are linked to regional susceptibility to atherogenesis. A complex hierarchy of transcriptional, translational, and post-translational mechanisms is greatly influenced by the characteristics of local arterial shear stress environments. We discuss the emerging role of localized disturbed blood flow on epigenetic mechanisms of endothelial responses to biomechanical stress, including transcriptional regulation by proximal promoter DNA methylation, and post-transcriptional and translational regulation of gene and protein expression by chromatin remodeling and noncoding RNA-based mechanisms. Dynamic responses to flow characteristics in vivo and in vitro include site-specific differentially methylated regions of swine and mouse endothelial methylomes, histone marks regulating chromatin conformation, microRNAs, and long noncoding RNAs. Flow-mediated epigenomic responses intersect with cis and trans factor regulation to maintain endothelial function in a shear-stressed environment and may contribute to localized endothelial dysfunctions that promote atherosusceptibility. # Significance {#article-title-72}Arterial endothelial phenotype is regulated by local hemodynamic forces that are linked to regional susceptibility to atherogenesis. A complex hierarchy of transcriptional, translational, and post-translational mechanisms is greatly influenced by the characteristics of local arterial shear stress environments. We discuss the emerging role of localized disturbed blood flow on epigenetic mechanisms of endothelial responses to biomechanical stress, including transcriptional regulation by proximal promoter DNA methylation, and post-transcriptional and translational regulation of gene and protein expression by chromatin remodeling and noncoding RNA-based mechanisms. Dynamic responses to flow characteristics in vivo and in vitro include site-specific differentially methylated regions of swine and mouse endothelial methylomes, histone marks regulating chromatin conformation, microRNAs, and long noncoding RNAs. Flow-mediated epigenomic responses intersect with cis and trans factor regulation to maintain endothelial function in a shear-stressed environment and may contribute to localized endothelial dysfunctions that promote atherosusceptibility.

An Aerodynamic Investigation of an Isolated Stationary Formula 1 Wheel Assembly

The flowfield around a 60% scale rotating Formula 1 tire in contact with the ground in a closed wind tunnel at a Reynolds number of 500,000 was examined computationally and experimentally. The goal of this study was to assess the accuracy of unsteady Reynolds-averaged Navier–Stokes (URANS) equations and confirm the existence of large scale vortical and flow recirculating features. A replica deformable F1 tire model that includes four tire treads and all brake components was used to determine the sensitivity of the wake to cross flow within the tire hub as well as the flow blockage caused by the brake assembly. Several turbulence closures were employed and the one that matched closest to the experimental PIV data was the Reynolds stress model. The variability between the six turbulence closures is shown by comparing velocity profiles, pressure distributions, and vortex eccentricity. The sensitivity of the wake to four different hub geometries, contact patch boundary conditions, multiple reference frame (MRF) rotor and spoke treatment, and time step size are also discussed.

The Effects of Fins on the Intermediate Wake of a Submarine Model

Results are presented on the behavior of the turbulent wake behind a submarine model for a range of Reynolds numbers based on the model length between 0.49 × 10 6 and 1.8 × 10 6 , for test locations between 3 and 9 diameters downstream of the stern. The shape of the model emulates an idealized submarine, and tests were performed with and without stern fins. In the absence of fins, the velocity profile in planes away from the influence of the sail rapidly becomes self-similar and is well described by a function of exponentials. The fins create defects in the velocity profiles in the outer region of the wake, while yielding higher values of turbulence at locations corresponding to the tips of the fins. Measurements conducted in planes away from the midline plane show that the velocity profiles remain self-similar while the shear stress profiles clearly show the effects of the necklace vortices trailing from the base of the fins.

Endothelial Epigenetics in Biomechanical Stress

Arterial endothelial phenotype is regulated by local hemodynamic forces that are linked to regional susceptibility to atherogenesis. A complex hierarchy of transcriptional, translational, and post-translational mechanisms is greatly influenced by the characteristics of local arterial shear stress environments. We discuss the emerging role of localized disturbed blood flow on epigenetic mechanisms of endothelial responses to biomechanical stress, including transcriptional regulation by proximal promoter DNA methylation, and post-transcriptional and translational regulation of gene and protein expression by chromatin remodeling and noncoding RNA-based mechanisms. Dynamic responses to flow characteristics in vivo and in vitro include site-specific differentially methylated regions of swine and mouse endothelial methylomes, histone marks regulating chromatin conformation, microRNAs, and long noncoding RNAs. Flow-mediated epigenomic responses intersect with cis and trans factor regulation to maintain endothelial function in a shear-stressed environment and may contribute to localized endothelial dysfunctions that promote atherosusceptibility. # Significance {#article-title-72}Arterial endothelial phenotype is regulated by local hemodynamic forces that are linked to regional susceptibility to atherogenesis. A complex hierarchy of transcriptional, translational, and post-translational mechanisms is greatly influenced by the characteristics of local arterial shear stress environments. We discuss the emerging role of localized disturbed blood flow on epigenetic mechanisms of endothelial responses to biomechanical stress, including transcriptional regulation by proximal promoter DNA methylation, and post-transcriptional and translational regulation of gene and protein expression by chromatin remodeling and noncoding RNA-based mechanisms. Dynamic responses to flow characteristics in vivo and in vitro include site-specific differentially methylated regions of swine and mouse endothelial methylomes, histone marks regulating chromatin conformation, microRNAs, and long noncoding RNAs. Flow-mediated epigenomic responses intersect with cis and trans factor regulation to maintain endothelial function in a shear-stressed environment and may contribute to localized endothelial dysfunctions that promote atherosusceptibility.

Biofluids, cell mechanics and epigenetics: Flow-induced epigenetic mechanisms of endothelial gene expression.

Epigenetics is the regulation of gene expression (transcription) in response to changes in the cell environment through genomic modifications that largely involve the non-coding fraction of the human genome and that cannot be attributed to modification of the primary DNA sequence. Epigenetics is dominant in establishing cell fate and positioning during programmed embryonic development. However the same pathways are used by mature postnatal and adult mammalian cells during normal physiology and are implicated in disease mechanisms. Recent research demonstrates that blood flow and pressure are cell environments that can influence transcription via epigenetic pathways. The principal epigenetic pathways are chemical modification of cytosine residues of DNA (DNA methylation) and of the amino tails of histone proteins associated with DNA in nucleosomes. They also encompass the post-transcriptional degradation of mRNA transcripts by non-coding RNAs (ncRNA). In vascular endothelium, epigenetic pathways respond to temporal and spatial variations of flow and pressure, particularly hemodynamic disturbed blood flow, with important consequences for gene expression. The biofluid environment is linked by mechanotransduction and solute transport to cardiovascular cell phenotypes via signaling pathways and epigenetic regulation for which there is an adequate interdisciplinary infrastructure with robust tools and methods available. Epigenetic mechanisms may be less familiar than acute genomic signaling to Investigators at the interface of biofluids, biomechanics and cardiovascular biology. Here we introduce a biofluids / cellular biomechanics readership to the principal epigenetic pathways and provide a contextual overview of endothelial epigenetic plasticity in the regulation of flow-responsive transcription.

Tip and Junction Vortices Generated by the Sail of a Yawed Submarine Model at Low Reynolds Numbers

Results are presented on the behavior of the tip and junction vortices generated by the sail of a SUBOFF submarine model at yaw angles from 6 deg to 17 deg for a Reynolds number of 94×103 based on model length. The measurements were conducted in a water channel on a spanwise plane 1.3 chord lengths downstream from the trailing edge of the sail. In the vicinity of the sail hull junction, the presence of streamwise vortices in the form of horseshoe or necklace vortices locally dominates the flow. As the yaw angle is increased from 6 deg to 9 deg, the circulation of the sail tip vortex increases, and is in good accordance with predictions from finite wing theory. However, as the yaw angle is further increased, the sail boundary layer separates with an overall drop in circulation. In contrast, the circulation value for the junction vortex increases with yaw angle, and only drops slightly at the highest yaw angle.