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Imaging of microvasculature is primarily performed with X-ray contrast agents, owing to the wide availability of absorption-contrast laboratory source microCT compared to phase contrast capable devices. Standard commercial contrast agents used in angiography are not suitable for high-resolution imaging ex vivo, however, as they are small molecular compounds capable of diffusing through blood vessel walls within minutes. Large nanoparticle-based blood pool contrast agents on the other hand exhibit problems with aggregation, resulting in clogging in the smallest blood vessels. Injection with solidifying plastic resins has, therefore, remained the gold standard for microvascular imaging, despite the considerable amount of training and optimization needed to properly perfuse the viscous compounds. Even with optimization, frequent gas and water inclusions commonly result in interrupted vessel segments. This lack of suitable compounds has led us to develop the polymeric, cross-linkable X-ray contrast agent XlinCA. As a water-soluble organic molecule, aggregation and inclusions are inherently avoided. High molecular weight allows it to be retained even in the highly fenestrated vasculature of the kidney filtration system. It can be covalently crosslinked using the same aldehydes used in tissue fixation protocols, leading to stable and permanent contrast. These properties allowed us to image whole mice and individual organs in 6 to 12-month-old C57BL/6J mice without requiring lengthy optimizations of injection rates and pressures, while at the same time achieving greatly improved filling of the vasculature compared to resin-based vascular casting. This work aims at illuminating the rationales, processes and challenges involved in creating this recently developed contrast agent., 10 pages, 6 figures

Our kidneys receive about one-fifth of the cardiac output at rest and have a low oxygen extraction ratio, but may sustain, under some conditions, hypoxic injuries that might lead to chronic kidney disease. This is due to large regional variations in renal blood flow and oxygenation, which are the prerequisite for some and the consequence of other kidney functions. The concurrent operation of these functions is reliant on a multitude of neuro-hormonal signaling cascades and feedback loops that also include the regulation of renal blood flow and tissue oxygenation. Starting with open questions on regulatory processes and disease mechanisms, we review herein the literature on renal blood flow and oxygenation. We assess the current understanding of renal blood flow regulation, reasons for disparities in oxygen delivery and consumption, and the consequences of disbalance between O2 delivery, consumption, and removal. We further consider methods for measuring and computing blood velocity, flow rate, oxygen partial pressure, and related parameters and point out how limitations of these methods constitute important hurdles in this area of research. We conclude that to obtain an integrated understanding of the relation between renal function and renal blood flow and oxygenation, combined experimental and computational modeling studies will be needed.

While earlier studies reported no relevant effect of the HeartMate 3 (HM3) artificial pulse (AP) on bulk pump washout, its effect on regions with prolonged residence times remains unexplored. Using numerical simulations, we compared pump washout in the HM3 with and without AP with a focus on the clearance of the last 5% of the pump volume. Results were examined in terms of flush-volume (Vf , number of times the pump was flushed with new blood) to probe the effect of the AP independent of changing flow rate. Irrespective of the flow condition, the HM3 washout scaled linearly with flush volume up to 70%washout and slowed down for the last 30%. Flush volumes needed to washout 95% of the pump were comparable with and without the AP (1.3–1.4 Vf ), while 99% washout required 2.1–2.2 Vf with the AP vs. 2.5 Vf without the AP. The AP enhanced washout of the bend relief and near-wall regions. It also transiently shifted or eliminated stagnation regions and led to rapid wall shear stress fluctuations below the rotor and in the secondary flow path. Our results suggest potential benefits of the AP for clearance of fluid regions that might elicit in-pump thrombosis and provide possible mechanistic rationale behind clinical data showing very low rate of in-pump thrombosis with the HM3. Further optimization of the AP sequence is warranted to balance washout efficacy while limiting blood damage., Frontiers in Cardiovascular Medicine, 9, ISSN:2297-055X

Background. To date, it remains difficult for clinicians to reliably assess the disease status of intracranial aneurysms. As an aneurysm's 3D shape is strongly dependent on the underlying formation processes, it is believed that the presence of certain shape features mirrors the disease status of the aneurysm wall. Currently, clinicians associate irregular shape with wall instability. However, no consensus exists about which shape features reliably predict instability. In this study, we present a classification pipeline that seeks to identify shape features that offer the highest predictive power of aneurysm rupture status.Methods. 3D models of aneurysms were extracted from medical imaging data (3D rotational angiographies) using a standardized protocol. For these aneurysm models, we calculated a variety of established representations of the 3D shape: Geometry indices such as undulation, ellipticity and non-sphericity; writhe- and curvature-based metrics; as well as indices based on Zernike moments. Using statistical learning methods, we investigated the association between shape features and aneurysm disease status. This processing pipeline was applied to a clinical dataset of 750 aneurysms registered in the AneuX morpho database. We report here principal statistical performance metrics (such as the area under curve AUC) for morphometric models to discriminate between ruptured and unruptured aneurysms.Results. Non-sphericity index NSI (AUC = 0.80), normalized Zernike energies (AUC = 0.80) and a modified writhe-index (AUC = 0.78) exhibited the strongest association with rupture status. The combination of predictors further improved the predictive performance (without location: AUC = 0.82, with location AUC = 0.87). The anatomical location was a good predictor for rupture status on its own (AUC = 0.78). Different protocols to isolate the aneurysm dome did not affect the prediction performance. We identified problems regarding generalizability if trained models are applied to datasets with different selection biases.Conclusions. Morphology provided a clear indication of the aneurysm disease status, with parameters measuring shape irregularity being better predictors than size. Because rupture rates vary with aneurysm location, predictive models should be compared to a baseline model using only location as predictor., + ID der Publikation: hslu_89608 + Art des Beitrages: Wissenschaftliche Medien + Jahrgang: 13 + Sprache: Englisch + Letzte Aktualisierung: 2022-05-03 13:08:38

Concurrent three-dimensional imaging of the renal vascular and tubular systems on the whole-kidney scale with capillary level resolution is labor-intensive and technically difficult. Approaches based on vascular corrosion casting and X-ray micro computed tomography (μCT), for example, suffer from vascular filling artifacts and necessitate imaging with an additional modality to acquire tubules. In this work, we report on a new sample preparation, image acquisition, and quantification protocol for simultaneous vascular and tubular μCT imaging of whole, uncorroded mouse kidneys. The protocol consists of vascular perfusion with the water-soluble, aldehyde-fixable, polymeric X-ray contrast agent XlinCA, followed by laboratory-source μCT imaging and structural analysis using the freely available Fiji/ImageJ software. We achieved consistent filling of the entire capillary bed and staining of the tubules in the cortex and outer medulla. After imaging at isotropic voxel sizes of 3.3 and 4.4 μm, we segmented vascular and tubular systems and quantified luminal volumes, surface areas, diffusion distances, and vessel path lengths. This protocol permits the analysis of vascular and tubular parameters with higher reliability than vascular corrosion casting, less labor than serial sectioning and leaves tissue intact for subsequent histological examination with light and electron microscopy.

Background: Postural changes are related to changes in cerebrospinal fluid (CSF) dynamics. While sitting up leads to a decrease in cranial CSF pressure, it also causes shifts in the craniospinal CSF volume and compliance distribution. We hypothesized that jugular vein collapse in upright posture is a major contributor to these shifts in CSF volume and compliance. Methods: To test this hypothesis, we implemented a mathematical lumped-parameter model of the CSF system and the relevant parts of the cardiovascular system. In this model, the CSF and the venous system are each divided into a cranial and a spinal part. The pressures in these cranial and spinal portions differ by the posture-dependent hydrostatic pressure columns in the connecting vessels. Jugular collapse is represented by a reduction of the hydrostatic pressure difference between cranial and spinal veins. The CSF pressure–volume relationship is implemented as a function of the local CSF to venous pressure gradient. This implies that an increase in CSF volume leads to a simultaneous displacement of blood from adjacent veins. CSF pulsations driven by the cardiovascular system are introduced through a pulsating cranial arterial volume. Results: In upright posture, the implemented CSF pressure–volume relationship shifts to lower cranial CSF pressures compared to the horizontal position, leading to a decrease in cranial CSF pressure when sitting up. Concurrently, the compliance of the spinal compartment decreases while the one of the cranial compartment increases. With this, in upright posture only 10% of the CSF system’s compliance is provided by the spinal compartment compared to 35% in horizontal posture. This reduction in spinal compliance is accompanied by a caudal shift of CSF volume. Also, the ability of the spinal CSF compartment to compensate for cerebral arterial volume pulsations reduces in upright posture, which in turn reduces the calculated craniospinal CSF flow pulsations. Conclusion: The mathematical model enabled us to isolate the effect of jugular collapse and quantify the induced shifts of compliance and CSF volume. The good concordance of the modelled changes with clinically observed values indicates that jugular collapse can be considered a major contributor to CSF dynamics in upright posture., Fluids and Barriers of the CNS, 14 (1), ISSN:2045-8118

The rapid increase in medical and biomedical image acquisition rates has opened up new avenues for image analysis, but has also introduced formidable challenges. This is evident, for example, in selective plane illumination microscopy where acquisition rates of about 1-4 GB/s sustained over several days have redefined the scale of I/O bandwidth required by image analysis tools. Although the effective bandwidth could, principally, be increased by lossy-to-lossless data compression, this is of limited value in practice due to the high computational demand of current schemes such as JPEG2000 that reach compression throughput of one order of magnitude below that of image acquisition. Here we present a novel lossy-to-lossless data compression scheme with a compression throughput well above 4 GB/s and compression rates and rate-distortion curves competitive with those achieved by JPEG2000 and JP3D.

High-contrast, high-resolution imaging of biomedical specimens is indispensable for studying organ function and pathologies. Conventional histology, the gold standard for soft-tissue visualization, is limited by its anisotropic spatial resolution, elaborate sample preparation, and lack of quantitative image information. X-ray absorption or phase tomography have been identified as promising alternatives enabling non-destructive, distortion-free three-dimensional (3D) imaging. However, reaching sufficient contrast and resolution with a simple experimental procedure remains a major challenge. Here, we present a solution based on x-ray phase tomography through speckle-based imaging (SBI). We demonstrate on a mouse kidney that SBI delivers comprehensive 3D maps of hydrated, unstained soft tissue, revealing its microstructure and delivering quantitative tissue-density values at a density resolution of better than 2 m g / c m 3 and spatial resolution of better than 8 µm. We expect that SBI virtual histology will find widespread application in biomedicine and will open up new possibilities for research and histopathology.

Ventricular assist devices (VADs), among which the HeartMate 3 (HM3) is the latest clinically approved representative, are often the therapy of choice for patients with end-stage heart failure. Despite advances in the prevention of pump thrombosis, rates of stroke and bleeding remain high. These complications are attributed to the flow field within the VAD, among other factors. One of the HM3's characteristic features is an artificial pulse that changes the rotor speed periodically by 4000 rpm, which is meant to reduce zones of recirculation and stasis. In this study, we investigated the effect of this speed modulation on the flow fields and stresses using high-resolution computational fluid dynamics. To this end, we compared Eulerian and Lagrangian features of the flow fields during constant pump operation, during operation with the artificial pulse feature, and with the effect of the residual native cardiac cycle. We observed good washout in all investigated situations, which may explain the low incidence rates of pump thrombosis. The artificial pulse had no additional benefit on scalar washout performance, but it induced rapid variations in the flow velocity and its gradients. This may be relevant for the removal of deposits in the pump. Overall, we found that viscous stresses in the HM3 were lower than in other current VADs. However, the artificial pulse substantially increased turbulence, and thereby also total stresses, which may contribute to clinically observed issues related to hemocompatibility.

Contemporary centrifugal continuous-flow left ventricular assist devices (LVADs) incorporate dynamic speed modulation algorithms. Hemocompatibility of these periodic unsteady pump operating conditions has been only partially explored. We evaluated whether speed modulation induces flow alterations associated with detrimental prothrombotic effects. For this aim, we evaluated the thrombogenic profile of the HeartWare ventricular assist device (HVAD) Lavare Cycle (LC) and HeartMate3 (HM3) artificial pulse (AP) via comprehensive numerical evaluation of (i) pump washout, (ii) stagnation zones, (iii) shear stress regimens, and (iv) modeling of platelet activation status via the platelet activity state (PAS) model. Data were compared between different simulated operating scenarios, including: (i) constant rotational speed and pump pressure head, used as reference; (ii) unsteady pump pressure head as induced by cardiac pulsatility; and (iii) unsteady rotor speed modulation of the LC (HVAD) and AP (HM3). Our results show that pump washout did not improve across the different simulated scenarios in neither the HVAD nor the HM3. The LC reduced but did not eliminate flow stagnation (-57%) and did not impact metrics of HVAD platelet activation (median PAS: +0.4%). The AP reduced HM3 flow stagnation by up to 91% but increased prothrombotic shear stress and simulated platelet activation (median PAS: +124%). Our study advances understanding of the pathogenesis of LVAD thrombosis, suggesting mechanistic implications of rotor speed modulation. Our data provide rationale criteria for the future design optimization of next generation LVADs to further reduce hemocompatibility-related adverse events.

Renal arteriovenous oxygen shunting has been proposed as a mechanism by which oxygen supplied to the kidney can bypass the renal parenchyma. Shunting could, therefore, play a crucial role in renal hypoxia and hyperoxia. In the absence of suitable quantitative experimental methods, computational modeling has been employed in recent years to estimate the extent and potential impact of oxygen shunting.Overestimation of the separation distance between arteries and veins was suggested to be responsible for previous findings that only negligible amounts of oxygen are shunted in the preglomerular vasculature. However, models considering the correct separation distance and wrapping of artery-vein pairs still showed shunting at negligible levels of less than 1% of total renal oxygen delivery. The effect of reverse CO2 shunting on the oxygen-hemoglobin dissociation curve was found to impair, rather than promote, preglomerular oxygen shunting.Oxygen is unlikely to be shunted along the preglomerular vasculature in sufficient quantities to affect renal oxygenation. There may be substantial shunting at the level of the postglomerular vasculature, but more extensive efforts in structural imaging and computational modeling are needed to quantify it reliably.

Reduced intracranial compliance is a key manifestation common to a number of pathological conditions of the brain. It is encountered in, but not limited to, traumatic brain injury, cerebral edema, and hydrocephalus. There are no clinically accepted methods to measure intracranial compliance available to date. Intracranial pressure (ICP) waveform analysis is seeing a revival driven by advances in our understanding of cerebrospinal fluid and pressure dynamics. Its translation to widespread clinical use is dependent on the possibility to derive relevant metrics such as intracranial compliance reliably and non-invasively. The B-wave is one of the features of the ICP waveform, reflecting vasogenic activity of cerebral autoregulation. B-waves were originally defined to occupy the 0.5 to 2 cycles per minute frequency range. Recently renamed and redefined as slow waves with an extended range of 0.33 to 3 cycles per minute, specific changes in their pattern of occurrence are considered to be indicative of reduced intracranial compliance. With the still unmet need for a clinically acceptable method for acquiring intracranial compliance, and the revival of ICP waveform analysis, B-waves are moving back into the research focus. Herein we provide a concise review of the literature on B-waves, including a critical assessment of non-invasive methods for obtaining B-wave surrogates.

The homeostatic regulation of large neutral amino acid (LNAA) concentration in the brain interstitial fluid (ISF) is essential for proper brain function. LNAA passage into the brain is primarily mediated by the complex and dynamic interactions between various solute carrier (SLC) transporters expressed in the neurovascular unit (NVU), among which SLC7A5/LAT1 is considered to be the major contributor in microvascular brain endothelial cells (MBEC). The LAT1-mediated trans-endothelial transport of LNAAs, however, could not be characterized precisely by available in vitro and in vivo standard methods so far. To circumvent these limitations, we have incorporated published in vivo data of rat brain into a robust computational model of NVU-LNAA homeostasis, allowing us to evaluate hypotheses concerning LAT1-mediated trans-endothelial transport of LNAAs across the blood brain barrier (BBB). We show that accounting for functional polarity of MBECs with either asymmetric LAT1 distribution between membranes and/or intrinsic LAT1 asymmetry with low intraendothelial binding affinity is required to reproduce the experimentally measured brain ISF response to intraperitoneal (IP) L-tyrosine and L-phenylalanine injection. On the basis of these findings, we have also investigated the effect of IP administrated L-tyrosine and L-phenylalanine on the dynamics of LNAAs in MBECs, astrocytes and neurons. Finally, the computational model was shown to explain the trans-stimulation of LNAA uptake across the BBB observed upon ISF perfusion with a competitive LAT1 inhibitor.

Background Cerebrospinal fluid (CSF) protein analysis is an important element in the diagnostic chain for various central nervous system (CNS) pathologies. Among multiple existing approaches to interpreting measured protein levels, the Reiber diagram is particularly robust with respect to physiologic inter-individual variability, as it uses multiple subject-specific anchoring values. Beyond reliable identification of abnormal protein levels, the Reiber diagram has the potential to elucidate their pathophysiologic origin. In particular, both reduction of CSF drainage from the cranio-spinal space as well as blood–CNS barrier dysfunction have been suggested ρas possible causes of increased concentration of blood-derived proteins. However, there is disagreement on which of the two is the true cause. Methods We designed two computational models to investigate the mechanisms governing protein distribution in the spinal CSF. With a one-dimensional model, we evaluated the distribution of albumin and immunoglobulin G (IgG), accounting for protein transport rates across blood–CNS barriers, CSF dynamics (including both dispersion induced by CSF pulsations and advection by mean CSF flow) and CSF drainage. Dispersion coefficients were determined a priori by computing the axisymmetric three-dimensional CSF dynamics and solute transport in a representative segment of the spinal canal. Results Our models reproduce the empirically determined hyperbolic relation between albumin and IgG quotients. They indicate that variation in CSF drainage would yield a linear rather than the expected hyperbolic profile. In contrast, modelled barrier dysfunction reproduces the experimentally observed relation. Conclusions High levels of albumin identified in the Reiber diagram are more likely to originate from a barrier dysfunction than from a reduction in CSF drainage. Our in silico experiments further support the hypothesis of decreasing spinal CSF drainage in rostro-caudal direction and emphasize the physiological importance of pulsation-driven dispersion for the transport of large molecules in the CSF.

The aim of this study was to evaluate whether possible preglomerular arterial-to-venous oxygen shunting is affected by the interaction between renal preglomerular carbon dioxide and oxygen transport. We hypothesized that a reverse (venous-to-arterial) shunting of carbon dioxide will increase partial pressure of carbon dioxide and decrease pH in the arteries and thereby lead to increased oxygen offloading and consequent oxygen shunting. To test this hypothesis, we employed a segment-wise three-dimensional computational model of coupled renal oxygen and carbon dioxide transport, wherein coupling is achieved by shifting the oxygen-hemoglobin dissociation curve in dependence of local changes in partial pressure of carbon dioxide and pH. The model suggests that primarily due to the high buffering capacity of blood, there is only marginally increased acidity in the preglomerular vasculature compared to systemic arterial blood caused by carbon dioxide shunting. Furthermore, effects of carbon dioxide transport do not promote but rather impair preglomerular oxygen shunting, as the increase in acidity is higher in the veins compared to that in the arteries. We conclude that while substantial arterial-to-venous oxygen shunting might take place in the postglomerular vasculature, the net amount of oxygen shunted at the preglomerular vasculature appears to be marginal.

Observations of fast transport of fluorescent tracers in mouse brains have led to the hypothesis of bulk water flow directed from arterial to venous paravascular spaces (PVS) through the cortical interstitium. At the same time, there is evidence for interstitial solute transport by diffusion rather than by directed bulk fluid motion. It has been shown that the two views may be consolidated by intracellular water flow through astrocyte networks combined with mainly diffusive extracellular transport of solutes. This requires the presence of a driving force that has not been determined to date, but for which arterial pulsation has been suggested as the origin. Here we show that arterial pulsation caused by pulse wave propagation is an unlikely origin of this hypothetical driving force. However, we further show that such pulsation may still lead to fast para-arterial solute transport through dispersion, that is, through the combined effect of local mixing and diffusion in the para-arterial space.

Encapsulated microbubbles (MBs) serve as endovascular agents in a wide range of medical ultrasound applications. The oscillatory response of these agents to ultrasonic excitation is determined by MB size, gas content, viscoelastic shell properties and geometrical constraints. The viscoelastic parameters of the MB capsule vary during an oscillation cycle and change irreversibly upon shell rupture. The latter results in marked stress changes on the endothelium of capillary blood vessels due to altered MB dynamics. Mechanical effects on microvessels are crucial for safety and efficacy in applications such as focused ultrasound-mediated blood--brain barrier (BBB) opening. Since direct in vivo quantification of vascular stresses is currently not achievable, computational modelling has established itself as an alternative. We have developed a novel computational framework combining fluid--structure coupling and interface tracking to model the nonlinear dynamics of an encapsulated MB in constrained environments. This framework is used to investigate the mechanical stresses at the endothelium resulting from MB shell rupture in three microvessel setups of increasing levels of geometric detail. All configurations predict substantial elevation of up to 150 {; ; ; \%}; ; ; for peak wall shear stress upon MB breakup, whereas global peak transmural pressure levels remain unaltered. The presence of red blood cells causes confinement of pressure and shear gradients to the proximity of the MB, and the introduction of endothelial texture creates local modulations of shear stress levels. With regard to safety assessments, the mechanical impact of MB breakup is shown to be more important than taking into account individual red blood cells and endothelial texture. The latter two may prove to be relevant to the actual, complex process of BBB opening induced by MB oscillations.

Hemodynamic factors such as low wall shear stress have been shown to influence endothelial healing and atherogenesis in stent-free vessels. However, in stented vessels, a reliable quantitative analysis of such relations has not been possible due to the lack of a suitable method for the accurate acquisition of blood flow. The objective of this work was to develop a method for the precise reconstruction of hemodynamics and quantification of wall shear stress in stented vessels. We have developed such a method that can be applied to vessels stented in or ex vivo and processed ex vivo. Here we stented the coronary arteries of ex vivo porcine hearts, performed vascular corrosion casting, acquired the vessel geometry using micro-computed tomography and reconstructed blood flow and shear stress using computational fluid dynamics. The method yields accurate local flow information through anatomic fidelity, capturing in detail the stent geometry, arterial tissue prolapse, radial and axial arterial deformation as well as strut malapposition. This novel compound method may serve as a unique tool for spatially resolved analysis of the relationship between hemodynamic factors and vascular biology. It can further be employed to optimize stent design and stenting strategies., PLoS ONE, 8 (3), ISSN:1932-6203

The brain possesses an intricate network of interconnected fluid pathways that are vital to the maintenance of its homeostasis. With diffusion being the main mode of solute transport in cerebral tissue, it is not clear how bulk flow through these pathways is involved in the removal of metabolites. In this computational study, we show that networks of astrocytes may contribute to the passage of solutes between tissue and paravascular spaces (PVS) by serving as low resistance pathways to bulk water flow. The astrocyte networks are connected through aquaporin-4 (AQP4) water channels with a parallel, extracellular route carrying metabolites. Inhibition of the intracellular route by deletion of AQP4 causes a reduction of bulk flow between tissue and PVS, leading to reduced metabolite clearance into the venous PVS or, as observed in animal studies, a reduction of tracer influx from arterial PVS into the brain tissue.

While there is growing experimental evidence that cerebrospinal fluid (CSF) flow induced by the beating of ependymal cilia is an important factor for neuronal guidance, the respective contribution of vascular pulsation-driven macroscale oscillatory CSF flow remains unclear. This work uses computational fluid dynamics to elucidate the interplay between macroscale and cilia-induced CSF flows and their relative impact on near-wall dynamics. Physiological macroscale CSF dynamics are simulated in the ventricular space using subject-specific anatomy, wall motion and choroid plexus pulsations derived from magnetic resonance imaging. Near-wall flow is quantified in two subdomains selected from the right lateral ventricle, for which dynamic boundary conditions are extracted from the macroscale simulations. When cilia are neglected, CSF pulsation leads to periodic flow reversals along the ventricular surface, resulting in close to zero time-averaged force on the ventricle wall. The cilia promote more aligned wall shear stresses that are on average two orders of magnitude larger compared with those produced by macroscopic pulsatile flow. These findings indicate that CSF flow-mediated neuronal guidance is likely to be dominated by the action of the ependymal cilia in the lateral ventricles, whereas CSF dynamics in the centre regions of the ventricles is driven predominantly by wall motion and choroid plexus pulsation.