Physiological Flow Research Articles

EP.TH.494Preclinical feasibility of in situ isolated normothermic liver chemoperfusion

Abstract Aims Up to 85% of patients with liver metastases have inoperable hepatic tumour burden. Isolated liver perfusion involves vascular isolation of the liver in situ and regional delivery of chemotherapy, avoiding dose-limiting extra-hepatic toxicity. In this series, we develop a surgical protocol to demonstrate the feasibility of isolated normothermic liver perfusion (INLP) and investigate short-term safety and feasibility of delivering high-dose chemotherapy. Methods Laparotomy and complete, vascular isolation of the liver was performed on 55-65Kg pigs (n = 6). The hepatic artery (HA), portal vein (PV) and inferior vena cava were cannulated and liver NMP established. Veno-venous bypass maintained systemic circulation. High-dose doxorubicin was administered to the isolated liver, circulated for 1 hour and vascular reconnection performed. Physiological parameters were measured and doxorubicin quantified in blood, bile and tissue by high-performance liquid chromatography. Results INLP with doxorubicin delivery achieved physiological flow rates (PV 0.7L/min (0.6-0.9L/min); HA 0.3L/min (0.2-0.4L/min)) and pH (median 7.3 (7.24-7.38)), with a median lactate of 0.42mmol/L. Median peak AST and ALT were 1045 U/L and 47 U/L respectively. Doxorubicin decay was fitted with a 2-compartmental model; distribution half-life was 1.9 minutes and plasma Cmax was higher than if given systemically resulting in mean hepatic tissue levels of 26+/-11.6 µg/g. There was no leak during INLP and doxorubicin was undetectable in kidney or heart. Conclusions Surgical isolation and NMP of the liver in situ, with concurrent veno-venous bypass is feasible and enables high-dose drug delivery resulting in therapeutic tissue levels with no off-target toxicity. Further safety studies are required.

Computational and Experimental Analysis of an In Vitro Microfluidic Experimental Setup on Testing Molteno, Ahmed Valve and Ex-Press Implants and Their Critical Comparisons

ABSTRACT Purpose/Aim of the study Researchers have investigated glaucoma drainage devices in various in vitro experimental setups to overcome their disadvantages. In this study, it is aimed to perform in vitro analyses of glaucoma drainage devices that are actively utilized for glaucoma treatment. Materials and Methods A new in vitro experimental setup is constructed and the first outcomes of numerical simulations and experimental trials are shared. Firstly, an in vitro experimental setup is designed and simulated in ANSYS Fluent, then assembled/fabricated using microfluidic equipment. Secondly, computational fluid dynamics results are expressed as pressure losses through an Ahmed Valve implant, a Molteno drainage device, an Ex-Press implant for physiological flow rates. Results In the scope of this study, Ahmed Valve (valved), Molteno (non-valved), Ex-Press (orbital shunt) implants are examined numerically using computational fluid dynamics tools. Results are compared with in vitro studies of the proposed experimental setup. Poiseuille and Reynolds numbers versus pressure drop characteristics of tested glaucoma drainage devices are also obtained using in vitro microfluidic experimental setup. In the range of 1.6–2.5 µl/min, Ahmed Valve implant created an active and effective pressure drop of 5.6 to 12 mmHg. Ahmed Valve and Molteno showed similar characteristics in terms of Poiseuille and Reynolds numbers variations with pressure drop across implants. Ex-Press, opposing Molteno and Ahmed Valve gave a reciprocal correlation between pressure drop and Po. Conclusions High resemblances of pressure drops between computational fluid dynamics results and in vitro microfluidic experimental results proved that the setup will be a better choice compared to syringe pump type setups for testing different glaucoma drainage devices at the same conditions. In conclusion, a new glaucoma drainage device should be equipped with a slimmer but larger end plate and a valve mechanism similar to Ahmed Valve in the perspective of intraocular pressure drop performance.

Effects of Low and High Aneurysmal Wall Shear Stress on Endothelial Cell Behavior: Differences and Similarities.

Background: Intracranial aneurysms (IAs) result from abnormal enlargement of the arterial lumen. IAs are mostly quiescent and asymptomatic, but their rupture leads to severe brain damage or death. As the evolution of IAs is hard to predict and intricates medical decision, it is essential to improve our understanding of their pathophysiology. Wall shear stress (WSS) is proposed to influence IA growth and rupture. In this study, we investigated the effects of low and supra-high aneurysmal WSS on endothelial cells (ECs).Methods: Porcine arterial ECs were exposed for 48 h to defined levels of shear stress (2, 30, or 80 dyne/cm2) using an Ibidi flow apparatus. Immunostaining for CD31 or γ-cytoplasmic actin was performed to outline cell borders or to determine cell architecture. Geometry measurements (cell orientation, area, circularity and aspect ratio) were performed on confocal microscopy images. mRNA was extracted for RNAseq analysis.Results: ECs exposed to low or supra-high aneurysmal WSS were more circular and had a lower aspect ratio than cells exposed to physiological flow. Furthermore, they lost the alignment in the direction of flow observed under physiological conditions. The effects of low WSS on differential gene expression were stronger than those of supra-high WSS. Gene set enrichment analysis highlighted that extracellular matrix proteins, cytoskeletal proteins and more particularly the actin protein family were among the protein classes the most affected by shear stress. Interestingly, most genes showed an opposite regulation under both types of aneurysmal WSS. Immunostainings for γ-cytoplasmic actin suggested a different organization of this cytoskeletal protein between ECs exposed to physiological and both types of aneurysmal WSS.Conclusion: Under both aneurysmal low and supra-high WSS the typical arterial EC morphology molds to a more spherical shape. Whereas low WSS down-regulates the expression of cytoskeletal-related proteins and up-regulates extracellular matrix proteins, supra-high WSS induces opposite changes in gene expression of these protein classes. The differential regulation in EC gene expression observed under various WSS translate into a different organization of the ECs’ architecture. This adaptation of ECs to different aneurysmal WSS conditions may affect vascular remodeling in IAs.

A novel MRI-based data fusion methodology for efficient, personalised, compliant simulations of aortic haemodynamics

We present a novel, cost-efficient methodology to simulate aortic haemodynamics in a patient-specific, compliant aorta using an MRI data fusion process. Based on a previously-developed Moving Boundary Method, this technique circumvents the high computational cost and numerous structural modelling assumptions required by traditional Fluid-Structure Interaction techniques. Without the need for Computed Tomography (CT) data, the MRI images required to construct the simulation can be obtained during a single imaging session. Black Blood MR Angiography and 2D Cine-MRI data were used to reconstruct the luminal geometry and calibrate wall movement specifically to each region of the aorta. 4D-Flow MRI and non-invasive pressure measurements informed patient-specific inlet and outlet boundary conditions. Luminal area closely matched 2D Cine-MRI measurements with a mean error of less than 4.6% across the cardiac cycle, while physiological pressure and flow distributions were simulated to within 3.3% of patient-specific targets. Moderate agreement with 4D-Flow MRI velocity data was observed. Despite lower peak velocity, an equivalent rigid-wall simulation predicted a mean Time-Averaged Wall Shear Stress (TAWSS) 13% higher than the compliant simulation. The agreement observed between compliant simulation results and MRI data is testament to the accuracy and efficiency of this MRI-based simulation technique.

A human brain test bed for research in large vessel occlusion stroke.

Endovascular removal of emboli causing large vessel occlusion (LVO)-related stroke utilizing suction catheter and/or stent retriever technologies or thrombectomy is a new standard of care. Despite high recanalization rates, 40% of stroke patients still experience poor neurological outcomes as many cases cannot be fully reopened after the first attempt. The development of new endovascular technologies and techniques for mechanical thrombectomy requires more sophisticated testing platforms that overcome the limitations of phantom-based simulators. The authors investigated the use of a hybrid platform for LVO stroke constructed with cadaveric human brains. A test bed for embolic occlusion of cerebrovascular arteries and mechanical thrombectomy was developed with cadaveric human brains, a customized hydraulic system to generate physiological flow rate and pressure, and three types of embolus analogs (elastic, stiff, and fragment-prone) engineered to match mechanically and phenotypically the emboli causing LVO strokes. LVO cases were replicated in the anterior and posterior circulation, and thrombectomy was attempted using suction catheters and/or stent retrievers. The test bed allowed radiation-free visualization of thrombectomy for LVO stroke in real cerebrovascular anatomy and flow conditions by transmural visualization of the intraluminal elements and procedures. The authors were able to successfully replicate 105 LVO cases with 184 passes in 12 brains (51 LVO cases and 82 passes in the anterior circulation, and 54 LVO cases and 102 passes in the posterior circulation). Observed recanalization rates in this model were graded using a Recanalization in LVO (RELVO) scale analogous to other measures of recanalization outcomes in clinical use. The human brain platform introduced and validated here enables the analysis of artery-embolus-device interaction under physiological hemodynamic conditions within the unmodified complexity of the cerebral vasculature inside the human brain.

Contributions towards Data driven Deep Learning methods to predict Steady State Fluid Flow in mechanical Heart Valves

Abstract It is commonly accepted that hemodynamic situation is related with cardiovascular diseases as well as clinical post-procedural outcome. In particular, aortic valve stenosis and insufficiency are associated with high shear flow and increased pressure loss. Furthermore, regurgitation, high shear stress and regions of stagnant blood flow are presumed to have an impact on clinical result. Therefore, flow field assessment to characterize the hemodynamic situation is necessary for device evaluation and further design optimization. In-vitro as well as in-silico fluid mechanics methods can be used to investigate the flow through prostheses. In-silico solutions are based on mathematical equitation’s which need to be solved numerically (Computational Fluid Dynamics - CFD). Fundamentally, the flow is physically described by Navier-Stokes. CFD often requires high computational cost resulting in long computation time. Techniques based on deep-learning are under research to overcome this problem. In this study, we applied a deep-learning strategy to estimate fluid flows during peak systolic steady-state blood flows through mechanical aortic valves with varying opening angles in randomly generated aortic root geometries. We used a data driven approach by running 3,500 two dimensional simulations (CFD). The simulation data serves as training data in a supervised deep learning framework based on convolutional neural networks analogous to the U-net architecture. We were able to successfully train the neural network using the supervised data driven approach. The results showing that it is feasible to use a neural network to estimate physiological flow fields in the vicinity of prosthetic heart valves (Validation error below 0.06), by only giving geometry data (Image) into the Network. The neural network generates flow field prediction in real time, which is more than 2500 times faster compared to CFD simulation. Accordingly, there is tremendous potential in the use of AIbased approaches predicting blood flows through heart valves on the basis of geometry data, especially in applications where fast fluid mechanic predictions are desired.

A modular in vitro flow model to analyse blood-surface interactions under physiological conditions

Abstract Newly developed materials for blood-contacting devices need to undergo hemocompatibility testing to prove compliance with clinical requirements. However, many current in vitro models disregard the influence of flow conditions and blood exchange as it occurs in vivo. Here, we present a flow model which allows testing of blood-surface interactions under more physiological conditions. This modular platform consists of a triple-pump-chip and a microchannel-chip with a customizable surface. Flow conditions can be adjusted individually within the physiological range. A performance test with whole blood confirmed the hemocompatibility of our modular platform. Hemolysis was negligible, inflammation and hemostasis parameters were comparable to those detected in a previously established quasi-static whole blood screening chamber. The steady supply of fresh blood avoids secondary effects by nonphysiological accumulation of activation products. Experiments with three subsequently tested biomaterials showed results similar to literature and our own experience. The reported results suggest that our developed flow model allows the evaluation of blood-contacting materials under physiological flow conditions. By adjusting the occurring wall shear stress, the model can be adapted for selected test conditions.

ACKR1 favors transcellular over paracellular T-cell diapedesis across the blood-brain barrier in neuroinflammation in vitro.

The migration of CD4+ effector/memory T cells across the blood–brain barrier (BBB) is a critical step in MS or its animal model, EAE. T‐cell diapedesis across the BBB can occur paracellular, via the complex BBB tight junctions or transcellular via a pore through the brain endothelial cell body. Making use of primary mouse brain microvascular endothelial cells (pMBMECs) as in vitro model of the BBB, we here directly compared the transcriptome profile of pMBMECs favoring transcellular or paracellular T‐cell diapedesis by RNA sequencing (RNA‐seq). We identified the atypical chemokine receptor 1 (Ackr1) as one of the main candidate genes upregulated in pMBMECs favoring transcellular T‐cell diapedesis. We confirmed upregulation of ACKR1 protein in pMBMECs promoting transcellular T‐cell diapedesis and in venular endothelial cells in the CNS during EAE. Lack of endothelial ACKR1 reduced transcellular T‐cell diapedesis across pMBMECs under physiological flow in vitro. Combining our previous observation that endothelial ACKR1 contributes to EAE pathogenesis by shuttling chemokines across the BBB, the present data support that ACKR1 mediated chemokine shuttling enhances transcellular T‐cell diapedesis across the BBB during autoimmune neuroinflammation.

Anti-inflammatory and Anti-thrombotic Efficacy of Targeted Ultrasound Microbubbles on LPS-induced HUVEC Cells.

The early stage of atherosclerosis (AS) demonstrates a lipid-driven inflammatory cytokine increase. In the present study, we aimed to use ultrasound-targeted microbubble delivery (UTMD) therapy with the Endostar-loaded target microbubbles (MBs) to reduce AS-related inflammatory response. Normal and lipopolysaccharide (LPS) induced human umbilical vein endothelial cells (HUVECs) were placed in a parallel-plate flow chamber. MBs were perfused through the parallel-plate flow chamber to mimic physiological blood flow. Five groups were set up: G1: Negative control (normal HUVECs); G2: LPS control (LPS induced HUVECs); G3: ICAM-1-loaded-MBs (MBi); G4: Endostar-loaded-MBs (MBe) and G5: Endostar-ICAM-1-loaded-MBs (MBei). mRNA expression of inflammatory factors and release of inflammatory cytokines were detected by RT-PCR and ELISA, respectively. After treatment with MBei, the mRNA expression of cell adhesion molecule-1 (CD31) (p=0.004), endothelin-1 (ET-1) (p=0.010), von willebrand factor (vWF) (p=0.018), extracellular regulated protein kinases (ERK) (p=0.046) and nuclear factor kappa B (NF-κB) (p=0.003) were significantly reduced compared to LPS-induced HUVECs. Release of inflammatory cytokines including tissue factor (TF) (p=0.033), tissue factor pathway inhibitor (TF-PI) (p=0.019), ET-1 (p=0.014), vWF (p=0.030) and blood-coagulation factor VIIα (FVIIα) (p=0.000) were also significantly reduced compared to LPS-induced HUVECs. UTMD therapy can inhibit the inflammatory response by reducing atherosclerotic-related inflammatory factors, suggesting a potential treatment at the early-stage of AS.

Microvessel-on-Chip Fabrication for the In Vitro Modeling of Nanomedicine Transport.

Tumor-on-chip devices are becoming ideal platforms to recreate in vitro the particular physiological microenvironment of interest for onco-nanomedicine testing and development. This work presents a strategy to produce a round artificial microvessel on-a-chip device for the study of physiologically relevant nanomedicine transport dynamics. The microchannels have a diameter in the range of the tumor capillaries and a semicircular geometry. This geometry is obtained through an intermediate thermal nanoimprint step using a master mold with square-shaped channel structures produced by standard silicon micromachining or by stereolithography three-dimensional (3D) printing. The working microfluidic chip devices are made by casting polydimethylsiloxane on the imprinted intermediate mold. Artificial blood microvessels are created by seeding human endothelial cells into the round-shaped channels acting as the scaffold. The microchip is connected by 3D-printed reservoirs to a pressure controller, allowing for a fine fluidic control. Under physiological flow conditions, the dynamic interaction of nanoparticles (NPs) with the artificial endothelium was assessed by high-magnification fluorescence microscopy. Overtime, internalization of NPs and clustering was observed and the accumulation rate into the endothelial cells could be characterized in real time.

A Thrombectomy Model Based on Ex Vivo Whole Human Brains.

The persistent challenges in thrombectomy for large-vessel occlusion, such as suboptimal complete recanalization and first-pass effect imply an insufficient understanding of the artery-clot-device interaction. In this study, we present a thrombectomy model using fresh human brains, which can capture the artery-clot-device interaction through concurrent transmural and angiographic visualizations. Fresh nonfrozen whole adult human brains were collected and connected to a customized pump system tuned to deliver saline flow at a physiologic flow rate and pressure. Angiography was performed to verify the flow in the anterior-posterior and vertebrobasilar circulations and collaterals. Large-vessel occlusion was simulated by embolizing a radiopaque clot analog. Thrombectomy was tested, and the artery-clot-device interactions were recorded by transmural and angiographic videos. Baseline cerebral angiography revealed excellent penetration of contrast in the anterior-posterior and vertebrobasilar circulations without notable arterial cutoffs and with robust collaterals. Small branches (<0.5 mm) and perforating arteries were consistently opacified with good patency. Three device passes were performed to achieve recanalization, with failure modes including elongation, fragmentation, and distal embolization. This model enables concurrent transmural and angiographic analysis of artery-clot-device interaction in a human brain and provides critical insights into the action mechanism and failure modes of current and upcoming thrombectomy devices.

Modelling uptake and transport of therapeutic agents through the lymphatic system

The ability of the lymphatic network to absorb large molecules and bypass the first-pass liver metabolism makes it appealing as a delivery system for therapeutic substances. In most cases, the drug is injected into the subcutaneous tissue and must negotiate the tissue space, before being drained via the lymphatics. Tracking the transport of drug molecules through this route is challenging, and computational models of lymphatic drainage can play an important role in assessing the efficacy of a proposed delivery strategy. The three-dimensional computational model we present here of the peripheral lymphatic network and surrounding interstitium is informed by anatomical data, and quantifies the degree to which uptake and transit times are affected by drug particle size, physiological flow rates, and specifics of drug injection.

Novel intrinsic neurogenic and myogenic mechanisms underlying the formation of faecal pellets along the large intestine of guinea-pigs.

Soft faecal material is transformed into discrete, pellet-shaped faeces at the colonic flexure. Here, analysis of water content in natural faecal material revealed a decline from cecum to rectum without significant changes at the flexure. Thus, pellet formation is not explained by changes in viscosity alone. We then used video imaging of colonic wall movements with electromyography in isolated preparations containing guinea-pig proximal colon, colonic flexure and distal colon. To investigate the pellet formation process, the colonic segments were infused with artificial contents (Krebs solution and 4-6% methylcellulose) to simulate physiological faecal content flow. Remarkably, pellet formation took place in vitro, without extrinsic neural inputs. Infusion evoked slowly propagating neurogenic contractions, the proximal colon migrating motor complexes (∼0.6cpm), which initiated pellet formation at the flexure. Lesion of the flexure, but not the proximal colon, disrupted the formation of normal individual pellets. In addition, a distinct myogenic mechanism was identified, whereby slow phasic contractions (∼1.9cpm) initiated at the flexure and propagated short distances retrogradely into the proximal colon and antegradely into the distal colon. There were no detectable changes in the density or distribution of pacemaker-type interstitial cells of Cajal across the flexure. The findings provide new insights into how solid faecal content is generated, suggesting the major mechanisms underlying faecal pellet formation involve the unique interaction at the colonic flexure between antegrade proximal colon migrating motor complexes, organized by enteric neurons, and retrograde myogenic slow phasic contractions. Additional, as yet unidentified extrinsic and/or humoral influences appear to contribute to processing of faecal content in vivo. KEY POINTS: In herbivores, including guinea-pigs, clearly defined faecal pellets are formed at a distinct location along the large intestine (colonic flexure). The mechanism underlying the formation of these faecal pellets at this region has remained unknown. We reveal a progressive and gradual reduction in water content of faecal content along the bowel. Hence, the distinct transition from amorphous to pellet shaped faecal content could not be explained by a dramatic increase in water reabsorption from a specific site. We discovered patterns of anterograde neurogenic and retrograde myogenic motor activity that facilitate the formation of faecal pellets. The formation of 'pellet-like' boluses at the colonic flexure involves interaction of an antegrade migrating motor complex in the proximal colon and retrograde myogenic slow phasic contractions that emerge from the colonic flexure. The findings uncover intrinsic mechanisms responsible for the formation of discrete faecal scybala in the large intestine of a vertebrate.

Miniaturized Vascularized Bleeding Model of Hemostasis.

This chapter describes the development of a poly(dimethylsiloxane)-based microfluidic platform that is able to holistically assess and visualize the entire hemostatic process in vitro. The microfluidic platform includes (1) integration of intact endothelium, (2) physiological flow conditions, (3) controlled mechanical injury to study global hemostatic potential of a patient's whole blood samples in a microvascular model and for dissecting pathophysiologic mechanisms of diseases.

Analytical and Computational Modeling of Sustained-Release Drug Implants in the Vitreous Humor.

Sustained ocular drug delivery systems are necessary for patients needing regular drug therapy since frequent injection is painful, undesirable, and risky. One type of sustained-release systems includes pellets loaded with the drug, encapsulated in a porous shell that can be injected into the vitreous humor. There the released drug diffuses while the physiological flow of water provides the convective transport. The fluid flow within the vitreous is described by Darcy's equations for the analytical model and Brinkman flow for the computational analysis while the drug transport is given by the classical convection-diffusion equation. Since the timescale for the drug depletion is quite large, for the analytical model, we consider the exterior surrounding the capsule to be quasi-steady and the interior is time dependent. In the vitreous, the fluid-flow process is relatively slow, and meaningful results can be obtained for small Peclet number whereby a perturbation analysis is possible. For an isolated capsule, with approximately uniform flow in the far field around it, the mass-transfer problem requires singular perturbation with inner and outer matching. The computational model, besides accommodating the ocular geometry, allows for a fully time-dependent mass-concentration solution and also admits moderate Peclet numbers. As expected, the release rate diminishes with time as the drug depletion lowers the driving potential. The predictive results are sufficient general for a range of capsule permeability values and are useful for the design of the sustained-release microspheres as to the requisite permeability for specific drugs.

Existence of solutions and continuous and semi-discrete stability estimates for 3D/0D coupled systems modelling airflows and blood flows

In this paper we analyse geometric multiscale models arising in the description of physiological flows such as blood flow in arteries or air flow in the bronchial tree. The geometrical complexity of the networks in which air/blood flows lead to a classical decomposition in two areas: a truncated 3D geometry corresponding to the largest contribution of the domain, and a 0D part connected to the 3D part, modelling air/blood flows in smaller airways/vessels. The fluid in the 3D part is described by the Stokes or the Navier–Stokes system which is coupled to 0D models orso-calledWindkessel models. The resulting Navier–Stokes–Windkessel coupled system involves Neumann non-local boundary conditions that depends on the considered applications. We first show that the different types of Windkessel models share a similar formalism. Next we derive existence results and stability estimates for the continuous coupled Stokes–Windkessel or Navier–Stokes–Windkessel problem as well as stability estimates for the semi-discretized systems with either implicit or explicit treatment of the boundary conditions. In all the calculations, we pay a special attention to the dependency of the various constants and smallness conditions on the data with respect to the physical and numerical parameters. In particular we exhibit different kinds of behavior depending on the considered 0D model. Moreover even if no energy estimates can be derived in energy norms for the Navier–Stokes–Windkessel system, leading to possible and observed numerical instabilities for large applied pressures, we show that stability estimates for both the continuous and semi-discrete problems, can be obtained in appropriate norms for small enough data by introducing a new well chosen Stokes-like operator. These sufficient stability conditions on the data may give a hint on the order of magnitude of the data enabling stable computations without stabilization method for the problem. Numerical simulations illustrate some of the theoretical results.

Physiologically Based Pharmacokinetic Modelling of Inhaled Nemiralisib: Mechanistic Components for Pulmonary Absorption, Systemic Distribution, and Oral Absorption.

Background and ObjectivesPhysiologically based pharmacokinetic (PBPK) modelling has evolved to accommodate different routes of drug administration and enables prediction of drug concentrations in tissues as well as plasma. The inhalation route of administration has proven successful in treating respiratory diseases but can also be used for rapid systemic delivery, holding great promise for treatment of diseases requiring systemic exposure. The objective of this work was to develop a PBPK model that predicts plasma and tissue concentrations following inhalation administration of the PI3Kδ inhibitor nemiralisib.MethodsA PBPK model was built in GastroPlus® that includes a complete mechanistic description of pulmonary absorption, systemic distribution and oral absorption following inhalation administration of nemiralisib. The availability of clinical data obtained after intravenous, oral and inhalation administration enabled validation of the model with observed data and accurate assessment of pulmonary drug absorption. The PBPK model described in this study incorporates novel use of key parameters such as lung systemic absorption rate constants derived from human physiological lung blood flows, and implementation of the specific permeability-surface area product per millilitre of tissue cell volume (SpecPStc) to predict tissue distribution.ResultsThe inhaled PBPK model was verified using plasma and bronchoalveolar lavage fluid concentration data obtained in human subjects. Prediction of tissue concentrations using the permeability-limited systemic disposition tissue model was further validated using tissue concentration data obtained in the rat following intravenous infusion administration to steady state.ConclusionsFully mechanistic inhaled PBPK models such as the model described herein could be applied for cross molecule assessments with respect to lung retention and systemic exposure, both in terms of pharmacology and toxicology, and may facilitate clinical indication selection.

Activation of the Constitutive Androstane Receptor Inhibits Leukocyte Adhesiveness to Dysfunctional Endothelium.

Leukocyte cell recruitment into the vascular subendothelium constitutes an early event in the atherogenic process. As the effect of the constitutive androstane receptor (CAR) on leukocyte recruitment and endothelial dysfunction is poorly understood, this study investigated whether the role of CAR activation can affect this response and the underlying mechanisms involved. Under physiological flow conditions, TNFα-induced endothelial adhesion of human leukocyte cells was concentration-dependently inhibited by preincubation of human umbilical arterial endothelial cells with the selective human CAR ligand CITCO. CAR agonism also prevented TNFα induced VCAM-1 expression, as well as MCP-1/CCL-2 and RANTES/CCL-5 release in endothelial cells. Suppression of CAR expression with a small interfering RNA abrogated the inhibitory effects of CITCO on these responses. Furthermore, CITCO increased interaction of CAR with Retinoid X Receptor (RXR) and reduced TNFα-induced p38-MAPK/NF-κB activation. In vivo, using intravital microscopy in the mouse cremasteric microcirculation treatment with the selective mouse CAR ligand TCPOBOP inhibited TNFα-induced leukocyte rolling flux, adhesion, and emigration and decreased VCAM-1 in endothelium. These results reveal that CAR agonists can inhibit the initial inflammatory response that precedes the atherogenic process by targeting different steps in the leukocyte recruitment cascade. Therefore, CAR agonists may constitute a new therapeutic tool in controlling cardiovascular disease-associated inflammatory processes.

Composition of Classification Models for Recognizing the Flow Velocity of Liquids in Capillaries

Purpose of research. Development of a technique for estimating the average flow rate of physiological fluids in capillaries from images obtained using laser speckle-contrast imaging. The technique includes obtaining experimental data in the form of an image of the fluid flow in a thin tube, their preliminary processing, including filtering and compressing data, as well as training and testing approximate models using modern machine learning methods.Methods. The experimental study of the fluid flow in the tube is based on the application of the laser speckle-contrast imaging method. The spatial speckle-contrast values are calculated from the obtained images. The obtained data are subjected to preliminary processing, including the data filtering out and extending to a steady flow mode, as well as compressing the obtained images using the principal component method, which allows reducing the dimension of the feature space. The problem of predicting the average velocity from the image of the fluid flow is solved as a classification problem based on the composition of decision trees constructed through the bagging procedure, as well as in the form of a random forest.Results. A technique for predicting the average velocity of liquid flow in a capillary from images obtained using the laser speckle-contrast imaging method has been developed. The accuracy of predicting the average velocity (or flow rate) based on the training sample was about 91%, on the validation and test samples - at least 81.5%.Conclusion. Based on the developed technique, it is planned to determine the kinematic characteristics of the parameters of physiological fluids flow, which will improve the inertial method of measuring the viscosity of the tested liquids developed earlier by the authors, getting rid of a number of assumptions about the velocity profile.

Carotid Duplex Velocity Alterations Among Left Ventricular Assist Device Patients: Need for a Shift in Criteria?

Carotid duplex interpretation are based on velocity cutoffs and internal carotid artery (ICA)/common carotid artery (CCA) ratios. Patients undergoing left ventricular assist device (LVAD) implantation pose a challenge in the standard interpretive criteria. The continuous flow produced by an LVAD alters normal pulsatile physiologic blood flow, lowering systolic flow and increasing diastolic flow. Therefore, we hypothesized that presence of an LVAD alters the velocities observed on carotid artery duplex ultrasound, rendering traditional criteria difficult to interpret.