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      Intimal and medial contributions to the hydraulic resistance of the arterial wall at different pressures: a combined computational and experimental study

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          Abstract

          The hydraulic resistances of the intima and media determine water flux and the advection of macromolecules into and across the arterial wall. Despite several experimental and computational studies, these transport processes and their dependence on transmural pressure remain incompletely understood. Here, we use a combination of experimental and computational methods to ascertain how the hydraulic permeability of the rat abdominal aorta depends on these two layers and how it is affected by structural rearrangement of the media under pressure. Ex vivo experiments determined the conductance of the whole wall, the thickness of the media and the geometry of medial smooth muscle cells (SMCs) and extracellular matrix (ECM). Numerical methods were used to compute water flux through the media. Intimal values were obtained by subtraction. A mechanism was identified that modulates pressure-induced changes in medial transport properties: compaction of the ECM leading to spatial reorganization of SMCs. This is summarized in an empirical constitutive law for permeability and volumetric strain. It led to the physiologically interesting observation that, as a consequence of the changes in medial microstructure, the relative contributions of the intima and media to the hydraulic resistance of the wall depend on the applied pressure; medial resistance dominated at pressures above approximately 93 mmHg in this vessel.

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          Physiological transport forces govern drug distribution for stent-based delivery.

          The first compounds considered for stent-based delivery, such as heparin, were chosen on the basis of promising tissue culture and animal experiments, and yet they have failed to stop restenosis clinically. More recent compounds, such as paclitaxel, are of a different sort, being hydrophobic in nature, and their effects after local release seem far more profound. This dichotomy raises the question of whether drugs that have an effect when released from a stent do so because of differences in biology or differences in physicochemical properties and targeting. We applied continuum pharmacokinetics to examine the effects of transport forces and device geometry on the distribution of stent-delivered hydrophilic and hydrophobic drugs. We found that stent-based delivery invariably leads to large concentration gradients, with drug concentrations ranging from nil to several times the mean tissue concentration over a few micrometers. Concentration variations were a function of the Peclet number (Pe), the ratio of convective to diffusive forces. Although hydrophobic drugs exhibited greater variability than hydrophilic drugs, they achieved higher mean concentrations and remained closer to the intima. Inhomogeneous strut placement influenced hydrophilic drugs more negatively than hydrophobic drugs, dramatically affecting local concentrations without changing mean concentrations. Because local concentrations and gradients are inextricably linked to biological effect, our results provide a potential explanation for the variable success of stent-based delivery. We conclude that mere proximity of delivery devices to tissues does not ensure adequate targeting, because physiological transport forces cause local concentrations to deviate significantly from mean concentrations.
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            Arterial paclitaxel distribution and deposition.

            Successful implementation of local arterial drug delivery requires transmural distribution of drug. The physicochemical properties of the applied compound, which govern its transport and tissue binding, become as important as the mode of delivery. Hydrophilic compounds distribute freely but are cleared rapidly. Hydrophobic drugs, insoluble in aqueous solutions, bind to fixed tissue elements, potentially prolonging tissue residence and biological effect. Paclitaxel is such a hydrophobic compound, with tremendous therapeutic potential against proliferative vascular disease. We hypothesized that the recent favorable preclinical data with this compound may derive in part from preferential tissue binding as a result of unique physicochemical properties. The arterial transport of paclitaxel was quantified through application ex vivo and measurement of the subsequent transmural distribution. Arterial paclitaxel deposition at equilibrium varied across the arterial wall and was everywhere greater in concentration than in the applied drug source. Permeation into the wall increased with time, from 15 minutes to 4 hours, and varied with the origin of delivery. In contrast to hydrophilic compounds, the concentration in tissue exceeds the applied concentration and the rate of transport was markedly slower. Furthermore, endovascular and perivascular paclitaxel application led to markedly differential deposition across the blood vessel wall. These data suggest that paclitaxel interacts with arterial tissue elements as it moves under the forces of diffusion and convection and can establish substantial partitioning and spatial gradients across the tissue. The complexity of paclitaxel pharmacokinetics requires in-depth investigation if this drug is to reach its full clinical potential in proliferative vascular diseases.
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              Specific binding to intracellular proteins determines arterial transport properties for rapamycin and paclitaxel.

              Endovascular drug-eluting stents have changed the practice of medicine, and yet it is unclear how they so dramatically reduce restenosis and how to distinguish between the different formulations available. Biological drug potency is not the sole determinant of biological effect. Physicochemical drug properties also play important roles. Historically, two classes of therapeutic compounds emerged: hydrophobic drugs, which are retained within tissue and have dramatic effects, and hydrophilic drugs, which are rapidly cleared and ineffective. Researchers are now questioning whether individual properties of different drugs beyond lipid avidity can further distinguish arterial transport and distribution. In bovine internal carotid segments, tissue-loading profiles for hydrophobic paclitaxel and rapamycin are indistinguishable, reaching load steady state after 2 days. Hydrophilic dextran reaches equilibrium in several hours at levels no higher than surrounding solution concentrations. Both paclitaxel and rapamycin bind to the artery at 30-40 times bulk concentration. Competitive binding assays confirm binding to specific tissue elements. Most importantly, transmural drug distribution profiles are markedly different for the two compounds, reflecting, perhaps, different modes of binding. Rapamycin, which binds specifically to FKBP12 binding protein, distributes evenly through the artery, whereas paclitaxel, which binds specifically to microtubules, remains primarily in the subintimal space. The data demonstrate that binding of rapamycin and paclitaxel to specific intracellular proteins plays an essential role in determining arterial transport and distribution and in distinguishing one compound from another. These results offer further insight into the mechanism of local drug delivery and the specific use of existing drug-eluting stent formulations.
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                Author and article information

                Journal
                J R Soc Interface
                J R Soc Interface
                RSIF
                royinterface
                Journal of the Royal Society Interface
                The Royal Society
                1742-5689
                1742-5662
                June 2016
                June 2016
                : 13
                : 119
                : 20160234
                Affiliations
                [1 ]Department of Bioengineering, Imperial College London , London, UK
                [2 ]Department of Aeronautics, Imperial College London , London, UK
                Author notes
                [†]

                Both authors contributed equally to this work.

                Author information
                http://orcid.org/0000-0002-3006-0077
                Article
                rsif20160234
                10.1098/rsif.2016.0234
                4938088
                27307514
                db09f337-8eaa-4c49-a4d9-ed2f78f07c6c
                © 2016 The Authors.

                Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.

                History
                : 23 March 2016
                : 18 May 2016
                Funding
                Funded by: British Heart Foundation, http://dx.doi.org/10.13039/501100000274;
                Award ID: RE/08/002/23906
                Award ID: RG11/5/28743
                Funded by: Research Executive Agency, http://dx.doi.org/10.13039/501100000783;
                Award ID: Marie Curie Actions / 294104
                Categories
                1004
                26
                25
                Life Sciences–Engineering interface
                Research Article
                Custom metadata
                June , 2016

                Life sciences
                permeability,hydraulic resistance,constitutive modelling,intima,media,artery
                Life sciences
                permeability, hydraulic resistance, constitutive modelling, intima, media, artery

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