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The preferential targeting of the diseased microvasculature by disk-like particles.

ABSTRACT: Different classes of nanoparticles (NPs) have been developed for controlling and improving the systemic administration of therapeutic and contrast agents. Particle shape has been shown to be crucial in the vascular transport and adhesion of NPs. Here, we use mesoporous silicon non-spherical particles, of disk and rod shapes, ranging in size from 200nm to 1800nm. The fabrication process of the mesoporous particles is described in detail, and their transport and adhesion properties under flow are studied using a parallel plate flow chamber. Numerical simulations predict the hydrodynamic forces on the particles and help in interpreting their distinctive behaviors. Under microvascular flow conditions, for disk-like shape, 1000×400nm particles show maximum adhesion, whereas smaller (600×200nm) and larger (1800×600nm) particles adhere less by a factor of about two. Larger rods (1800×400nm) are observed to adhere at least 3 times more than smaller ones (1500×200nm). For particles of equal volumes, disks adhere about 2 times more than rods. Maximum adhesion for intermediate sized disks reflects the balance between adhesive interfacial interactions and hydrodynamic dislodging forces. In view of the growing evidence on vascular molecular heterogeneity, the present data suggests that thin disk-like particles could more effectively target the diseased microvasculature as compared to spheres and slender rods.

SUBMITTER: Adriani G

PROVIDER: S-EPMC3371358 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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The preferential targeting of the diseased microvasculature by disk-like particles.

Adriani Giulia G de Tullio Marco Donato MD Ferrari Mauro M Hussain Fazle F Pascazio Giuseppe G Liu Xuewu X Decuzzi Paolo P

Biomaterials 20120511 22

Different classes of nanoparticles (NPs) have been developed for controlling and improving the systemic administration of therapeutic and contrast agents. Particle shape has been shown to be crucial in the vascular transport and adhesion of NPs. Here, we use mesoporous silicon non-spherical particles, of disk and rod shapes, ranging in size from 200nm to 1800nm. The fabrication process of the mesoporous particles is described in detail, and their transport and adhesion properties under flow are ...[more]

PMID: 22579236

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Project description:AimsThrombotic complications and vasculopathy have been extensively associated with severe COVID-19 infection, however the mechanisms inducing endotheliitis and the disruption of endothelial integrity in the microcirculation are poorly understood. We hypothesized that within the vessel wall, pericytes preferentially take up viral particles and mediate the subsequent loss of vascular integrity.Methods and resultsImmunofluorescence of post-mortem patient sections were used to assess pathophysiological aspects of COVID19 infection. The effects of COVID-19 on the microvasculature were assessed using a vascular organoid model exposed to live viral particles or recombinant viral antigens. We find increased expression of the viral entry receptor ACE2 on pericytes when compared to vascular endothelium, and a reduction in the expression of the junctional protein CD144, as well as increased cell death, upon treatment with both live virus and/or viral antigens. We observe a dysregulation of genes implicated in vascular permeability including NOTCH3, angiopoietin-2 and TEK. Activation of vascular organoids with IL-1β did not have an additive effect on vascular permeability. Spike antigen was detected in some patients' lung pericytes, which was associated with a decrease in CD144 expression and increased platelet recruitment and VWF deposition in the capillaries of these patients, with thrombi in large vessels rich in VWF and fibrin.ConclusionsTogether our data indicates that direct viral exposure to the microvasculature modelled by organoid infection and viral antigen treatment result in pericyte infection, detachment, damage and cell death, disrupting pericyte-endothelial cell crosstalk and increasing microvascular endothelial permeability, which can promote thrombotic and bleeding complications in the microcirculation.Translational perspectiveEndotheliitis is a serious complication of severe COVID-19 patients which remains poorly understood. We identify a pericyte mediated mechanism by which the vasculature becomes compromised, contributing to thrombotic complications, highlighting important avenues for the development of therapies.

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The preferential targeting of the diseased microvasculature by disk-like particles.

Publications

The preferential targeting of the diseased microvasculature by disk-like particles.

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