1 The Effects of Particle Size, Shape, Density and Flow Characteristics on Particle Margination to Vascular Walls in Cardiovascular Diseases Abstract Introduction: Vascular-targeted drug delivery is a promising approach for the treatment of atherosclerosis due to the vast involvement of endothelium in the initiation and growth of plaque, a characteristic of atherosclerosis. One of the major challenges in carrier design for targeting cardiovascular diseases (CVD) is that carriers must be able to navigate the circulation system and efficiently marginate to the endothelium in order to interact with the target receptors. Areas covered: This review draws on studies that have focused on the role of particle size, shape, and density, along with flow hemodynamics and hemorheology on the localization of the particles to activated endothelial cell surfaces and vascular walls under different flow conditions, especially those relevant to atherosclerosis. Expert opinion: Generally the size, shape, and density of a particle affect its adhesion to vascular walls synergistically, and these three factor should be considered simultaneously in designing an optimal carrier for targeting CVD. Available preliminary data should encourage more studies to be conducted to investigate the use of nano-constructs, characterized by a sub- micrometer size, a non-spherical shape, and a high material density to maximize vascular wall margination and minimize capillary entrapment, as carriers for targeting CVD. Keywords: particle physical properties, particle shape, particle size, particle density, flow characteristics, margination, cardiovascular dieases, atherosclerosis. 1. Introduction
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The Effects of Particle Size, Shape, Density and Flow Characteristics on
Particle Margination to Vascular Walls in Cardiovascular Diseases
Abstract
Introduction: Vascular-targeted drug delivery is a promising approach for the treatment of
atherosclerosis due to the vast involvement of endothelium in the initiation and growth of
plaque, a characteristic of atherosclerosis. One of the major challenges in carrier design for
targeting cardiovascular diseases (CVD) is that carriers must be able to navigate the circulation
system and efficiently marginate to the endothelium in order to interact with the target
receptors.
Areas covered: This review draws on studies that have focused on the role of particle size,
shape, and density, along with flow hemodynamics and hemorheology on the localization of
the particles to activated endothelial cell surfaces and vascular walls under different flow
conditions, especially those relevant to atherosclerosis.
Expert opinion: Generally the size, shape, and density of a particle affect its adhesion to
vascular walls synergistically, and these three factor should be considered simultaneously in
designing an optimal carrier for targeting CVD. Available preliminary data should encourage
more studies to be conducted to investigate the use of nano-constructs, characterized by a sub-
micrometer size, a non-spherical shape, and a high material density to maximize vascular wall
margination and minimize capillary entrapment, as carriers for targeting CVD.
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Article highlights
• The physical characteristics of the particles are key factors in the design of carrier systems to target atherosclerosis from the main vessel lumen as they significantly affects carrier performance.
• Local hemodynamic conditions at the site of atherosclerosis also determine the extent of particle adhesion to the vascular walls.
• Microparticles display better adhesion than nanoparticles, regardless of shape. However, they are potentially susceptible to physical entrapment in the capillaries in vivo.
• Non-spherical particles exhibit higher adhesion than their spherical counterparts. Disks adhere to the vascular walls better than rods.
• There is a lack of thorough understanding of the side effects, degradation, and toxicity of non-spherical particles at different biological levels such as the body, organs, and cells.
• There is a clear need for thorough studies of the cellular uptake of particles of different size, shape, and density under different flow conditions, particularly those relevant to atherosclerosis
• The effect of particle’s physical properties on atherosclerosis targeting from the vasa vasorum site should be thoroughly investigated
The box summarizes key points contained in the article.
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Figures
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Figure 1: Baseline endothelial shear stress patterns along the course of a coronary
artery obstruction.
33
Figure 2: Visualization of flow patterns created in a vertical-step flow channel (VSFC)
and typical adhesion profiles of microspheres in VSFC. (A) Schematic diagram of the
flow channel showing the flow pattern immediately beyond the step: h and H are the heights
of the channel above the step and beyond the step, respectively. (B top) Phase-contrast
photomicrograph (top view) of experimental flow patterns in the VSFC. Flow is from left to
right and is made visible with 1 μm marker microparticles. Flow separation occurs in the
region distal to the step, forming four specific flow areas: a, the stagnant flow area; b, the
center of the recirculation eddy; c, the reattachment flow area; and d, the fully developed
flow area. From online microscopic observations, the particles transported from the bulk flow
along the curved streamlines with decreasing velocities toward the wall near the reattachment
point (area c). While some of the particles moved forward to rejoin the mainstream with
increasing velocities, others moved in a retrograde direction toward the step as recirculation
eddies. These latter particles moved upstream initially with increasing velocities, and
decelerated when approaching the wall of the step (area a), from where they were carried
C
D
34
away from the floor of the chamber by upward curved streamlines. (B bottom) Schematic
drawing of the side view of the streamlines in the VSFC deduced from the top-view
photograph. (C & D) sLeA-coated spheres binding in the VSFC with reconstituted blood
flow. Far downstream conditions are 200 s−1 and 500 s−1 of laminar WSR, respectively. The
dashed lines represent the observed reattachment points. Reproduced with permission from
references [109] and [24].
Figure 3: Schematic showing differently-shaped non-spherical particles investigated for
vascular wall margination.
35
Figure 4: Local shape illustration and macrophage uptake of elliptical disks. (A)
Schematic diagram illustrating how local shape is defined. T̄ represents the average of
tangential angles near the point of cell contact. Ω is the angle between T̄ and the membrane
normal at the site of attachment, N̄. A1, Ω = 2.5° for cell attachment at end of worm. A2, Ω =
87.5° for cell attachment on side of worm. Reproduced with permission from reference [68].
(B) Time-lapse video microscopy clips spanning 39 min of macrophages interacting with
identical non-opsonized elliptical disk (ED) particles (major axis 14 μm, minor axis 3 μm) from
two different orientations. B1, cell attaches along the major axis of an ED and internalizes it
completely in 3 min. B2, cell attaches to the flat side of an identical ED and spreads, but does
not internalize the particle. Continued observation indicated that this particle was not
internalized for >110 min. (scale bars: 10 μm). At least three cells were observed for each
orientation of each particle type and size. Similar results were observed in all repetitions.
Reproduced with permission from reference [61].
36
Figure 5: Effects of the morphology of the particles on their margination and binding
strength (avidity). (A) Margination: Non-spherical particles such as disks and rods are
subjected to torque forces within blood flow, and therefore they have a tendency to tumble out
of the general circulation and scavenge along vessel walls. Spherical particles, on the other
hand, tend to follow the streamlines. (B) Binding avidity: Particle elongation and flatness
increase the particle surface area in contact with the endothelium and thereby present a greater
number of targeting ligands to the endothelium in cases where all particles have a fixed ligand