Red blood cells affect the margination of microparticles in synthetic microcapillaries and intravital microcirculation as a function of their size and shape

Abstract

A key step in particle-based drug delivery throughmicrocirculation is particlemigration from blood flow to vesselwalls, also known as “margination”,which promotes particle contact and adhesion to the vesselwall. Margination and adhesion should be independently addressed as two distinct phenomena, considering that the former is a fundamental prerequisite to achieve particle adhesion and subsequent extravasation. Although margination has beenmodeled by numerical simulations and investigated inmodel systems in vitro, experimental studies including red blood cells (RBCs) are lacking. Here, we evaluate the effect of RBCs on margination through microfluidic studies in vitro and by intravital microscopy in vivo.We showthatmargination,which is almost absent when particles are suspended in a cell-free medium, is drastically enhanced by RBCs. This effect is size- and shape-dependent, larger spherical/discoid particles being more effectively marginated both in vitro and in vivo. Our findings can be explained by the collision of particles with RBCs that induces the drifting of the particles towards the vessel walls where they become trapped in the cell-free layer. These results are relevant for the design of drug delivery strategies based on systemically administered carriers.

Direct Tracking of Particles and Quantification of Margination in Blood Flow

“…However, margination is not limited to WBCs and has been observed for other particles as well (2). This has sparked a lot of interest because of its potential applications in relation to cancer therapy (3)(4)(5)(6)(7). Tumor sites are generally characterized by 1) leaky vasculature, which allows drugcarrying particles to diffuse into them, and 2) a lack of lymphatics, which allows these particles to remain inside the tumor.…”

“…This so-called enhanced permeability and retention effect (8) further opens up the possibility of delivering chemotherapeutic drugs passively and more specifically to tumor sites, thereby limiting any damage to healthy tissues (9,10). A number of recent experimental (3,7,(11)(12)(13)(14)(15)(16)(17) and theoretical (18)(19)(20)(21)(22)(23) studies have suggested that particles of certain sizes and shapes have a higher margination propensity. This would facilitate the diffusion of these particles into tumor sites by allowing them to reach the leaky blood vessel walls and, ultimately, the tumors.…”

“…A number of experimental (3,7,(11)(12)(13)(14)(15)(16)(17) and theoretical (19,(21)(22)(23) studies have explored the effect of varying particle size on the margination propensity of particles. Several studies suggested that larger particles marginate much more readily than smaller particles, and that there is an optimal particle size for margination (3,12,14,15,19,22,23).…”

“…This work differs from previous studies in a number of ways. First, all previous experimental studies, with only two exceptions (7,38), assessed margination propensity based on the number density, or, more precisely, the fluorescence intensity, of fluorescent particles that adhered to the channel wall after a particle suspension and subsequently a buffer solution passed through the channel (3,(11)(12)(13)(14)(16)(17)(18)39). Although adhesion is related to margination, adhesion also depends on other factors such as hydrodynamic drag, the densities of ligands and receptors grafted onto the particle surface and the wall channel, the particle shape and contact orientation, and the particle size relative to the CFL (10,16,17,20,21).…”

Imaging the pharmacology of nanomaterials by intravital microscopy: Toward understanding their biological behavior

“…For instance, imaging has shown how red blood cells influence nano- and micro-particle margination in flow through capillary beds [35], which is more pronounced for larger (>100 nm) particles [46] compared to smaller NPs. Such margination impacts fluid mechanics and stresses experienced by the particles, is a function of both NP size and shape, and may actually be beneficial for extravasation at target sites [35]. IVM furthermore supports measurement of NP aggregation and clotting processes, especially as they occur in microvasculature, for instance as was seen with cationic siRNA-loaded hydrogel NPs [155].…”