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.

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Interfacial tension is a key parameter affecting industrially relevant properties of emulsions, such as morphology and stability. Although several methods are available to measure interfacial tension, they are based on generation of droplets starting from separate emulsion components and cannot directly probe the interfacial tension of an emulsion as such. Here, a novel microfluidic tensiometry device to measure interfacial tension of a water-in-oil emulsion in situ as a function of surfactant concentration is presented. In our approach, interfacial tension is obtained from a quantitative analysis of the deformation of individual emulsion droplets under steady state shear flow in microfluidic channels. The technique is validated by comparing the results with experimental data obtained by the pendant drop method in a broad range of interfacial tension values. A very good agreement is found, and an estimate of the surfactant critical micellar concentration (CMC) is also obtained. The proposed microfluidic setup can be used even at high surfactant concentrations, where the measurement is made more challenging by sample viscoelasticity, thus providing a powerful tool to determine the interfacial tension of complex systems in an extended concentration range. The technique could be also used for in-line monitoring of emulsion processing.

Blood is a complex biological fluid composed of deformable cells and platelets suspended in plasma, a protein-rich liquid. The peculiar nature of blood needs to be considered when designing a drug delivery strategy based on systemically administered carriers. Here, we report on an in vitro fluid dynamic investigation of the influence of the microcapillary flow of red blood cells (RBCs) on micron sized carriers by high speed imaging methods. The experiments were carried out in a 50 m diameter glass capillary that mimicked the hydrodynamic conditions of human microcirculation. Spherical particles (-Ps), with sizes ranging between 0.5 and 3 m, were tested. Images of the flowing RBCs and -Ps were acquired by a highspeed/high-magnification microscopy. The transport and distribution of rigid particles in a suspension of RBCs under shear flow were followed for: i) the migration of RBCs towards the vessel centerline due to their deformability; ii) the cross-flow migration of -Ps towards the vessel wall due to their hydrodynamic interactions with RBCs; iii) the radial distribution of Ps in the presence of RBCs. This study suggests that the therapeutic efficacy of Ps could be ultimately affected by their interactions with the flowing RBCs in the vasculature.

Nano-carrier drug transport in blood microcirculation is one of the hotspots of current research in drug development due to many advantages over traditional therapies, such as reduced sideeffects, target delivery, controlled release, improved pharmacokinetics and therapeutic index. Despite the substantial efforts made in the design of nanotherapeutics, the big majority of the used strategies failed to overcome the biological barriers to drug transport encountered in human microvasculature, such as transport by blood flow via the microcirculatory network and margination, the mechanism according to which particles migrate along vessel radius to the wall. In fact, drug transport efficiency in microvasculature is affected by both the particulate nature of blood and drug carrier properties, such as size, shape and surface charge. In this work, the effect of the surface charge of liposomes on their margination in blood flow in microcapillaries was experimentally evaluated. By high-speed video microscopy and image analysis it was found that the two custom-made liposomes (one neuter and the other positively charged) tend to drift laterally, moving towards the wall and accumulating in the cell-free layer. In particular, neuter and cationic liposomes showed a comparable margination propensity, suggesting that the presence of blood cells governs the flow behavior independently on liposome surface charge.

The last decade has seen the emergence of vascular-targeted drug delivery systems as a promising approach for the treatment of many diseases, such as cardiovascular diseases and cancer. In this field, one of the major challenges is carrier margination propensity (i.e., particle migration from blood flow to vessel walls); indeed, binding of these particles to targeted cells and tissues is only possible if there is direct carrier–wall interaction. Here, a microfluidic system mimicking the hydrodynamic conditions of human microcirculation in vitro is used to investigate the effect of red blood cells (RBCs) on a carrier margination in relation to RBC concentration (hematocrit) and pressure drop. As model drug carriers, fluorescent polymeric nanoparticles (FNPs) were chosen, which were obtained by using as starting material a pegylated polylactic acid–polyaspartamide copolymer. The latter was synthesized by derivatization of α,β-poly(N-2-hydroxyethyl)-d,l-aspartamide (PHEA) with Rhodamine (RhB), polylactic acid (PLA) and then poly(ethyleneglycol) (PEG) chains. It was found that the carrier concentration near the wall increases with increasing pressure drop, independently of RBC concentration, and that the tendency for FNP margination decreases with increasing hematocrit. This work highlights the importance of taking into account RBC–drug carrier interactions and physiological conditions in microcirculation when planning a drug delivery strategy based on systemically administered carriers.

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