Polymer nanoparticles (NPs), due to their small size and surface functionalization potential have demonstrated effective drug transport across the blood–brain–barrier (BBB). Currently, the lack of in vitro BBB models that closely recapitulate complex human brain microenvironments contributes to high failure rates of neuropharmaceutical clinical trials. In this work, a previously established microfluidic 3D in vitro human BBB model, formed by the self‐assembly of human‐induced pluripotent stem cell‐derived endothelial cells, primary brain pericytes, and astrocytes in triculture within a 3D fibrin hydrogel is exploited to quantify polymer NP permeability, as a function of size and surface chemistry. Microvasculature are perfused with commercially available 100–400 nm fluorescent polystyrene (PS) NPs, and newly synthesized 100 nm rhodamine‐labeled polyurethane (PU) NPs. Confocal images are taken at different timepoints and computationally analyzed to quantify fluorescence intensity inside/outside the microvasculature, to determine NP spatial distribution and permeability in 3D. Results show similar permeability of PS and PU NPs, which increases after surface‐functionalization with brain‐associated ligand holo‐transferrin. Compared to conventional transwell models, the method enables rapid analysis of NP permeability in a physiologically relevant human BBB set‐up. Therefore, this work demonstrates a new methodology to preclinically assess NP ability to cross the human BBB.

In vitro prediction of physiologically relevant transport of therapeutic molecules across the microcirculation represents an intriguing opportunity to predict efficacy in human populations. On‐chip microvascular networks (MVNs) show physiologically relevant values of molecular permeability, yet like most systems, they lack an important contribution to transport: the ever‐present fluid convection through the endothelium. Quantification of transport through the MVNs by current methods also requires confocal imaging and advanced analytical techniques, which can be a bottleneck in industry and academic laboratories. Here, it is shown that by recapitulating physiological transmural flow across the MVNs, the concentration of small and large molecule therapeutics can be directly sampled in the interstitial fluid and analyzed using standard analytical techniques. The magnitudes of transport measured in MVNs reveal trends with molecular size and type (protein versus nonprotein) that are expected in vivo, supporting the use of the MVNs platform as an in vitro tool to predict distribution of therapeutics in vivo.

We present a two phase model for microcirculation that describes the interaction of plasma with red blood cells. The model takes into account of typical effects characterizing the microcirculation, such as the Fahraeus-Lindqvist effect and plasma skimming. Besides these features, the model describes the interaction of capillaries with the surrounding tissue. More precisely, the model accounts for the interaction of capillary transmural flow with the surrounding interstitial pressure. Furthermore, the capillaries are represented as one-dimensional channels with arbitrary, possibly curved configuration. The latter two features rely on the unique ability of the model to account for variations of flow rate and pressure along the axis of the capillary, according to a local differential formulation of mass and momentum conservation. Indeed, the model stands on a solid mathematical foundation, which is also addressed in this work. In particular, we present the model derivation, the variational formulation and its approximation using the finite element method. Finally, we conclude the work with a comparative computational study of the importance of the Fahraeus-Lindqvist, plasma skimming and capillary leakage effects on the distribution of flow in a microvascular network.

Fluid homeostasis is required for life. Processes involved in fluid balance are strongly related to exchanges at the microvascular level. Computational models have been presented in the literature to analyze the microvascular-interstitial interactions. As far as we know, none of those models consider a physiological description for the lymphatic drainage-interstitial pressure relation. We develop a computational model that consists of a network of straight cylindrical vessels and an isotropic porous media with a uniformly distributed sink term acting as the lymphatic system. In order to describe the lymphatic flow rate, a nonlinear function of the interstitial pressure is defined, based on literature data on the lymphatic system. The proposed model of lymphatic drainage is compared to a linear one, as is typically used in computational models. To evaluate the response of the model, the two are compared with reference to both physiological and pathological conditions. Di↵erences in the local fluid dynamic description have been observed using the non-linear model. In particular, the distribution of interstitial pressure is heterogeneous in all the cases analyzed. The resulting averaged values of the interstitial pressure are also di↵erent, and they agree with literature data when using the non-linear model.

We address a mathematical model for oxygen transfer in the microcirculation. The model includes blood flow and hematocrit transport coupled with the interstitial flow, oxygen transport in the blood and the tissue, including capillary-tissue exchange effects. Moreover, the model is suited to handle arbitrarily complex vascular geometries. The purpose of this study is the validation of the model with respect to classical solutions and the further demonstration of its adequacy to describe the heterogeneity of oxygenation in the tissue microenvironment. Finally, we discuss the importance of these effects in the treatment of cancer using radiotherapy.