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The blood-brain barrier (BBB) protects the brain from pathogens but also hinders drug delivery to the central nervous system. Most of the BBB models developed up to date failed to reproduce the human anatomical complexity of brain barriers, contributing to less predictive experimental platforms and poor patient outcomes. To overcome those limitations, the development of reliable in vitro models represents a crucial step towards more effective therapies. This contribution was focused on the development of an in vitro microfluidic model of the BBB able to replicate the human neurovascular organization. The microfluidic model included human induced pluripotent stem cell-derived endothelial cells, brain pericytes, and astrocytes as self-assembled microvascular networks in a 3-dimensional fibrin gel. As previously demonstrated, the BBB model exhibited perfusable and selective microvasculature, with permeability lower than conventional in vitro models and comparable with in vivo rat brain. Permeability of polystyrene nanoparticles (NPs) and synthesized polyurethane NP was measured across the BBB model as compared to conventional Transwell assays. This physiologically relevant BBB model offers an innovative and valuable platform to preclinically predict transport efficacy of drugs and carriers. Introduction The blood-brain-barrier (BBB) is a selective barrier that help to maintain brain homeostasis, however it also constitutes a nearly-impenetrable obstacle against therapeutic delivery to the central nervous system. Since only small compounds can cross the BBB, this reduces the treatments available for neurodegenerative diseases and cancer.1 Polymer-based nanoparticles (NPs), due to their small size and surface functionalization potential, have emerged as a solution to deliver therapeutic cargo across the BBB. Although these techniques are considered the gold standard, current models, such as transwell or mouse models, fail to reproduce the anatomical complexity of the human BBB. Indeed, 80% of drug candidates that were successful tested in vitro and in animals later failed in clinical trials.2 Moreover, as transport across the BBB represents the first evidence of NP delivery capabilities, the development of a in vitro testing platform and method for quantifying NP transport behavior provides an invaluable tool to assess therapeutic efficacy. For these reasons, a cost-effective and reliable in vitro BBB model and method that adequately reflects human in vivo conditions is required. Materials and Methods PDMS microfluidic devices were designed (Autocad) and fabricated by soft lithography. To develop our 3D BBB model, human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs, CDI), primary astrocytes and pericytes (ScienCell) were suspended in fibrin gel (3 mg/mL), injected into the device, incubate to allow the gel polymerization and supported with culture medium (Vasculife) (Figure 1a).3 RT-PCR, vascular permeability and immunocytochemistry assays were performed. Polystyrene NPs (PS-NPs) (FluoSpheres) and synthesized polyurethane NPs (PU-NPs) transport was preliminary evaluated across the human BBB model. 3D permeability was quantified by the increase in fluorescence intensity in the region outside the BBB vasculature in confocal z-stack images (Figure 1b-d).

In vitro microfluidic modelling of the human blood-brain-barrier microvasculature and testing of nanocarrier transport