Challenges in drug development of neurological diseases remain mainly ascribed to the blood-brain barrier (BBB). Despite the valuable contribution of animal models to drug discovery, it remains difficult to conduct mechanistic studies on the barrier function and interactions with drugs at molecular and cellular levels. Here we present a microphysiological platform that recapitulates the key structure and function of the human BBB and enables 3D mapping of nanoparticle distributions in the vascular and perivascular regions. We demonstrate on-chip mimicry of the BBB structure and function by cellular interactions, key gene expressions, low permeability, and 3D astrocytic network with reduced reactive gliosis and polarized aquaporin-4 (AQP4) distribution. Moreover, our model precisely captures 3D nanoparticle distributions at cellular levels and demonstrates the distinct cellular uptakes and BBB penetrations through receptor-mediated transcytosis. Our BBB platform may present a complementary in vitro model to animal models for prescreening drug candidates for the treatment of neurological diseases.

OLED arrays were fully 3D-printed under ambient conditions to produce a flexible information display technology.

The endothelial microenvironment is critical in maintaining the health and function of the intimal layer in vasculature. In the context of cardiovascular disease (CVD), the vascular endothelium is the layer of initiation for the progression of atherosclerosis. While laminar blood flows are known to maintain endothelial homeostasis, disturbed flow conditions including those the endothelium experiences in the carotid artery are responsible for determining the fate of CVD progression. We present a microfluidic device designed to monitor the endothelium on two fronts: the real-time monitoring of the endothelial permeability using integrated electrodes and the end-point characterization of the endothelium through immunostaining. Our key findings demonstrate endothelial monolayer permeability and adhesion protein expression change in response to oscillatory shear stress frequency. These changes were found to be significant at certain frequencies, suggesting that a frequency threshold is needed to elicit an endothelial response. Our device made possible the real-time monitoring of changes in the endothelial monolayer and its end-point inspection through a design previously absent from the literature. This system may serve as a reliable research platform to investigate the mechanisms of various inflammatory complications of endothelial disorders and screen their possible therapeutics in a mechanistic and high-throughput manner.

The sonic hedgehog subtype of medulloblastoma (SHH MB) is associated with treatment failure and poor outcome. Current strategies utilizing whole brain radiation therapy result in deleterious off-target effects on the normal developing childhood brain. Most conventional chemotherapies remain limited by ineffective blood–brain barrier (BBB) penetrance. These challenges signify an unmet need for drug carriers that can cross the BBB and deliver drugs to targeted sites with high drug-loading efficiency and long-term stability. We herein leverage the enhanced stability and targeting ability of engineered high-density lipoprotein-mimetic nanoparticles (eHNPs) to cross the BBB and deliver a SHH inhibitor effectively to the cancer stem-like cell population in SHH MB. Our microfluidic technology enabled highly reproducible production of multicomponent eHNPs incorporated with apolipoprotein A1, anti-CD15, and a SHH inhibitor (LDE225). We demonstrate the dual-targeted delivery and enhanced therapeutic effect of eHNP-A1-CD15-LDE225 via scavenger receptor class B type 1 (SR-B1) and CD15 on brain SHH MB cells in vitro, ex vivo, and in vivo. Moreover, we show that eHNP-A1 not only serves as a stable drug carrier, but also has a therapeutic effect itself through SR-B1-mediated intracellular cholesterol depletion in SHH MB cells. Through the facilitated and targeted cellular uptake of drugs and direct therapeutic role of this engineered biomimetic nanocarrier in SHH MB, our multifunctional nanoparticle provides intriguing therapeutic promise as an effective and potent nanomedicine for the treatment of SHH MB.