Korin, N. | Search bioRxiv

bioRxiv2025

Engeneering the neurovascular unit: a novel sensorized microfluidic platform to study barrier function and maturation

Central nervous system diseases pose a significant challenge for the development of effective drugs and therapies. A major limiting factor is the neurovascular unit (NVU), which is both anatomically complex and characterized by a highly selective barrier. Conventional 2D in-vitro models and in-vivo animal models do not adequately replicate its pathophysiology. Organ-on-a-Chip technology provides a powerful platform to model the NVU, enabling replication of its anatomical and functional features within a dynamic microenvironment that closely mimics the human brain. However, the requirement for specialized facilities and technical expertise limits accessibility, reducing broader translational applications. Additionally, conventional endpoint analyses constrain real-time monitoring of cellular behavior. Here, we present and validate a novel bi-modular microfluidic chip that offers an easy-to-use and scalable solution for studying cellular cross-talk, while enabling live imaging and real-time measurements. The model incorporates human endothelial cells and primary neurons that were investigated through immunofluorescence and live imaging. The design overcomes key fabrication challenges and integrates a simplified method for Trans-Epithelial/Endothelial Electrical Resistance (TEER) monitoring, allowing in situ real-time assessment of barrier integrity. Overall, this platform represents a robust and versatile tool for in-vitro studies of the NVU, facilitating comprehensive evaluation of its structural and functional dynamics. Our microfluidic NVU-on-chip represents a significant advancement in NVU modelling, providing a versatile platform for CNS drug screening, disease modelling, and personalized medicine applications.

bioengineering↗

bioRxiv2025

Shear stress targeted delivery of nitroglycerin to brain collaterals improves ischaemic stroke outcome

In patients with ischaemic stroke, retrograde perfusion of the penumbra by the leptomeningeal collateral vessels (LMCs) is a strong predictor of clinical outcome, thus raising the possibility that enhancing LMC flow could offer a novel therapeutic approach. Here, using computational modelling we show that LMCs experience elevated fluid shear stress that is significantly higher than that in other blood vessels during ischaemic stroke in animals and humans. We take advantage of this to selectively enhance flow in LMCs using shear-activated nanoparticle aggregates carrying the vasodilator nitroglycerin (NG-NPAs) that specifically release drug in regions of vessels with high shear stress ([≥]100 dyne/cm2). The NG-NPAs significantly increased LMC-mediated penumbral perfusion, decreased infarct volume, and reduced neurological deficit without altering systemic blood pressure in a rat ischaemic stroke model. The NG-NPAs also did not cause known common side effects of systemic nitrate administration, such as systemic hypotension, cerebral vascular steal, cortical vein dilation, or intracranial pressure elevation. Systemic administration of free NG at the maximal tolerated dose, which was ten times higher than the dose of NG used in the NG-NPAs, did not enhance LMC perfusion and dropped blood pressure. Thus, packaging NG within shear-activated NPAs can potentially enable this widely available vasodilator to become a highly effective therapeutic for ischaemic stroke.

physiology↗