The disruption of the blood–brain barrier (BBB) in Alzheimer’s Disease (AD) is largely influenced by amyloid beta (Aβ). In this study, we developed a high-throughput microfluidic BBB model devoid of a physical membrane, featuring endothelial cells interacting with an extracellular matrix (ECM). This paper focuses on the impact of varying concentrations of Aβ_1–42 oligomers on BBB dysfunction by treating them in the luminal. Our findings reveal a pronounced accumulation of Aβ_1–42 oligomers at the BBB, resulting in the disruption of tight junctions and subsequent leakage evidenced by a barrier integrity assay. Additionally, cytotoxicity assessments indicate a concentration-dependent increase in cell death in response to Aβ_1–42 oligomers (LC50 ~ 1 µM). This study underscores the utility of our membrane-free vascular chip in elucidating the dysfunction induced by Aβ with respect to the BBB.

Traumatic brain injury (TBI) presents a major biomedical challenge due to its complex biomechanics and the heterogeneous cellular responses it elicits, including neuronal death, glial activation, and blood–brain barrier disruption. Traditional in vitro models, including 2D neuronal cultures, brain slices and transwell systems, have provided valuable insights into molecular and cellular biology but remain limited by their lack of human-specific architecture, vascularization, and neurovascular interactions. The purpose of this review is to systematically examine advances in in vitro TBI modeling, with particular attention to studies leveraging human induced pluripotent stem cell (iPSC)-derived neural and vascular tissues, organoids, hydrogel scaffolds, microfluidic platforms, and mechanical injury. We highlight how the integration of neurovascular unit (NVU) components has improved the physiological and functional relevance of these models. Finally, we identify key limitations, including variability in organoid maturation, incomplete vascularization, and lack of methodological standardization, and outline future directions for improving translational fidelity. Therefore, this review contributes to a critical evaluation of emerging technologies and their potential to advance neurotrauma research and therapeutic discovery.