A critical appraisal of drug transport across the blood-brain barrier: Evaluation using new-age microfluidic technique

Research over the past few decades has focused on elucidating the role of the blood-brain barrier (BBB) in neuroprotection, regulation of the brain microenvironment, and mediation of the selective permeability of substances, including drug molecules. This has highlighted its significance in preclinical research, particularly in the screening of novel chemical entities with neuromodulatory properties. The BBB is not a static barrier but a dynamic, multicellular interface known as the neurovascular unit (NVU), which actively regulates brain homeostasis. A persistent challenge in neurotherapeutics is the translatability crisis, where promising results from traditional preclinical models fail to materialize in human trials. Current in vivo models, such as those using rodents and zebrafish, replicate the complexity of the human BBB and demonstrate satisfactory reproducibility, but are limited by their cost, time-consuming nature, and critical issues of interspecies translatability, particularly in the expression and function of key drug transporters. This has driven the development of in vitro models. In recent years, organ-on-a-chip technologies, which utilize the principles of microfluidics, have emerged at the forefront. These models are robust, cost-effective, and enable high-throughput screening of experimental results. By incorporating human-derived cells, physiological shear stress, and 3D architecture, these platforms are evolving from simple permeability-screening tools into sophisticated "pathophysiology-in-a-dish" systems. They combine the advantages of both in vivo and in vitro systems and offer promising scalability for modeling neurodegenerative diseases, neuroinflammation, and cancer, thereby enabling more predictive screening of therapeutic candidates. This review aims to provide a perspective on the current understanding of the BBB and its associated transport mechanisms, followed by a discussion of various contemporary models with the potential to transform the drug discovery landscape. The application of microfluidics in designing these models, along with noteworthy case studies in disease modeling, is explored. Finally, a brief overview of current challenges in the field, including the need for standardization, and exciting future directions spurred by regulatory shifts toward non-animal alternative methods is presented.