Regulation of BBB function and pathological evolution of PD by microenvironment "spatiotemporal gradient": unique...

Parkinson's disease (PD), a prevalent neurodegenerative disorder, exhibits an exceedingly intricate pathological process characterized by multifaceted neuronal loss, inflammatory responses, protein misfolding, and blood-brain barrier (BBB) dysfunction. In the pathogenesis of PD, the BBB serves not only as a protective interface for the central nervous system but also actively contributes to the regulation of neural microenvironment homeostasis. Consequently, its impaired functionality can markedly exacerbate disease progression. Within the in vivo microenvironment, factors such as chemical gradients, fluid shear stress, and physical-mechanical signals play pivotal roles in modulating cellular behavior and organ function. The spatiotemporal dynamics of these gradients critically influence BBB integrity and neuroinflammatory responses. However, traditional in vitro models struggle to faithfully replicate such multidimensional dynamic microenvironmental changes. Recently, microfluidic chip technology has emerged as a transformative platform capable of simulating in vivo conditions through precise control of microenvironmental spatiotemporal gradients. This review examines the advancements of microfluidic chips in reproducing in vivo dynamic microenvironment gradients, regulating BBB function, and elucidating the pathological evolution of PD. It delves into the fundamental principles of microfluidic technology, gradient generation and control methodologies, and provides examples of BBB organoid models and PD pathological environment simulations constructed on this platform. Additionally, it systematically evaluates the technical bottlenecks, standardization challenges, and data integration issues associated with current model development, while exploring the potential for future technological convergence and interdisciplinary collaboration in advancing PD precision simulation and personalized treatment.